Ataxia with Identified Genetic and Biochemical Defects
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Hereditary genetic and metabolic disorders involve the nervous system at multiple levels, resulting in varied manifestations; common clinical presentations of such disorders in childhood include the following features in combination:
Developmental delay
Neurologic or developmental regression
Family history of similar symptoms in a sibling or closely related individual
Episodic alteration in level of consciousness or recurrent neurologic symptoms
Multisystem involvement (in addition to neurologic systems)
Development and progression of a particular neurologic sign such as ataxia or seizures
Ataxia is defined as an inability to maintain normal posture and smoothness of movement. Neurologic symptoms and signs such as seizures and movement disorders (eg, dystonia, chorea) may accompany ataxia. Consequently, many variations are encountered in the clinical phenotype, ranging from findings of pure cerebellar dysfunction to mixed patterns of involvement reflecting extrapyramidal pathways, brainstem, and cerebral cortical involvement. [78] A wide range of molecular defects have been identified in which the spinocerebellar pathways are involved. [1, 79]
Despite this remarkable diversity of genetic defects and mechanisms, the pathologic responses within the nervous system are limited in terms of the targeted pathways. This feature likely contributes to significant overlap seen in the clinical presentation. Nevertheless, delineation of the clinical phenotype represents an important first step in the diagnostic process. The clinical phenotype guides the geneticist in a search for appropriate diagnostic tests, reducing costs of laboratory workup.
The group of disorders manifesting with ataxia is expanding constantly (29 spinocerebellar ataxias [SCAs] are now recognized) as the genetic basis for many of the dominant and recessively inherited ataxias are unraveled. Study of subcellular organelle structures has enabled delineation of aspects of mitochondrial, lysosomal, and peroxisomal disorders. However, despite the advances in the understanding of pathogenesis, there has been a lag in the development of effective treatments for this group of disorders. [2]
As the underlying mechanisms of disease begin to be understood, the inherent challenges are apparent; for instance, several ataxias are caused by defects in DNA repair, while others may result from protein folding and chaperoning defects. Advances in genomics, proteomics, transcriptomics, and metabolomics are paving the way towards understanding of gene function, protein synthesis and transcription, and gene-gene and protein-protein interactions. These studies hopefully will provide the basis for a new set of designer drugs geared towards individualized treatments.
This article reviews the present understanding of inherited neurologic and metabolic disorders manifesting with ataxia as a clinical feature, focusing on key clinical features, laboratory findings, and pathophysiologic insights gleaned from molecular genetic studies, as well as current treatment strategies in management. [3, 77]
The transverse lobular arrangement of cerebellum has been described extensively in classic neuroanatomical literature. On the other hand, 7 longitudinal mediolateral parallel zones on each side of midline have been described as functional units of the cerebellar cortex. These zones are apparently formed via developmental mechanisms and the cerebellum has expanded mediolaterally with evolution. The medial zone is involved in adaptive control of somatic and autonomic reflexes and compound movements such as locomotion and saccadic eye movements. These functions are common across vertebrate species. The intermediate zone developed in relation to voluntary movement in mammals. The lateral zones are related to higher order functions of the cerebral association area. The most lateral zone in humans is likely to be associated with cognition.
Each zone receives afferents from discrete areas, and the Purkinje cell axons from each area project to a particular region of the cerebellar or vestibular nucleus. The input into the cerebellum is from all 3 peduncles with the ascending input through the inferior and the cortical input through the middle cerebellar peduncle. The superior cerebellar peduncle is responsible predominantly for the output from the cerebellum. The afferents received by the cerebellum have specific functional relevance in terms of occurrence of the pathology and lesion placement. These afferents will be briefly reviewed first. The subsequent sections will focus upon the 5 major functions ascribed to the cerebellum, the putative anatomical pathways, and the structures responsible for these functions and therefore the clinical manifestations of lesions in these structures. These functions are locomotion, postural control, voluntary movements, and finally cognition within the cerebellum. [4]
Most of the afferents enter the cerebellum via mossy or climbing fibers. These 2 fiber systems transmit distinct types of information and influence cerebellar Purkinje cells in distinct ways. The mossy fiber system carries afferent information from the spinal cord, brain stem, and cerebral cortex via pons and is responsible for moment-to-moment, rapid firing of Purkinje cells and then modulates ongoing movements. The climbing fibers relay information to the cerebellum from the inferior olivary nucleus which results in slow firing of Purkinje cells that seems to be important for motor learning. [5]
The cerebellum has a crucial role in balance and locomotion. Functional specificity allows regions of the cerebellum to control aspects of motor control. These anatomical-functional relationships are discussed below.
The medial zone of cerebellum: This zone integrates spinal and vestibular inputs and subsequently projects out through the fastigial nucleus to vestibulospinal and reticulospinal tracts. They appear to exert modulatory control of the rhythmic flexor and extensor locomotor pattern generated by vestibular and reticular nuclei. These connections also control extensor tone to maintain upright balance and stance. A lesion in this zone leads to a significant balance problem and impairment of postural tone.
Intermediate zone (paravermal region): This zone receives input from the spine (via spinocerebellar tracts) and projects out through the globose and emboliform nuclei to the red nucleus and cerebral cortex. It integrates spinal and cortical inputs and influences locomotion through projections to motor cortical areas. The main function of this region is related to specific control of limb placement including timing, elevation and trajectory of limb elevation, and descent. Damage to this region leads to gait ataxia and swing phase overshoot of legs but no overt change in balance or postural tone.
Lateral zone: This area receives input primarily from cerebral cortical area via pontine nucleus (corticopontocerebellar fibers) and projects out via the dentate nucleus through the red nucleus to the thalamus and cerebral cortical areas. This zone influences motor activities via cortical interactions and has an important role in voluntary modification of motor activities and the locomotor cycle. Lateral cerebellum is especially active in novel walking conditions where precise limb placement is necessary. It modulates visually guided motor activities because of the robust projection it receives from the visual cortex. A lesion in this region leads to limb ataxia and locomotion problems in novel and challenging situations. During uninterrupted walking, balance deficits contribute much more strongly to cerebellar gait ataxia (medial and intermediate zone) than do visually guided leg control deficits seen in the lateral zone.
Many of the cerebellar mechanisms are based on animal studies. But humans using bipedal locomotor mechanisms pose different challenges. Cerebellar damage in humans typically results in postural sway. Balance deficits as a result of lesion in midline cerebellar structures (vestibulocerebellum) lead to low frequency, high amplitude postural sway without a preferred direction and without intersegmental movements. On the other hand, in those with lesions in the intermediate zone (including anterior lobe), balance deficit is characterized by increased postural sway of high velocity and low amplitude; anteroposterior direction; postural tremor; and increased intersegmental movements of the head, trunk, and legs. Subjects with lesions in the lateral zone have only slight postural instability or sway.
Cerebral cortical association areas plan voluntary movements and the plan is executed by the motor cortex. The motor cortex may act as a controller driving lower motor neurons in the brain stem and spinal cord. But there is a robust cerebellocerebral loop that modulates these motor functions. These loops connect the intermediate part of the cerebellum to the association cortex and the motor cortex. In turn, the outputs from the intermediate zone of the cerebellum converge down to meet the cerebral output at red nucleus and olive. Thus, both loop and parallel pathways exist between the cerebrum and cerebellum. The cerebellum influences voluntary activities through these pathways.
One of the major functions of the cerebellum is motor adaptation based on trial and error practice (error driven learning mechanism). That requires a memory mechanism that has activity-dependent modifiability. This memory mechanism is considered to be located at the convergence of intrinsic cerebellar fibers (parallel fibers) and climbing fibers to the Purkinje cells. The process takes place through long-term depression (LTD), a characteristic form of synaptic plasticity occurring at parallel fiber-Purkinje cell synapses. [6, 7]
Reaching movement requires multiple interacting torques working at the concerned joints. In cerebellar dysfunction, during reaching these torques have impaired control, which results in hypermetria. Decomposition of movement is a strategy of breaking down multijoint movements to compensate for impaired multijoint coordination.
A closed cerebellocerebral loop is found in the prefrontal cortex and thus the cerebellum provides a forward model for mental functions in the cerebral cortex. This is analogous to already discussed cerebellocerebral loop concerned with motor functions. A primary cerebellar injury in premature infants has shown to be associated with contralateral decrease in cerebral volume. [8] This strengthens the importance of the cerebellocerebral connections responsible for important cognitive functions.
A mental model of image, idea, or concept is formed in the temporoparietal association cortex. These already formed mental models are manipulated by the prefrontal cortex. After repeated exercise, the cerebellum copies a mental model to form an internal model through cerebello-cerebral loop. Because of this internal model formed by the cerebellum, we are able to conduct movements and thoughts unconsciously (processes occurring in the cerebellum are felt to not reach awareness). For this reason, an idea “just comes out of the blue” without an obvious conscious effort to think over it. This internal model hypothesis could also help explain delusions and hallucinations in schizophrenia.
Thus, the localization and regional distribution of pathology within the cerebellum dictates the clinical findings. Lesions of the midline cerebellar vermis produce truncal and gait ataxia, while involvement of the lateral cerebellar hemispheres produces a limb ataxia. Interruption of afferent and efferent connections within the neocerebellar system results in an ataxic gait (ie, swaying in the standing posture, staggering while walking with a tendency to fall, and the adoption of a compensatory wide base), scanning dysarthria, explosive speech, hypotonia, intention tremor (ie, oscillation of limbs that is pronounced at the end of a planned movement), dysdiadochokinesia (ie, impaired alternating movements), dysmetria (ie, impaired judgment of distance), decomposition of movement, and abnormalities of eye movements (ie, nystagmus).
Clinical phenotypes show considerable overlap; however, the genetic, molecular, and biochemical causes for these disorders are often distinct. Some phenotypes (dominant ataxias) show considerable genetic heterogeneity. These phenotypes may manifest with pure ataxia or involve multiple levels of the nervous system (including dementia, seizures, disturbance in proprioceptive function, movement disorders, and polymyoclonus).
Early attempts to classify inherited ataxias were based on anatomic localization of pathologic changes (eg, spinocerebellar, pure cerebellar). In 1993, Harding introduced another classification in which the ataxias were placed into 3 categories, congenital, inherited metabolic syndromes with known biochemical defects, and degenerative ataxias of unknown cause. [9] The last category was subdivided further into early onset (< 25 y) and late-onset types. Although widely accepted, this classification does not incorporate or reflect current understanding of this group of disorders.
Although ataxia is a prominent feature of all these disorders, the presentation can be variable (eg, static vs progressive, intermittent vs chronic, early vs delayed). The mode of inheritance also varies. Autosomal dominant, recessive, and nonmendelian inheritance patterns have been described. Nonmendelian inheritance patterns have become increasingly significant in the understanding of the biology of human diseases. The term refers to disorders of inheritance for which the rules of Mendelian genetics do not apply. Disorders of triplet repeat expansion and certain mitochondrial defects are examples of nonmendelian inheritance.
Clearly, a revision of the classification of hereditary ataxias is necessary to include current concepts. Such a classification system is obviously an evolving one, with a separate category that includes those disorders where the molecular basis is presently unknown. Selected conditions in each category are discussed below. The following outline includes clinical features and known information about gene products and known or putative function. Treatment options are only included where specific measures are available. The reader interested in the specifics of different conditions is referred to one of several excellent reviews on the subject in the Reference section.
Classification using a genetic-biochemical basis is as follows:
Nonprogressive ataxias [10]
Pure congenital cerebellar ataxias with or without cerebellar hypoplasia
Autosomal recessive
Autosomal dominant
X-linked
Unknown
With posterior fossa malformations – Autosomal recessive (eg, Dandy Walker syndrome)
Congenital ataxia syndromes with cerebellar malformations
Autosomal recessive (eg, Joubert syndrome)
X-linked recessive (eg, X-linked congenital cerebellar hypoplasia and external ophthalmoplegia)
Intermittent/episodic ataxias
Autosomal dominant – Channelopathies (eg, episodic ataxias [EA] 1, EA 2])
Autosomal recessive – Enzyme defects (eg, maple syrup urine disease [MSUD], urea cycle defects)
X-linked – Enzyme defects (eg, ornithine transcarbamylase [OTC] deficiency)
Progressive ataxias with or without multisystem involvement
Autosomal dominant – Ataxias with spinocerebellar dysfunction
Triplet repeat disorders and polyglutamine accumulation (eg, SCAs 1-23, dentatorubropallidoluysian atrophy [DRPLA])
Autosomal recessive
Triplet repeat disorders (eg, Friedreich ataxia)
Impaired DNA repair mechanisms (eg, xeroderma pigmentosum, Cockayne syndrome)
Enzyme defects (eg, Refsum disease, sphingolipidosis)
Protein misfolding (eg, spastic ataxia of Charlevoix-Saguenay)
Maternal inheritance – Mitochondrial disorders (eg, neuropathy, ataxia, retinitis pigmentosa [NARP])
Ataxias with polymyoclonus and seizures
Autosomal recessive
Dodecamer repeat expansions (eg, Baltic myoclonus)
Enzyme defects (eg, neuronal ceroid lipofuscinosis)
Maternal inheritance – Mitochondrial cytopathies (eg, myoclonic epilepsy with ragged-red fiber disease [MERRF])
Other (unidentified mechanisms)
Angelman syndrome
Fragile X–related ataxia/tremor
In summary, the authors suggest a system of classification based on clinical features as the first distinction, mode of inheritance as the second distinction, and pathogenetic mechanisms as the third distinction. Although far from an ideal system, it serves to bring some order into a heterogeneous group of disorders. Clearly the classification is an evolving process because some disorders could be considered in more than one tier, eg, mitochondrial cytopathies can manifest with myoclonic epilepsy and ataxia, as well as chronic progressive ataxia as in the NARP syndrome.
The mechanisms underlying disorders with cerebellar ataxia as a symptom reflect the diversity of etiologies that have been identified. For instance, genetic mutations affecting ion channel structure and function cause both intermittent and chronic symptoms, [11] and recessively inherited enzymopathies (enzyme deficiency) cause symptoms through accumulation of neurotoxic storage material and/or precursor metabolites. The understanding of mechanisms of neurodegeneration resulting in cerebellar disease has been influenced by discoveries in the molecular genetics of nontraditional inheritance patterns underlying conditions such as SCAs and mitochondrial disorders. Therefore, special aspects of molecular genetics and putative mechanisms of cerebellar disease are discussed together (see image below).
This class of mutation is characterized by dynamic expansion of tandem nucleotide repeats in the human genome. These stretches of repeats tend to be inherently unstable, and this instability favors expansion. When the length of the repeat expansion exceeds the range in the general population, a symptomatic state may result. These mutations help explain clinical observations of increasing severity of symptoms and an earlier age of onset in successive generations seen with several of the dominantly inherited disorders—a phenomenon termed genetic anticipation. Such dynamic mutations form the basis of an increasing list of inherited neurologic disorders that includes mental retardation (fragile X syndrome), myotonic dystrophy, oculopharyngeal muscular dystrophy, Friedreich ataxia, Huntington disease, and the dominantly inherited cerebellar ataxias.
The trinucleotide expansion of cytosine, adenine, and guanine (CAG) repeats is translated into a polyglutamine tail, a common feature of several of the dominantly inherited ataxias. The expansion above a critical threshold, which appears to be different for each SCA type, determines presence of disease. The causative proteins for each type bear no homology to other known proteins or to each other apart from the polyglutamine tail. The polyglutamine tails themselves appear to be toxic once a disease-specific threshold is reached, and this central feature suggests a final common pathway.
The pathogenic mechanism(s) underlying cerebellar disease appear to involve proteolytic cleavage and nuclear accumulation of toxic products. Such proteolytic cleavage by releasing toxic fragments containing an expanded polyglutamine tail, may serve to further facilitate entry of cytoplasmic polyglutamine proteins to the nucleus. Secondary processes for neuronal injury likely involve downstream effects of apoptotic activation, accumulation, misfolding, aggregation, and sequestration of other proteins such as transcription factors and chaperones, leading to dysfunction of proteins and their intranuclear or intracellular accumulation. The putative disease mechanisms involved in the SCAs can be categorized into the following:
Transcriptional abnormalities (SCA17 and SCA7): Ataxins appear to function as transcriptional regulators, and the interaction with polyglutamine proteins results in an impairment of transcription. At other times, transcription factors may be sequestered into the polyglutamine aggregates, leading to transcriptional shutdown and neuronal death.
Calcium signaling defects (SCA6 and SCA14): In SCA6, the expanded CAG repeat is within a gene coding for the alpha subunit of the voltage-gated calcium channel. The polyglutamine aggregates in this disorder are cytoplasmic, and altered channel function may be responsible rather than a toxic gain in function.
Phosphorylation defects (SCA12 and SCA14): In these disorders, protein phosphorylation mediated through specific enzymes belonging to serine/threonine phosphatase (SCA12) and serine threonine kinase (SCA14) families is affected. A wide variety of cellular signaling pathways where these function as second messengers can be secondarily affected.
Defective ubiquitination and proteosome function (SCA3): Protein handling and clearance in the cell is affected through the ubiquitin-proteosome pathway. Components of this pathway may get sequestered in the polyglutamine aggregates, leading to a perturbation in cellular protein homeostasis.
Protein misfolding and chaperone defects: Protein folding and structure are vital to normal function; chaperone proteins facilitate this folding properly. Dysfunction of chaperone proteins may contribute to protein misfolding. Such a process may underscore the pathogenic mechanism in SCA1, in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), and in the leukoencephalopathy associated with vanishing white matter (VWM).
Since mitochondria were established to carry unique functions through their own functional genome, a new mechanism of nonmendelian inheritance, maternal inheritance, was discovered. All the mitochondria in the newly formed zygote are derived from the ovum (ie, maternally derived). Mitochondrial disorders can result from defects of mitochondrial proteins, either coded by the nuclear or by the mitochondrial DNA (mt DNA). Mitochondrial DNA is more vulnerable to mutations in the oxidizing environment of mitochondria because its repair mechanisms are poor compared to nuclear DNA. Mutations in mitochondria accumulate in cells until a threshold is reached. Eventually, the proportion of mutant mitochondria exceeds wild type, resulting in the manifestation of impaired cell function. [12]
The process of uneven replicative segregation ensures different proportions of mutant and wild types in different tissues, a condition termed heteroplasmy. Mildly-to-moderately deleterious mutations can persist and be transferred to offspring. The differential segregation and production of reactive oxygen species can vary among tissues and organ systems in affected individuals, giving rise to varying phenotypes.
Postmitotic cells such as neurons appear to carry higher ratios of mutant mitochondrial DNA, which thereby confer vulnerability to metabolic stress. This vulnerability may show a regional variation within the different regions of the brain, thereby partially explaining the variable patterns of neurologic involvement in many mitochondrial disorders. Some of the examples of mitochondrial disorders manifesting with ataxia include Friedreich ataxia (GAA repeat expansion-nuclear), MELAS syndrome ([mitochondrial myopathy, encephalopathy, lactacidosis, stroke syndrome] A3243-G mutation-maternal), ataxia with selective vitamin E deficiency (AVED), and X-linked ataxia with sideroblastic anemia. [13]
Mutations in proteins involved in repairing DNA breaks seem to provide yet another pathway resulting in disorders with ataxia (eg, ataxia -telangiectasia, ataxia with oculomotor apraxia types 1 and 2, SCA with sensory neuropathy [SCAN1]). The ataxia telangiectasia mutated (ATM) protein functionally belongs to a family of protein kinases with the critical role of rapidly healing DNA breaks. Mutations in this protein cause ataxia telangiectasia. Aprataxin, a histidine triad protein is involved similarly in single-stranded DNA repair, while senataxin is involved in splicing and termination of tRNA and may also function as a DNA helicase. [14]
This group includes diverse conditions that manifest either at birth or in early life. A structural abnormality in the form of cerebellar hypoplasia with or without other posterior fossa malformations affecting the brainstem structures may or may not be demonstrable. Because of the complex maturational and myelination processes within the brain that are age related, the clinical presentation of these disorders in early life is marked by symptoms other than ataxia. Most often hypotonia and developmental delays are striking. Ataxia is only recognized when efforts at independent walking are unsuccessful. In early life, considerable overlap of the neurologic phenotype occurs.
The classification of nonprogressive ataxias is challenging. At the risk of oversimplification, the hereditary nonprogressive ataxias may be categorized as the following:
Pure congenital cerebellar ataxias
Cerebellar ataxias associated with posterior fossa malformations
Congenital ataxic syndromes
Ataxic syndromes without cerebellar malformations
The principal differential diagnosis needs to include metabolic and neurodegenerative conditions manifesting in early life discussed in this article. The suggested metabolic testing and neuroimaging studies can help distinguish this category from other hereditary conditions that are progressive in nature.
A long list of conditions is reported featuring ataxia in association with other clinical features. A few conditions such as Gillespie syndrome include 1 or 2 additional features (eg, mental retardation, partial aniridia), while other conditions such as Joubert syndrome (ie, hypotonia, hyperventilation, facial dysmorphism, retinal dystrophy, renal involvement) and COACH syndrome (ie, cerebellar hypoplasia, oligophrenia, ataxia, coloboma, hepatic fibrosis) feature malformations in multiple organ systems. Inheritance patterns are usually autosomal recessive or X linked depending on the syndrome. In the case of Joubert syndrome, evidence for genetic heterogeneity exists. Currently, mutations in 9 different genes are known to be associated with a Joubert syndrome phenotype.
Table 1. Nonprogressive Congenital Ataxias (Open Table in a new window)
Disorder/Syndrome
Phenotype*
Inheritance
NPCA with or without cerebellar hypoplasia
Early hypotonia
Delayed motor and speech development
Autosomal recessive
Autosomal dominant
X linked recessive
Sporadic
NPCA with posterior fossa malformations (eg, Dandy Walker syndrome)
Variable association with hydrocephalus
Delays in motor development
Cognitive delay
N/A
Ataxia syndromes, multiple congenital anomalies, and cerebellar hypoplasia (eg, Joubert syndrome, Varadi syndrome, COACH syndrome)
Encephalo-oculo-hepato-renal anomalies with recognized association patterns of anomalies
Autosomal recessive
Autosomal dominant
X linked
Ataxia syndromes with cerebellar hypoplasia (eg, Gillespie syndrome)
Partial aniridia
Hypogonadotrophic hypogonadism
External exophthalmoplegia
Autosomal recessive
*Gait ataxia is a constant feature.
See the list below:
Early hypotonia
Developmental delay
Feeding difficulties and oromotor dysfunction
Speech delay secondary to articulatory difficulties
Cognitive difficulties (may be recognized at a later age)
Specific pattern of inheritance upon genetic assessment of the family
See the list below:
Genetic mutation tests: These are available only in selected conditions, eg, certain forms of Joubert syndrome. Testing is available for at least 4 of the causative genes in which mutations appear in Joubert syndrome: AHI1, CEP290, NPHP1, and TMEM67. Gillespie syndrome is known to be associated with mutations in the PAX6 gene.
Metabolic screening: Results are negative.
Neuroimaging studies: MRI is superior because it permits better visualization of the posterior fossa. Variable degrees of hypoplasia of the cerebellar vermis are reported. In more severe cases, the entire vermis may be absent, and associated abnormalities are noted in the cerebellar hemispheres. However, in mild cases, the cerebellum is morphologically normal on imaging studies. Associated abnormalities of the brainstem and supratentorial structures may be of additional value in the diagnosis of syndromes such as Dandy Walker malformation. In Joubert syndrome, a characteristic neuroimaging finding of the “molar-tooth” sign is helpful.
Channelopathies represent a number of neurologic disorders that manifest with symptoms of an episodic or transient nature. [15] The underlying molecular defect affects the functioning of a voltage-gated ion channel, thereby altering membrane excitability in neurons. External stimuli often trigger symptoms or episodes. Clinical and genetic heterogeneity is evident in the episodic ataxias with up to 6 additional forms currently recognized. So far the mutations appear to involve ion channel subunits.
See the list below:
Gene, inheritance, and pathogenesis: EA1 is a rare autosomal dominant disorder and represents a channelopathy. It is caused by point missense mutations that affect the human voltage-gated potassium channel (KCNA1 gene on band 12p13). This channel is widely expressed, but is especially prominent in the cerebellum. The mutation can impair channel function by reducing the amplitude of the potassium current and by altering its voltage-dependent kinetics. [16, 17]
Clinical features
Continuous myokymia between attacks
Duration of seconds to minutes
Partial epilepsy (some individuals in affected families)
Sudden episodes of ataxia precipitated by movement, startle, or emotion
Laboratory findings
Electroencephalography (EEG) may show continuous rhythmic muscle discharge artifact, which may become more prominent with hyperventilation.
Electromyography is the only helpful investigation; it usually demonstrates continuous motor unit activity in all patients.
Treatment: Partial responses to acetazolamide, carbamazepine, phenytoin, and phenobarbital have been reported.
See the list below:
Gene, inheritance, and pathogenesis: EA2 is an autosomal dominant disorder that has been associated with mutations that affect the calcium channel (CACNA1A [18] ) gene at the 19p13 locus. It is allelic to familial hemiplegic migraine and SCA6, wherein mutations affecting the same gene have been described. Haploinsufficiency may underlie the EA2 pathogenesis because the majority of the mutations causing EA2 result in nonfunctional calcium channels. EA2 exhibits incomplete penetrance and variable expressivity both between and within families. [16]
Clinical features
Headache (in some families)
Intermittent midline cerebellar dysfunction characterized by bouts of ataxia, nystagmus, dysarthria, and vertigo
Absence of myokymia
Provoking factors – Stress, exercise, and fatigue, among others
Laboratory findings: CACNA1A gene mutation testing is available in certain laboratories.
Treatment: A few patients with EA2 may respond to acetazolamide
See the list below:
A clinically distinct form of autosomal dominant episodic ataxia occurs in the Canadian Mennonite population. The candidate gene maps to a 4 cM region on chromosome 1q42 between markers D1S2712 and D1S2678. No mutations have been identified to date.
Clinical features
Variable age of onset
Vestibular ataxia, vertigo, tinnitus, and interictal myokymia
Symptoms triggered by sudden movement, stress, exertion, and fatigue
Laboratory findings: No gene tests are available.
Treatment: The condition responds well to acetazolamide.
Table 2. Episodic Ataxias (Open Table in a new window)
Disorder/Syndrome
Phenotype*
Inheritance
Gene Locus
Gene Product/Biochemical Defect
EA1
Intermittent ataxia
Autosomal dominant
12q13
Missense point mutations affecting the voltage-gated potassium channel (KCNA1)
EA2
Intermittent ataxia
Autosomal dominant
19q13
Point mutations or deletions allelic with SCA6 and familial hemiplegic migraine
Altered calcium channel function
EA2
Intermittent ataxia
Autosomal dominant
2q22-q23
Voltage-dependent L-type calcium channel, beta subunit
EA3
Intermittent ataxia with vertigo and tinnitus
Autosomal dominant
1q42
Not identified
Inherited enzyme defects are discussed below.
A delayed presentation of this autosomal recessive form of a branched chain aminoacidopathy may occur at any age from infancy to adulthood. [19, 20, 21, 22, 23]
Gene, inheritance, and pathogenesis: This is an autosomal recessive disorder caused by a deficiency of branched chain alpha keto acid dehydrogenase complex. Mutations of at least 4 gene loci are known to result in this condition, including 19q13.1-q13.2 and 7q31.
Clinical features
Characteristic urine odor of maple syrup, as well as in other body fluids and earwax
Intermittent bouts of ataxia and neurologic obtundation progressing to coma
Possibly, mental retardation and motor delay in intermediate form
Laboratory findings
Elevation of branched chain amino acids and branched chain keto acids in the urine, plasma, and cerebrospinal fluid (CSF)
Metabolic acidosis, ketonemia, and ketonuria; occasional hypoglycemia and hypoalaninemia
L-alloisoleucine in body fluids (pathognomonic) [24]
Assay of branched chain keto acid dehydrogenase activity in skin fibroblasts
Mutation testing
Treatment [25]
Treatment includes restriction of dietary protein intake and supplementation of branched chain amino acid–free synthetic formula to meet protein and other dietary needs.
Begin thiamine supplementation in thiamine-responsive individuals (5-20 mg/kg/d, not to exceed 100 mg/d) immediately. In adults, 100 mg may be administered immediately in the acute situation, followed by further supplementation of 50-100 mg/d until adequate oral intake and a stable clinical state are achieved.
The incidence based on neonatal screening data is estimated at 1 in 30,000. The reduced availability of tryptophan may lead to a secondary deficiency of the vitamin niacin (nicotinic acid). [26, 27]
Gene, inheritance, and pathogenesis: The locus associated with Hartnup disease is 5p15. This autosomal recessive disorder is caused by defective intestinal transport and renal tubular reabsorption of neutral amino acids (primarily tryptophan). Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. SLC6A19 is a sodium-dependent and chloride-independent neutral amino acid transporter, expressed predominately in kidney and intestine.
Clinical features
Intermittent ataxia and other cerebellar signs
Neuropsychiatric dysfunction ranging from emotional lability to frank psychosis
Pellagralike skin rash induced by exposure to sunlight
Normal intelligence and no abnormal neurologic signs in most patients with the biochemical phenotype
Laboratory findings
Excessive excretion of monoamino-monocarboxylic amino acids in urine
Urinary indoxyl derivatives (5-hydroxyindoleacetic acid) detectable in urine following an oral tryptophan load
Treatment: Treatment includes a high-protein diet. Niacin supplementation reverses the skin and neuropsychiatric manifestations. A tendency exists for spontaneous improvement.
See the list below:
Gene, inheritance, and pathogenesis: The commonest form of pyruvate dehydrogenase (PDH) deficiency is an X-linked recessive disorder that affects a mitochondrial multienzyme complex, which is involved in the conversion of pyruvate to acetyl-CoA. The PDHA1 gene codes for 3 enzymes of the PDH complex. The E1 alpha1 subunit of this complex is most often affected. Inheritance is X linked for the latter form. A high proportion of heterozygous females manifest severe symptoms (in the X-linked form).
Clinical features
Many present in early infancy with a catastrophic neurologic picture of hypotonia, lactic acidosis, and seizures (associated with cerebral malformations).
About 30% present with facial dysmorphic features, including microcephaly, narrow head, frontal bossing, long philtrum, episodic ptosis, abnormal eye movements, wide nasal bridge, upturned nose, and flared nostrils.
A benign late-infantile variant can occur.
Episodic ataxia is characteristic.
Uncommonly, mental and motor development is normal.
Fatigue is noticed after exercise.
Transient paraparesis is a feature.
Laboratory findings
Serum and CSF lactic acidosis is characteristic. The lactate-to-pyruvate ratio is normal.
PDH activity in skin fibroblasts is reduced.
Mutation testing is available in certain laboratories only.
In the prenatal and early infantile form, multiple areas of necrosis in the gray matter, white matter, and basal ganglia are noted on imaging studies.
Limited information is available concerning late benign presentations of this disorder. Postmortem and autopsy in one affected male who died at age 50 years showed findings of cerebellar degeneration and lesions around the third ventricle and cerebral aqueduct. This case suggests findings that overlap with Leigh disease and Wernicke encephalopathy.
Treatment
Thiamine supplementation in high doses (5-20 mg/kg/d, not to exceed 100 mg/d in acute stage) may be effective in the thiamine-responsive form of the disease.
A ketogenic diet has been effective in some patients.
Treatment of lactic acidosis by dichloroacetate may be helpful. Administer 2 doses of dichloroacetate (50 mg/kg body weight) separated by 2 hours. If the level does not drop 20% below baseline after 6 hours, the patient is considered a nonresponder. For a partial response of less than 20% of baseline levels but above 5 µmol/L, 2 additional doses may be tried. Published open trials on dichloroacetate indicate improved survival (with reduced morbidity) in responders. However, questions remain regarding the efficacy of this treatment. Long-term side effects of peripheral neuropathy associated with this therapy are reported.
Pyruvate carboxylase (PC) is a nuclear-encoded mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. PC deficiency can be categorized into 3 types. Type A, found in North American Indians, involves lactic acidosis and psychomotor retardation. Type B, found in France and the United Kingdom, has a severe phenotype with hyperammonemia. Patients with type B die by age 3 months. [28] Type C manifests with relatively benign intermittent ataxia, and affected individuals may have normal development. PC deficiency usually manifests in the neonatal period with severe lactic acidosis or in early infancy with features similar to PDH deficiency with psychomotor retardation, hypotonia, and seizures.
Gene, inheritance, and pathogenesis: The most common disorder of pyruvate metabolism is an autosomal recessive inherited deficiency of PC. Identified mutations affect the gene locus on chromosome 11 (11q13.4-q13.5). Common founder 1828G–>A missense mutation has been described in Ojibway-Cree patients in Manitoba. [29]
Laboratory findings
Lactic acidosis (elevated plasma lactate)
Increased lactate-to-pyruvate ratio
Elevated blood levels of ammonia, citrulline, proline, and lysine in type B (French form)
Reported abnormality on ultrastructural examination of skeletal muscle in the neonatal form: Subsarcolemmal aggregation of lipid droplets, glycogen granules, and pleomorphic mitochondria is found. Although nonspecific, these findings in combination with age of onset, clinical features, and lactic acidosis are often helpful in diagnosis.
Cystic periventricular white matter changes in the neonatal form on magnetic resonance imaging (MRI)
Assay for enzyme activity in cultured fibroblasts
Mutation testing
Treatment: Options are limited to symptomatic treatment of lactic acidosis and are similar to those employed for the treatment of PDH deficiency. Biotin and aspartate have been used in selected patients. Prognosis remains poor for types A and B.
See the list below:
Gene, inheritance, and pathogenesis: Recessively inherited defects that affect mitochondrial beta-oxidation can result in intermittent episodes of neurologic symptoms (eg, weakness, ataxia, coma) in affected individuals. Defective fatty acid oxidation carries with it the consequence of energy deficit in the nervous system. The results are reflected in diffuse CNS dysfunction in situations of metabolic decompensation, such as that which accompanies prolonged fasting. Examples of such defects are as follows: [30]
Carnitine palmitoyltransferase-1 deficiency
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
Multiple-acyl-CoA dehydrogenase deficiency (glutaric aciduria type II)
Primary systemic carnitine deficiency
Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency
Short-chain acyl-CoA dehydrogenase deficiency
Trifunctional enzyme deficiency
Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD)
Clinical features
Episodic vomiting
Intermittent bouts of weakness, lethargy, ataxia, and coma
Neurologic symptoms induced by fasting
Laboratory findings
Hypoglycemia with minimal-to-absent ketonemia and ketonuria
Mild lactic acidosis, hyperammonemia
Reduced plasma carnitine levels (free and total) in many fatty acid oxidation disorders
Increased dicarboxylic aciduria (suberic, sebacic, adipic acids) upon urinary organic acid analysis
Characteristic acylcarnitine profiles and urinary acyl-glycines associated with specific disorders of fatty acid oxidation
Specific enzyme assays on cultured skin fibroblasts
Mutation analysis (eg, the common A985G mutation in MCADD)
Treatment
Avoidance of prolonged fasting
Carnitine supplementation in doses of 50-100 mg/kg/d divided into 3 doses
Adequate caloric intake through intravenous glucose during acute presentations
Substitution of dietary fat with medium-chain triglycerides (may be helpful in bypassing metabolic block in VLCAD)
Corn starch feeds prior to bedtime (may help prevent hypoglycemia)
See the list below:
Gene, inheritance, and pathogenesis: Defects of each of the 5 enzymes of the urea cycle and 1 of its activators have been described. Most manifest with hyperammonemic coma in the neonatal period. Partial deficiencies can result in delayed presentation or intermittent symptoms during periods of decompensation. Elevated ammonia is poorly handled within the nervous system because of its ability to cross the blood-brain barrier. Secondary excitotoxicity related to release of glutamate and free radical–induced injury lead to diffuse cerebral dysfunction. Four of the 5 enzyme deficiencies (except ornithine transcarbamylase) are inherited as autosomal recessive defects. The 5 urea cycle enzymes are as follows: [31]
Carbamyl phosphate synthetase
Ornithine transcarbamylase (X-linked inheritance)
Argininosuccinate synthetase
Argininosuccinate lyase
Arginase
Clinical features: Delayed presentations of partial enzyme deficiencies in children and adults include the following:
Behavioral abnormalities such as self-abusive behavior
Episodic hyperammonemia
Intermittent ataxia and spasticity
Protein intolerance with intermittent vomiting
In adults, migrainelike episodes, confusional states, visual impairment, hallucinations, and neuropsychiatric symptoms
Presentation in ornithine transcarbamylase heterozygotes during pregnancy
Hyperactive deep tendon reflexes, papilledema, and decerebrate or decorticate posturing
Arginase deficiency clinically similar to spastic diplegic cerebral palsy [32]
Laboratory findings [33]
Respiratory alkalosis
Elevated plasma ammonium (ionized form at physiologic pH)
Abnormalities in plasma amino acids
Elevated glutamine and alanine in blood and CSF
Indication of precise urea cycle enzyme deficiency possible by presence or absence of citrulline, argininosuccinic acid in plasma, and orotic acid in urine
Enzyme assays on tissue from liver biopsy
DNA analysis (can be confirmatory and is less invasive)
Treatment
Reduction of dietary protein intake with special dietary formulas
Supplementation of arginine and/or citrulline (depending on site of urea cycle defect)
Aggressive treatment of hyperammonemic coma using alternative pathway activation (eg, via sodium benzoate/sodium phenylacetate, and arginine)
Orthotopic liver transplant (another therapeutic option)
Gene therapy for OTC deficiency (remains experimental)
Table 3. Intermittent Ataxias Related to Enzyme Defects (Open Table in a new window)
Disorder/Syndrome
Phenotype*
Inheritance
Gene Locus
Gene Product/Biochemical Defect
Maple syrup urine disease
Intermittent ataxia
Autosomal recessive
19q13.2
Mutations affect the E1 alpha subunit of branched-chain alpha-keto dehydrogenase complex that catalyzes the conversion of alpha keto acids to acyl-CoA and carbon dioxide
Hartnup disease
Intermittent ataxia
Autosomal recessive
11q13
Abnormality in the intestinal and renal transport of neutral alpha amino acids
Pyruvate dehydrogenase deficiency
Intermittent ataxia
Lactic acidosis
X-linked recessive
Xp22.2-p22.1
Defective E1 component of the PDH complex
Pyruvate carboxylase deficiency
Intermittent ataxia
Lactic acidosis
Autosomal recessive
11q13.4-q13.5
N/A
Defects of mitochondrial fatty acid beta-oxidation
Intermittent ataxia
Metabolic acidosis
Elevated ammonia
Autosomal recessive
N/A
Multiple defects affecting different acyl-CoA dehydrogenases
Late-onset urea cycle defects
Argininosuccinic acidemia
Carbamyl phosphate synthetase deficiency
Citrullinemia
Ornithine transcarbamoylase deficiency
Argininemia
Intermittent ataxia
Episodic encephalopathy
Autosomal recessive
7q21.3-q22 (arginosuccinate lyase)
2q33-q36 (carbamoyl-phosphate synthetase I)
9q34 (arginosuccinate synthetase)
Xp21.1 (ornithine carbamoyltransferase)
6q23 (arginase)
N/A
The following disorders are dominantly or recessively inherited. They manifest primarily with ataxia and cerebellar dysfunction, which are chronic and may be progressive with or without the presence of other neurologic abnormalities. This group of disorders is large; many have been associated with molecular genetic abnormalities, linking them to identifiable biochemical defects. DNA-based laboratory testing is available for many of these disorders. SCAs 1, 2, 3, 6, and 7, and dentatorubropallidoluysian atrophy (DRPLA) are caused by dynamic mutations that affect tandem triplet nucleotide repeats. The salient phenotypic features and the degree of triplet repeat expansions necessary to produce pathologic symptoms are summarized in the tables accompanying this discussion.
The number of dominantly inherited SCAs that have been described has increased to 29 and are labeled SCA1 onwards in sequence. SCA9 refers to a hitherto unknown variety, while SCA24 describes a recessively inherited SCA with saccadic intrusions. The genetic basis for most of these disorders is related to expansion of triplet nucleotide repeats. (See the tables for a summary of the gene loci and putative mechanisms related to these disorders). A great degree of overlap in phenotype is noted, including the age of onset, with the major group of symptoms related to cerebellar and spinocerebellar pathway dysfunction. Other than distinguishing features described in selected cases, findings from neuroimaging studies are relatively nonspecific. Most of the triplet expansions affect CAG repeats; in the SCA8 form, an untranslated CTG expansion is involved.
A slowly progressive cerebellar syndrome with various combinations of oculomotor disorders, dysarthria, dysmetria/kinetic tremor, and ataxic gait are key presenting features. In addition, pigmentary retinopathy, extrapyramidal movement disorders (parkinsonism, dyskinesias, dystonia, chorea), pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioral symptoms), and peripheral neuropathy are also noted.
The following selected clinical features are often helpful in predicting association with a gene defect:
SCA2 – Slowing of saccades
SCA1, SCA2, and SCA3 – Ophthalmoplegia
SCA1, SCA2, SCA3, SCA4, SCA8, SCA18, and SCA25 – Associated signs of peripheral neuropathy
SCA7 – Pigmentary retinopathy
SCA3 – Spasticity
SCA17 and DRPLA – Cognitive impairment/behavioral symptoms
SCA27 – Associated with dyskinesias
SCA10, SCA17, and DRPLA – Seizures
Three patterns of atrophy are described on brain MRI: pure cerebellar atrophy, olivopontocerebellar atrophy, and global brain atrophy. The presence of dentate nuclei calcifications in SCA20 can result in a hypointense/low signal on certain brain MRI sequences. Several identified mutations correspond to expansions of repeated trinucleotides (CAG repeats in SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, and DRPLA; CTG repeats in SCA8). A pentanucleotide repeat expansion (ATTCT) is associated with SCA1.
The following is a discussion of the clinical features of the dominantly inherited ataxias. Most of the SCAs are accounted for by the SCA1, SCA2, SCA3, SCA6, SCA7, and SCA8 subtypes; the remaining types are rare and have been reported in few families or in specific ethnic backgrounds. Treatment, for the most part, is restricted to the use of pharmacologic agents for targeted symptoms, such as the use of 5 hydroxytryptophan and acetazolamide for ataxia, amantadine/levodopa/dopamine agonists in SCA2-SCA3, and the use of tizanidine/baclofen for spasticity.
A clinical trial from has shown that varenicline (Chantix), can be used to improve axial symptoms and rapidly alternating movements in patients with SCA3. [34] However, other groups have failed to reproduce the same results. [35] Deep brain stimulation has been used for the treatment of tremor in SCA2.
See the list below:
Clinical features
Onset in the fourth decade of life
Gait ataxia, dysarthria, dysmetria, nystagmus, peripheral neuropathy, muscle wasting, and dystonia in late stages of the disease
Gain of function mutation, resulting in an abnormal protein (ataxin-1)
See the list below:
Clinical features
Age of onset from 2-65 years
Ataxia, facial fasciculation, lid retraction, and reduced ocular saccadic velocity
SCA2 protein product termed ataxin-2
The disorder is allelic to Machado-Joseph disease, which affects individuals of Portuguese-Azorean descent.
Clinical features
Age of onset after the fourth decade of life
Ataxia, pyramidal and extrapyramidal signs, amyotrophy, facial and lingual fasciculations, ophthalmoplegia, and exophthalmos
Protein product termed ataxin-3
See the list below:
Clinical features
Late-onset ataxia, sensory axonopathy
Symptoms beginning in second to fourth decade of life
Pathologic examination findings demonstrating degeneration of cerebellar Purkinje cells, dorsal root sensory ganglion neurons, and ascending posterior columns
See the list below:
Clinical features
Cerebellar ataxia, facial myokymia, impaired vibration sense, and very slow progression
Age of onset variable, with a mean age of 37 years (10-68 y)
First family described descending from Abraham Lincoln’s grandparents; second family described in northeastern France
See the list below:
Clinical features
Ataxia, nystagmus, dysarthria, and loss of vibration and joint position sense
Pathologic examination showing loss of Purkinje cells, granule cells, neurons of the inferior olive nucleus, and dentate nucleus
Progressive pancerebellar dysfunction without involvement of cognitive, pyramidal, or extrapyramidal function
Slow progression over 20-30 years
Symptoms beginning in the fourth or fifth decade of life
Allelic with episodic ataxia type 2
See the list below:
Clinical features
Ophthalmoplegia, dysarthria, pyramidal and extrapyramidal signs, and impaired vibration sense
Visual loss due to macular retinal degeneration (unique finding in this disorder)
See the list below:
Clinical features
Onset of symptoms ranging from age 18-65 years, with a mean of 39 years
Dysarthria and gait instability (commonly initial symptoms)
Examination findings including spastic dysarthria, nystagmus, limb spasticity, limb and gait ataxia, and diminished vibration perception
Progression generally slow
See the list below:
Clinical features
Onset in third to fifth decade of life
Pure cerebellar ataxia, nystagmus, dysarthria, dysphagia, hypotonia, and generalized and/or complex partial epilepsy
See the list below:
Clinical features
Mild disorder, with pure ataxia as a major feature
Normal life span with mean age of onset of 30 years (15-70 y)
Retained capacity for ambulation
See the list below:
Clinical features
Tremor in early stages
Later development of a pure SCA
See the list below:
Clinical features
Early age of onset
Progressive cerebellar gait ataxia
Cerebellar dysarthria
Mild mental retardation
Horizontal nystagmus
Pyramidal signs
Slow progression of symptoms
See the list below:
Clinical features
Progressive cerebellar ataxia
Dysarthria
Myoclonus (rare)
Facial myokymia
Hyperreflexia
Cerebellar atrophy
The diagnosis of SCA16 has now been included into the diagnosis of SCA15. SCA16 has been shown to share the same gene mutation as SCA15. [36]
Clinical features
Onset of symptoms ranging from 10-66 years, mean of 25 years
Slow progression
Limb ataxia
Upper limb tremor
Dysarthria
Dysphagia
Gaze evoked occular nystagmus
Dysmetric saccades
Pyramidal signs
Mild cognitive dysfunction
See the list below:
Clinical features
Progressive ataxia
Dysmetria
Dementia
Bradykinesia
Hyperreflexia
See the list below:
Clinical features
Early age of onset
Gait difficulty (most common initial symptom)
Decreased vibratory and proprioceptive sense
Hyporeflexia
Dysmetria
Muscle weakness and atrophy
See the list below:
Clinical features
Gait and limb ataxia
Cognitive impairment
Myoclonus
Postural tremor
See the list below:
Clinical features
Age of onset – 19-64 years (median 46.5 y)
Most common symptom is dysarthria due to spasmodic dysphonia
Gait and upper limb ataxia
Nystagmus
Mild pyramidal signs
Hypermetric saccades
See the list below:
Clinical features
Age of onset – 6-30 years
Gait and limb ataxia
Akinesia
Dysarthria
Dysphagia
Hyporeflexia
Postural and resting tremor
Rigidity
Cognitive impairment
Cerebellar atrophy
See the list below:
Clinical features
Slowly progressive
Gait and limb ataxia
Hyporeflexia
Dysarthria with scanning speech and dysphagia
Intermittent saccadic pursuits
Gaze directed horizontal nystagmus
See the list below:
Clinical features
Age of onset – 43-56 years
Slow progression
Gait and limb ataxia
Dysarthria
Occular dysmetria
Slow saccades
Decreased vibratory sense below the knees
Hyperreflexia
Also known as autosomal recessive spinocerebellar ataxia type 4 (SCAR4).
See the list below:
Clinical features
Age of onset – 17 months to 39 years, childhood onset most affected
Cerebellar ataxia
Areflexia in lower limbs
Peripheral sensory neuropathy
Nystagmus
Visual sensory acuity
Facial tics
GI problems
Urinary urgency
See the list below:
Clinical features
Age of onset – 26 to 60 years (mean age is 42 y)
Slowly progressive gait and upper limb ataxia
Dysarthria
Pure cerebellar signs
Irregular visual pursuits movements
This disorder presents with distinct clinical features, initially described in a Dutch kindred, with autosomal dominant inheritance.
Clinical features
Early onset tremor, ataxia in the second decade, and orofacial dyskinesias
Aggressive behavioral outbursts
See the list below:
Clinical features
Age of onset – 6-60 years (mean 30.7 y)
Slowly progressive
Standing and gait abnormalities
Limb ataxia
Dysarthria
Slow and lower limb hyperreflexia
Opthalmoplegia
Patients with shorter disease duration – Gaze-evoked nystagmus
Patients with longer disease duration – Dysmetric saccades, slow saccades, ophthalmoparesis, and ptosis
Cerebellar atrophy
See the list below:
Clinical features
Nonprogressive ataxia
Nystagmus
Dysarthria
Psychomotor display
Clumsiness
Cognitive impairment
Frequent falling early in disease
Dysdiadochokinesis
See the list below:
Clinical features
Age of onset – 42-76 years (mean is 52 y)
Relatively pure, slowly progressing gait and appendicular ataxia
Dysarthria
Lower limb hyperreflexia
Hypermetric saccades
See the list below:
Clinical features
Late age of onset (approximately 60 y)
Gait ataxia
Nystagmus
Dysarthria
Cerebellar atrophy
Hearing loss
Reduced tendon reflexes
Decreased vibration sense
Spinocerebellar ataxia 32 [37]
Clinical features
Broad age of onset
People with age of onset before 40 had cognitive impairment and cerebellar atrophy
Males are infertile and experience azoospermia
Spinocerebellar ataxia 34 [38]
The appearance of papulosquamous erythematous ichthyosiform plaques begin soon after birth. In most cases, these plaques disappear by age 25 years.
At age 40 years, patients have slowly progressive symptoms, such as the following:
Gait ataxia
Decreased tendon reflexes
Dysarthria
Nystagmus
Spinocerebellar ataxia 35 [39]
Clinical features
Age of onset – 40-48 years (mean is 43.9 y)
Early features – Difficulty with walking, ataxia, cerebellar dysarthria
Wheelchair bound after 10 years
Tremor
Hyperreflexia
Torticollis
Occular dysmetria
Position sense defects
Spinocerebellar ataxia 36 [40]
Clinical features
Mean age of onset – Approximately 53 years
Truncal ataxia
Ataxic dysarthria
Limb ataxia
Dysdiadochokinesis
Increased muscle tone
Hyperreflexia
Impaired smooth pursuits
Nystagmus
See the list below:
Gene, inheritance, and pathogenesis: The condition is allelic to the Haw River syndrome reported in blacks. Pathologic features include nerve cell loss and gliosis affecting the dentate nucleus, red nucleus, pallidum, and subthalamic nucleus of Luys. The age of onset varies. It has been reported in Japan and Europe.
Clinical features
Ataxia
Dementia
Polymyoclonus
Chorea
Laboratory findings
Imaging studies demonstrate spinocerebellar atrophy and varying degrees of multisystem atrophy.
Diagnosis rests on molecular DNA confirmation of expansion of the number of CAG repeats. Molecular genetic testing is available for SCA types 1, 2, 3, 6, 7, and DRPLA.
Table 4. Dominantly Inherited Chronic/Progressive Ataxias (Open Table in a new window)
Autosomal Dominant Ataxias
Neurologic Phenotype
(Gait ataxia is a constant feature)
Triplet Repeat Size
Gene Locus/Gene Product
Spinocerebellar ataxia
(SCA1)
Peripheral neuropathy
Pyramidal signs
Ophthalmoparesis
CAG expansion 39-83 (6-36 normal range)
6p23
Ataxin-1
(ATXN1)
Spinocerebellar ataxia
(SCA2)
Abnormal ocular saccades
Hyporeflexia
Dementia
Peripheral neuropathy, less frequent
Extrapyramidal findings
CAG expansion 34-400 (15-31 normal range)
12q24.1
Ataxin-2
(ATXN2)
Spinocerebellar ataxia
(SCA3/MJ disease)
Pyramidal, extrapyramidal, and ocular movement abnormalities
Amyotrophy
Sensory neuropathy
“Bulging eyes” (eyelid retraction)
CAG expansion 53-86 (≤47 normal range)
14q21
Ataxin-3
(ATXN3)
Spinocerebellar ataxia
(SCA4)
Sensory axonal neuropathy
Pyramidal signs
—
16q22.1
Secretory carrier-associated membrane protein 4 (SCA4)
Spinocerebellar ataxia
(SCA5)
Early onset, relatively pure cerebellar ataxia with dysarthria
Slow progression
—
11p13
Mutation in SPTBN2 gene
Spinocerebellar ataxia
(SCA6)
Slowly progressive, pure cerebellar ataxia with dysarthria, nystagmus
Occasional mild sensory loss
CAG expansion 20-33 (≤18 normal range)
19p13
Altered a1A subunit of the voltage-dependent calcium channel (CACNA1A)
Spinocerebellar ataxia
(SCA7)
Visual loss, retinal degeneration
Dysarthria
Variable pyramidal signs
CAG expansion 37->300 (4-35 normal range)
3p14.1-p12
Ataxin-7
Spinocerebellar ataxia
(SCA8)
Hyperreflexia, spasticity
Impaired vibration sense
CTG expansion 100-250 (15-52 normal range)
13q21
KLHL1AS
Spinocerebellar ataxia
(SCA9)
SCA9 has not yet been characterized.
—
—
Spinocerebellar ataxia
(SCA10)
Frequent seizures
Neuropathy
ATTCT expansion
280->4500 (10-22 normal range)
22q13
Ataxin-10
(ATXN10)
Spinocerebellar ataxia
(SCA11)
Rare
Slowly progressive mild ataxia
—
15q14-q21.3
SCA11
Spinocerebellar ataxia
(SCA12)
Tremor at onset
Late dementia
Noncoding CAG expansion 51-78 (7-31 normal range)
5q31
Serine
Threonine
Protein phosphatase 2A (PPP2R2B)
Spinocerebellar ataxia
(SCA13)
Childhood onset
Associated cognitive delay
Short stature
—
19q13.3- q14.4
KCNC3 gene
Spinocerebellar ataxia (SCA14)
Facial myokymia
Eye movement abnormalities
Axial myoclonus, dystonia, vibratory loss
Late onset can be pure ataxia
—
19q13.4
Protein kinase C gamma type (PRKC)
Spinocerebellar ataxia
(SCA15/SCA 16)
Pure ataxia with slow progression
Tremor
Mutations or deletions on ITPR1 gene
3p26.1
Spinocerebellar ataxia (SCA17)
Ataxia
Pyramidal and extrapyramidal signs
Dementia
Widespread cerebellar and cerebral atrophy
CAG expansion 45-63 (25-42 repeats normal range)
6q27
TATA-box binding protein
Spinocerebellar ataxia (SCA18)
Ataxia
Sensorimotor neuropathy
—
7q22-q32
Spinocerebellar ataxia
(SCA19)
Slowly progressive ataxia
Hyporeflexia
Cognitive decline
Myoclonus tremor
—
1p21-q21
Spinocerebellar ataxia (SCA20)
Dysarthria
Dystonia
Calcification of dentate nucleus
Palatal tremor
—
11p13-q11
Spinocerebellar ataxia
(SCA21)
Mild ataxia
Cognitive delay
Extrapyramidal features
Hyporeflexia
—
7p21-p15.1
Spinocerebellar ataxia (SCA22)
Gradual onset, slow progression pure ataxia, nystagmus, and dysarthria
—
1p21-q23
Spinocerebellar ataxia (SCA23)
Ataxia of late onset, slow progression
Sensory loss
Vibration loss
—
20p13-p12.3
Spinocerebellar ataxia(SCA24)
Renamed autosomal recessive cerebellar ataxia 4 (SCAR4)
—
—
Spinocerebellar ataxia (SCA25)
Severe sensory neuropathy
Gastrointestinal symptoms
—
2p21-q15
Spinocerebellar ataxia
(SCA26)
Dysarthria
Ocular pursuit abnormalities
—
19p13.3
Spinocerebellar ataxia (SCA27)
Gait and limb ataxia, tremors
Orofacial dyskinesias
Behavioral outbursts
Fibroblast growth factor 14–related truncating mutations
13q34
Spinocerebellar ataxia (SCA28)
Ophthalmoparesis
Hyperreflexia
—
18p11.22-q11.2
Spinocerebellar ataxia (SCA29)
Early onset, nonprogressive ataxia
Vermian hypoplasia
—
18p11.22-q11.2
Spinocerebellar ataxia(SCA30)
Dysarthria
Lower limb hyperreflexia
Hypermetric saccades
—
4q34.3-q35.1
Spinocerebellar ataxia (SCA31)
Late-onset ataxia
Hearing loss
Slowly progressive gait and limb ataxia
Cerebellar dysarthria,
Decreased muscle tone
Horizontal gaze nystagmus
Cerebellar atrophy
2.5-kb to 3.8-kb insertion containing pentanucleotide repeats including (TGGAA)n within an intron of the BEAN gene (612051)
16q21-q22
Spinocerebellar ataxia (SCA32)
Variable cognitive impairment, and azoospermia in males
—
7q32-q33
Spinocerebellar ataxia (SCA34)
Ichthyosiform skin lesions
—
6p12.3-q16.2
Spinocerebellar ataxia (SCA35)
Upper limb involvement and torticollis
—
20p13
Mutation in the TGM6 gene
Spinocerebellar ataxia (SCA36)
Truncal instability
Dysarthria
Dysdiadochokinesis
Hyperreflexia
Impaired smooth pursuit and horizontal gaze nystagmus,
Dysphagia
GGCCTG hexanucleotide repeat. affected individuals carry 1,500-2,000 repeats
NOP56 gene on chromosome 20p13
Dentatorubropallidoluysian atrophy (DRPLA)
Chorea
Seizures
Myoclonus
Dementia
Triplet repeat expansion leads to altered protein product
12p13.31
Atrophin-1 with toxic gain of function
*Gait ataxia is a constant feature
Autosomal dominant SCA (Chinese ancestry) [41]
Gene, inheritance, and pathogenesis·
Caused by heterozygous mutations in TGM6 (a member of the transglutaminase family), 2 different missense mutations in 2 different autosomal-dominant SCA families [c.1550T–G transition (L517W) in exon 10 and c.980A–G transition (D327G) in exon 7]. Clinical phenotype similar for both of the mutations.
Molecular studies done by exome sequencing is a new technique combining strategy using whole-exome capture and high-throughput sequencing technology, which provides a powerful means to identify causative genes. The 2 different missense mutations were further confirmed by using polyphen (data base), which showed that the mutations affected the functional properties of the protein. Both the mutations are also in a highly conserved region. The mutations segregated with affected individuals and were absent in 500 healthy unaffected individuals of matched geographical ancestry.
Previous work has shown that there is a much higher activity of transglutaminases and transglutaminase-catalyzed products in several neurodegenerative disorders, including Parkinson disease, Huntington disease, Alzheimer disease, and supranuclear palsy. Moreover, increased intracellular Ca2+, which promotes transglutaminase activation, is of vital importance in the etiology of neurologic diseases. TGM6 is predominantly expressed by a subset of neurons in the central nervous system, including Purkinje cells, and TGM6 deposits are present in the cerebellum of patients with gluten ataxia.
Clinical features
Late-onset ataxia
Slowly progressive
Lower limb more affected than upper limb
Dysarthria, ocular dysmetria
Spasmodic torticollis in some
Brain MRI shows cerebellar atrophy in some
No anticipation
Cognitive deterioration, epilepsy, signs of saccadic eye movements, nystagmus, visual problems, ophthalmoplegia, and peripheral nerve involvement absent in all patients
Recessively inherited ataxias with spinocerebellar dysfunction are discussed below.
See the list below:
Gene, inheritance, and pathogenesis: This is a rare autosomal recessive disorder resulting from a mutation that affects the gene for alpha-tocopherol transfer protein.
Clinical features
It is phenotypically similar to Friedreich ataxia (FRDA), with head titubation (28%), SCA, areflexia, and proprioception loss.
Skin is affected by xanthelasmata and tendon xanthomas.
Onset varies from ages 2-52 years and usually occurs in people younger than 20 years; it slowly progresses over decades.
Laboratory findings: Measurements include low-to-absent serum vitamin E and high serum cholesterol, triglyceride, and beta-lipoprotein.
Treatment: Treatment consists of vitamin E supplementation. A dose of 400-1200 IU/d improves neurologic function. This should be maintained for life.
See the list below:
Gene, inheritance, and pathogenesis
The prototype disorder of familial spinocerebellar degeneration, FRDA was the first identified recessively inherited condition with a mutation involving a triplet repeat expansion. Of patients with FRDA1, 96% are homozygous for a GAA expansion in intron 1 of the X25 gene. The number of GAA repeats ranges from 7-38 in normal alleles and from 66 to more than 1700 triplets in disease-causing alleles. The remaining cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. Most affected individuals carry more than 600 repeats. The DNA-based test for FRDA1 evaluates genomic DNA for the presence of a GAA trinucleotide repeat expansion in the X25 gene. The mutation leads to formation of the abnormal protein termed frataxin. Tissues carrying this mutation appear to be sensitive to oxidative stress. There is locus heterogeneity.
Great phenotype variation exists among affected individuals, even within the same family; the types have been divided arbitrarily into late-onset FRDA (LOFA), occurring in people aged 25-39 years, and very-late-onset FRDA (VLOFA), occurring in those older than 40 years. Deep tendon reflexes are retained, and progression is very slow, particularly in Arcadians. These variants have been found to have generally shorter GAA expansions (< 600) in at least 1 of the X25 alleles. Other postulated mechanisms to account for the differences include tissue-specific variability in triplet expansion size secondary to mitotic instability, cis -acting sequence alterations, and other genetic or environmental modifiers.
Clinical features
Onset – Variable age of onset when younger than 20 years
Neurologic symptoms – Cerebellar ataxia, dysarthria, nystagmus, uncoordinated limb movements, hypoactive knee and ankle deep tendon reflexes, Babinski sign, impaired position sense, and impaired vibratory sense
Cardiac findings – Symmetric concentric hypertrophic cardiomyopathy, congestive heart failure, and subaortic stenosis
Skeletal findings – Pes cavus, scoliosis, and hammer toes
Metabolic abnormalities – Abnormal glucose tolerance test results, diabetes mellitus, and diabetic ketoacidosis
Laboratory findings
Abnormal electrocardiographic findings
Abnormal echocardiographic findings
Abnormal findings on motor and sensory nerve conduction studies
Cerebellar atrophy and a thin spinal cord on MRI
Evidence of iron accumulation within mitochondria of FRDA fibroblasts subjected to oxidative stress, resulting in impaired respiratory function
DNA mutation analysis
Treatment [42] : Treatment protocols currently include coenzyme Q and other antioxidants that are being newly developed (eg, mitoquinone, idebenone). [43, 44] Preliminary trials have shown a favorable effect on the bioenergetics of cardiac and skeletal muscle and slowing of progression of selected aspects in the ataxia rating scale used.
See the list below:
Gene, inheritance, and pathogenesis: This rare autosomal recessive disorder is characterized by low levels of low-density lipoproteins (LDLs) and very low-density lipoproteins (VLDLs). It features defective assembly and secretion of apolipoprotein B (Apo-B)–containing lipoproteins by the intestines and the liver. Mutations appear to affect the microsomal triglyceride transfer protein (MTP) gene. The heterodimeric protein is responsible for transfer of neutral lipids across cell membranes. MTP may have an added role as a chaperone involved in Apo-B binding.
Clinical features
Areflexia, proprioceptive dysfunction, loss of reflexes, and Babinski sign (prominent findings)
By 5-10 years, gait disturbances and cerebellar signs
Malabsorptive state in the early years with steatorrhea and abdominal distension
Pes cavus and scoliosis present in some patients
Pigmentary retinopathy
Laboratory findings
Acanthocytosis on peripheral blood smears (constant finding)
Decreased serum cholesterol
Increased high-density lipoprotein cholesterol levels
Low levels of LDL and VLDL
Low triglyceride levels
DNA mutation analysis
Treatment
High-dose supplementation of vitamin E has a beneficial effect on neurologic symptoms.
Administer other fat-soluble vitamins (ie, vitamin D, vitamin A, vitamin K).
Because of the clinical similarity with abetalipoproteinemia, this autosomal dominant disorder is discussed in this section. It is clinically indistinguishable from abetalipoproteinemia, especially in its homozygous form. It is caused by mutations that affect the APOB gene, which affects turnover of Apo-B. Neurologic and nonneurologic manifestations are similar in homozygotes. Heterozygotes, on occasion, also may be affected. It is characterized by extremely low plasma levels of Apo-B, as well as low levels of total cholesterol and LDL cholesterol.
Table 5. Recessively Inherited Chronic/Progressive Ataxias with Spinocerebellar Dysfunction (Open Table in a new window)
Disorder/Syndrome
Neurologic Phenotype
Inheritance
Gene Locus
Gene Product/Biochemical Defect
Ataxia with selective vitamin E deficiency
Chronic ataxia
Autosomal recessive
8q13.1-q13.3
Mutated alpha-tocopherol transfer protein (ATTP) binds alpha-tocopherol, enhancing its transfer between separate membranes
Vitamin E likely has a role in preventing modification of lipoproteins by oxidative stress
Friedreich ataxia
Progressive ataxia plus
Autosomal recessive
9q13-q21.1
Expansion of GAA triplet repeats leads to a defective protein frataxin, abnormal mitochondrial function, oxidative stress, and accumulation of iron
Abetalipoproteinemia
Progressive ataxia plus
Autosomal recessive
4q24
MTP catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces and is also required for the secretion of plasma lipoproteins that contain Apo-B
Defects in the transfer protein result in loss of ability to produce Apo-B–containing lipoproteins with secondary malabsorption of vitamin E
Hypobetalipoproteinemia*
Chronic ataxia
Autosomal dominant
2q24
In the homozygous state, affected individuals are indistinguishable from those with abetalipoproteinemia
Defective Apo-B, VLDL, and LDL result in hypocholesterolemia
*Listed here due to overlap of clinical features with abetalipoproteinemia.
Many of the disorders discussed involve defects in DNA repair that require a complex sequence of events. In disorders of these pathways, multiple gene defects are involved. These disorders carry a poor outcome because no specific treatments are available at present. Complementation analysis helps determine if pathogenic mutations are in the same or different genes. Cell fusion of 2 different (diploid) cell lines from affected individuals (eg, from xeroderma pigmentosum) is attempted; DNA repair mechanisms then are studied in the new cell line. If the DNA repair defect is corrected in a tetraploid cell line, the mutations complement, and the 2 cell lines are said to define 2 separate complementation groups.
See the list below:
Gene, inheritance, and pathogenesis: Type 1 (or A) and type II (or B) are the 2 predominant forms. Inheritance is autosomal recessive for both. Defective repair of transcriptionally active DNA is the underlying basis of the disorder. Cultured skin fibroblasts from these patients display abnormal UV sensitivity. Mutations in the excision-repair cross-complementing group 8 gene (ERCC8) in type I or the excision-repair cross-complementing group 6 gene (ERCC6) in type II result in Cockayne syndrome. Early death in the second or third decade is usual.
Clinical features
Blindness, cataracts, and pigmentary retinopathy
No increase in incidence of malignancy in these patients
Microcephaly
Neurologic features including ataxia, pyramidal and extrapyramidal dysfunction, and seizures
Photosensitivity of skin
Systemic hypertension, sexual infantilism, renal and hepatic dysfunction
Wizened facies (similar to progeria)
Laboratory findings
Calcification of basal ganglia on CT scanning, and white matter changes on MRI
At least 2 complementation groups
Disturbed visual and brainstem auditory evoked responses indicative of CNS demyelination
Increased cellular sensitivity to UV light
Mutation testing in specialized laboratories
See the list below:
Gene, inheritance, and pathogenesis
This genetically heterogeneous disorder is due to a defect in DNA excision repair following UV exposure.
The condition differs from Cockayne syndrome because of the presence of skin tumors, absence of intracranial calcifications, and a different molecular defect. This disorder also has a poor prognosis.
Clinical features
Ataxia, chorea, and axonal polyneuropathy
Cutaneous photosensitivity and multiple cancers
Mental and motor retardation
Microcephaly
Sensorineural deafness
Laboratory findings: Defective DNA repair after ultraviolet radiation damage
This progressive, recessively inherited ataxia manifests in early childhood. It is more common in certain ethnic populations, including in those of Amish, Mennonite, Costa Rican, Polish, British, Italian, Turkish, Iranian, and Israeli descent.
Gene, inheritance, and pathogenesis: A defective truncated protein that belongs to the phosphatidylinositol-3 kinase family of proteins results from mutations that affect the ATM gene locus. This protein phosphorylates key substrates that are involved in DNA repair. The disease begins when patients are aged 1-3 years. No treatment is available other than supportive care and careful management of complications with modified chemotherapy
Clinical features
Choreoathetosis
Cutaneous and bulbar telangiectasia (present in teenagers and older individuals)
Immunodeficiency and increased susceptibility to infections
Oculomotor apraxia
Progressive ataxia and slurred speech
Susceptibility to cancer (eg, leukemia, lymphoma)
Laboratory findings
Molecular genetic testing is performed for mutations affecting the ATM gene locus (11q22.3). For those patients in whom mutations cannot be identified, other supportive laboratory evidence must be sought
Elevated (>10 ng/mL) serum alpha-fetoprotein is found in 90-95% of patients.
Findings on colony survival assay, ie, colony formation of a lymphoblastoid cell line following irradiation, are abnormal.
Karyotyping abnormalities involve 7-14 chromosomal translocation in 5-15% of cells after phytohemagglutinin stimulation of lymphocytes in peripheral blood.
Breakpoints result in translocation at the 14q11 and 14q32 sites.
This group includes the following disorders: ataxia with oculomotor apraxia type 1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2), and ARSACS. [45]
Ataxia with oculomotor apraxia type I
Gene, inheritance, and pathogenesis: The disorder begins in childhood, proceeding to loss of ambulation in 7-10 years. The gene locus at 9p13.3 codes for a protein aprataxin. Mutations in this gene are pathogenic. The protein appears to have a role in DNA repair.
Clinical features
Progressive cerebellar ataxia
Oculomotor apraxia progressing to complete ophthalmoplegia
Motor neuropathy, progressive distal amyotrophy
Normal cognition in Portuguese families, decline in cognition noted in Japanese families
Laboratory findings
Hypoalbuminemia
No specific diagnostic tests available
Ataxia with oculomotor apraxia type 2
Gene, inheritance, and pathogenesis: The disorder begins in the second decade of life. The gene locus is 9q34, and the gene product is called senataxin. The protein is thought to function as a helicase involved in various aspects of DNA transcription and repair, RNA maturation, and termination.
Clinical features
Axonal sensorimotor neuropathy
Oculomotor apraxia is an inconsistent feature.
Laboratory findings
Cerebellar atrophy on imaging
Elevated alpha-fetoprotein
Table 6. Recessively Inherited Chronic/Progressive Ataxias Associated with DNA Repair Defects (Open Table in a new window)
Disorder/Syndrome
Neurologic Phenotype
Inheritance
Gene Locus
Gene Product/Biochemical Defect
Cockayne syndrome type A
Progressive ataxia plus
Early onset severe syndrome
Autosomal recessive
5q11
ERCC8
Cockayne syndrome type B
Progressive ataxia plus
Classical type
Autosomal dominant
10q11-q21
ERCC6
Xeroderma pigmentosum
Progressive ataxia plus
Autosomal recessive
Genetically heterogeneous with several complementation groups identified
9q34 locus (A)
Other complementation groups involved are 2q21 (B & CS); 3p25.1 (C); 19q13.2(D); Unknown (E); 16p13 (F); 13q32-33 (G & CS)
Mutations result in either defective damage-specific DNA-binding protein or defective excision repair (ERCC)
Neurologic manifestations beginning in childhood relate to complementation group
Ataxia
Telangiectasia
Progressive ataxia plus
Autosomal recessive
11q22-q23
ATM gene
Product belongs to the P-13 kinase family of proteins involved in DNA damage recognition
Ataxia with oculomotor apraxia type 1 (AOA1)
FRDA-like hypoalbuminemia
Autosomal recessive
9p13.3
Aprataxin (APTX)
Role in single-stranded DNA repair
Ataxia with oculomotor apraxia type 2 (AOA2)
Changed to autosomal recessive cerebellar ataxia (SCAR1)
Ocular apraxia is an inconsistent feature.
Ataxia
Distal amyotrophy
Peripheral neuropathy
Autosomal recessive
9q34
Senataxin (SETX)
Protein involved in RNA maturation and termination
Recessively inherited ataxias associated with protein translocation/folding defects are discussed below.
See the list below:
Gene, inheritance, and pathogenesis
ARSACS is an autosomal recessive spastic ataxia of Charlevoix-Saguenay region. This is an early-onset ataxia, manifesting in infancy or early childhood, with a high prevalence in the Charlevoix-Saguenay region of northeastern Quebec.
The estimated carrier frequency in Charlevoix-Saguenay region is 1/22. It has also been described in other regions of the world such as Mediterranean areas and Japan. Mutations in the SACSIN gene encode a protein sacsin that is believed to function as a chaperone involved in protein folding.
Clinical features
Progressive ataxia with pyramidal, cerebellar, and distal neuropathy sensorimotor neuropathy
Nystagmus
Slurred speech
Hypermyelinated retinal nerve fibers leading to retinal striations
Skeletal abnormalities, including swan neck–like deformities of the fingers, pes cavus, and hammer toes
Laboratory findings
Decreased sensory nerve conduction velocities (NCV)
Decreased motor NCV
Loss of large myelinated fibers on nerve biopsy
See the list below:
Gene, inheritance, and pathogenesis
Leukoencephalopathy with vanishing white matter (VWM) has an autosomal recessive inheritance with an age-dependent penetrance.
The gene is located on band 3q27. [46] The mutation involves a gene that codes for the eukaryotic translation initiation factor (eIF2B). The gene likely controls regulation of translation under conditions of stress. No effective treatment is known to halt progression of the disorder, although symptomatic and supportive measures can improve the quality of life. [47, 48]
Clinical features
Cerebellar ataxia and spasticity are prominent.
Chronic progressive neurologic deterioration and episodic exacerbation follow in late infancy or early childhood.
Episodes of deterioration follow minor infection and head trauma, leading to periods of lethargy or coma.
Cognitive ability may show decline but is relatively preserved compared to the severity of motor deficit.
Initial motor and mental development is normal or mildly delayed.
Optic atrophy and epilepsy may be additional features.
Laboratory findings
Cerebellar atrophy varies from mild to severe and primarily involves the vermis.
Elevated CSF glycine is a marker for this disorder.
MRI indicates symmetric involvement of the cerebral hemispheric white matter, which acquires a signal intensity close to or the same as CSF on proton density, T2-weighted, T1-weighted, and fluid-attenuated inversion recovery images.
Magnetic resonance spectroscopy shows a significant decrease to near absence of normal signals from the white matter, except for lactate and glucose (the signals of which become more prominent with disappearance of other normal signals). Signals over the cortex remain relatively normal.
Pathologic studies confirm white matter rarefaction and loss of myelinated white fibers. Microcystic changes are reported in the periventricular white matter.
See the list below:
4H syndrome is a recessively inherited phenotype with distinctive clinical features and a hypomyelinating leukodystrophy. To date, no gene locus or mutations have been identified.
Clinical features
Early onset progressive ataxia
Short stature
Hypodontia
Delayed puberty secondary to gonadal dysfunction
Laboratory
MRI shows white matter signal abnormalities consistent with central hypomyelination and cerebellar atrophy.
Sural nerve biopsy shows debris-lined myelin clefts, vacuolar disruption, and loss of normal myelin periodicity.
Table 7. Recessively Inherited Chronic/Progressive Ataxias Associated with Protein Translation and Folding Defects (Open Table in a new window)
Disorder/Syndrome
Neurologic Phenotype
Inheritance
Gene Locus
Gene Product/Biochemical Defect
Autosomal recessive spastic ataxia of Charlevoix-Saguenay
Chronic ataxia
Spasticity
Retinal
abnormalities
Autosomal recessive
13q11
SACS gene codes for sacsin, which is involved in chaperone-mediated protein folding
Leukoencephalopathy with VWM
Progressive ataxia
Spasticity
Optic atrophy
Seizures
Autosomal recessive
3q27
Mutations affect eIF2B
4H syndrome
Short stature
Slowly progressive ataxia
Hypogonadism
Hypomyelination
hypodontia
Autosomal recessive
Not known
Not known
Recessively inherited chronic/progressive ataxias associated with inherited enzymatic defects are discussed below.
See the list below:
Gene, inheritance, and pathogenesis: This autosomal recessive disorder is associated with impaired oxidation of phytanic acid. Elevated phytanic acid levels in the nervous system are associated with neurotoxicity.
Clinical features
Onset in the second to third decade of life
Cerebellar ataxia (may be superimposed in some patients)
Early presentation of night blindness and pigmentary degeneration of the retina
Polyneuropathy with elevated CSF protein
Sensorineural deafness
Skin (ichthyosis) and cardiac (arrhythmia) abnormalities
Laboratory findings
Cultured fibroblasts show reduced ability to oxidize phytanic acid.
Elevated phytanic acid levels in the plasma and urine are diagnostic.
Treatment: Refsum disease has a relapsing-remitting course. Drastic reduction in dietary phytanic acid (supplemented by plasmapheresis) at onset can ameliorate the neuropathy and possibly other clinical abnormalities.
See the list below:
Gene, inheritance, and pathogenesis: This autosomal recessive disorder is caused by a defect in bile acid synthesis. Cholestanol accumulates in the tissues, including the nervous system. The defect is due to deficiency of hepatic sterol 27-hydroxylase, a mitochondrial enzyme.
Clinical features
Palatal myoclonus and seizures
Peripheral neuropathy
Progressive ataxia with mental decline
Pseudobulbar palsy
Tendon xanthomas
Cataracts
Laboratory findings
Elevated cholestanol and Apo-B in CSF
Low plasma cholesterol; elevated plasma cholestanol
Low-to-absent chenodeoxycholic acid in the bile
Treatment: Lifelong oral administration of chenodeoxycholic acid (750 mg/d) is effective if initiated early (see chenodiol). A 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor also can be added to inhibit cholesterol biosynthesis.
See the list below:
Gene, inheritance, and pathogenesis: Because of the lack of free biotin, biotinidase deficiency results in dysfunction of 3 mitochondrial carboxylases. It is recessively inherited, and the underlying defect involves mutations of the 3p25 locus for biotinidase.
Clinical features
Delayed presentation (second year of life)
Intermittent ataxia, sensorineural hearing loss
Myoclonic seizures, developmental delay
Skin rashes, alopecia
Laboratory findings
Organic aciduria (eg, elevated beta-hydroxyisovalerate, lactate, beta-methylcrotonylglycine, beta-hydroxypropionate, methylcitrate)
Mild hyperammonemia
Diffuse cerebral and cerebellar atrophy on cranial MRI
Metabolic acidosis, lactic acidosis
Biotinidase activity in serum and fibroblasts
Mutation analysis
Treatment
Biotin 5-20 mg/d PO is remarkably effective in reversing neurologic and cutaneous symptoms.
Hearing and visual dysfunction may be resistant to treatment.
See the list below:
Gene, inheritance, and pathogenesis: This autosomal recessive inherited defect is characterized by excessive excretion of L-2-hydroxyglutaric acid in the urine. The precise molecular basis is not well established. The clinical course is of slowly progressive neurodegenerative disorder.
Clinical features
Age of onset from 6-20 years
Presence of cognitive delay and epileptic seizures
Progressive ataxia, dysarthria, and extrapyramidal dysfunction
Added features of short stature and macrocrania
Laboratory findings
Elevated 2-hydroxyglutaric acid in plasma, urine, and CSF
Elevated lysine in plasma and CSF
Highly specific MRI pattern showing subcortical leukoencephalopathy with bilateral high signal intensity in dentate nuclei and putaminal regions
See the list below:
Gene, inheritance, and pathogenesis: Succinic-semialdehyde dehydrogenase deficiency (SSADH) is a recessively inherited disorder affecting the gamma-aminobutyric acid (GABA) degradation pathway. Although it is characterized by excretion of large amounts of 4-hydroxybutyric acid in the urine, phenotype varies widely. [49]
Clinical features
Ataxia
Hypotonia
Nonspecific neurologic features such as cerebral palsy and developmental delay
Psychomotor retardation, language delay
Laboratory findings
Elevated 4-hydroxybutyric acid in plasma, urine, and CSF
High free GABA in CSF
Cerebellar atrophy on MRI
Treatment
L-carnitine supplementation has been tried with improvement in muscle tone.
Vigabatrin, an inhibitor of GABA transaminase, has proven effective in low doses of 25 mg/kg/d.
These complex biochemical defects are related to specific deficiencies of lysosomal enzymes (see Table 8 below). The brain and other tissues such as the liver store abnormal sphingolipids. The presentation is a combination of cognitive deterioration, seizures, and gait abnormalities due to a combination of pyramidal features (spasticity), cerebellar dysfunction (ataxia), extrapyramidal features (eg, dystonia), choreoathetosis, and ophthalmologic abnormalities. Ataxia almost never is the sole clinical symptom. Other systemic features can include coarse facies, organomegaly, and dysostosis multiplex. Because these disorders are progressive, symptoms and signs can be seen in combination. The disorders are autosomal recessive. Skin fibroblast examination under electron microscope is an effective screening tool. Definitive diagnosis can be established by lysosomal enzyme assay in leukocytes or cultured skin fibroblasts.
The congenital disorders of glycosylation (CDG) represent a new class of disorders that result from abnormalities of carbohydrate-deficient glycoproteins, particularly transferrin. The disorder has been reported from Scandinavian countries as well as other European countries. Most are autosomal recessive conditions; several (nearly 20 at the latest count) clinical and biochemical types have been characterized. Because glycoproteins are important constituents of the developing brain, CNS involvement and multisystem manifestations are frequent.
Gene, inheritance, and pathogenesis: CDG type 1a is caused by mutations affecting the enzyme phosphomannomutase; the gene locus is located on sub band 16p13.3. The enzyme is involved in the N-glycosylation pathway. Several other disorders involving the O-glycosylation pathway have now been recognized; the Walker-Warburg syndrome and the muscle-eye-brain disease are examples. For the purposes of the present discussion on ataxia the authors restrict discussion to CDG type 1a. The mortality rate is approximately 20% in the first 2 years. Only supportive treatment is available.
Clinical features
Stage of ataxia; mental deficiency during infantile and childhood stage
Delayed development, failure to thrive, hypotonia, and multisystem organ failure
Dysmorphic facial features, including prominent ears and nose
Fat pads over buttocks, abnormal patches of skin over thighs (orange peel skin), and inverted nipples (considered characteristic clinical features)
In the teenage years, evident lower limb atrophy and peripheral neuropathy
Severe mental retardation and hypogonadism recognized in later years
Laboratory findings
Decreased serum glycoproteins
MRI showing striking pontocerebellar atrophy
Reduced thyroxine-binding globulin levels
Sialic acid, galactose, and N -acetylglucosamine deficiency in total serum glycoproteins
Synthesized proteins with fewer attached carbohydrate moieties than normal glycoproteins
Separation of proteins based on charge when an electric field is applied to serum
Sialotransferrins, a specific class of glycoproteins, behave differently in serum from patients with CDG than in serum from individuals without CDG; patients with CDG have less sialic acid, a negatively charged sugar.
The pattern of separation during electrophoresis (transferrin isoimmunoelectrophoresis) is considered diagnostic for this disorder.
Phosphomannomutase deficiency in leukocytes, fibroblasts, or liver
Consideration of molecular analysis of phosphomannomutase 2 gene (PMM2) in some subtypes
See the list below:
Gene, inheritance, and pathogenesis: Marinesco-Sjögren syndrome (MSS) is an autosomal recessive disorder. MSS is mapped to chromosome arm 5q31, but genetic heterogeneity is evident. In some families, mutations have been identified in the gene SIL1, [50] which encodes a nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5. The disorder is now thought to be a consequence of dysfunction of the endoplasmic reticulum and disturbed SIL1-HSPA5 interaction and protein folding. This disorder has overlapping features with lysosomal disorders. Ophthalmologic, skeletal, and gonadal abnormalities are frequently seen.
Clinical features
Microcephaly
Cataracts
Cerebellar ataxia
Mild-to-moderate mental retardation
Neuromuscular weakness
Short stature
Hypergonadotropic hypogonadism
Skeletal anomalies of kyphosis, scoliosis, and coxa valga
Laboratory findings
Massive cerebellar cortical atrophy on imaging
Elevated serum creatine kinase
Myopathic changes on muscle biopsy and numerous enlarged lysosomes containing whorled lamellar or amorphous inclusion bodies by electron microscopy
Table 8. Recessively Inherited Chronic/Progressive Ataxias Associated with Inherited Enzyme Defects (Open Table in a new window)
Disorder/Syndrome
Neurologic Phenotype
Inheritance
Gene Locus
Gene Product/Biochemical Defect
Refsum disease
Progressive ataxia plus
Autosomal recessive
10pter-p11.2
Mutations affecting the gene coding for phytanoyl-CoA hydroxylase
Cerebrotendinous xanthomatosis
Chronic progressive ataxia
Autosomal recessive
2q3-qter
Defective mitochondrial cytochrome-P450 sterol27-hydroxylase CYP-27A1 leading to accumulation of plasma cholestanol
Biotinidase deficiency
Progressive ataxia plus
Autosomal recessive
3q25
Deletions resulting in multiple carboxylase deficiency and impaired release of biotin from biocytin, the product of biotin-dependent carboxylase degradation
L-2 hydroxyglutaric acidemia
Chronic progressive ataxia
Autosomal recessive
Unknown locus
Deficiency of hepatic hydroxyglutaric acid dehydrogenase
Succinic-semialdehyde dehydrogenase deficiency
Progressive ataxia plus
Autosomal recessive
6p22
Deficiency of succinic semialdehyde dehydrogenase
Accumulation of 4-hydroxybutyric acid in plasma and urine
Late infantile and juvenile sphingolipidoses
1. Metachromatic leukodystrophy
2. Krabbe globoid cell leukodystrophy
3. Gaucher type III
4. Niemann-Pick C disease
5. GM2 gangliosidosis
Progressive ataxia plus
Seizures
Psychomotor regression
Spasticity
Extrapyramidal features
Supranuclear gaze palsies
Autosomal recessive
1. 22q13.3-qter/
2. 14q31
3. 1q21 18q11-q12
4. 15q23-q24
1. Deficiency of arylsulfatase A/sphingolipid activator Protein (SAP)
2. Deficiency of galactosylceramide beta-galactosidase
3. Deficiency of beta-glucocerebrosidase
4. Abnormal uptake of cholesterol and defective esterification leading abnormal cholesterol ester storage
5. Defect in hexoaminidase A or of the GM2 protein activator
Congenital disorders of glycosylation type Ia
Progressive ataxia plus
Autosomal recessive
16p13.3-p13.2
Mutations in the gene encoding for phosphomannomutase
Marinesco-Sjögren syndrome
Chronic ataxia
Cataract
Hypotonia
Myopathy
Autosomal recessive
5q31
Disturbed SIL1 and HSP70 chaperone HSPA5 protein folding interaction
Recessively inherited ataxias associated with mitochondrial cytopathies are discussed below.
Gene, inheritance, and pathogenesis: Neuropathy, ataxia, retinitis pigmentosa, and peripheral neuropathy (NARP) syndrome is a mitochondrial disorder that displays maternal inheritance. Affected individuals present with features of cerebellar ataxia, seizures, cognitive impairment, and peripheral neuropathy. The condition carries a variable phenotype and also may occur sporadically. The underlying defect involves a mitochondrial adenosine triphosphate (ATP) synthase gene (subunit 6) affecting nucleotide 8993, mutations of which also can result in the Leigh syndrome phenotype. The diagnosis can be confirmed by mitochondrial DNA mutation analysis.
See the list below:
Gene, inheritance, and pathogenesis: This disorder has distinct neuropathologic findings, highly variable clinical presentation, and can be caused by multiple biochemical and molecular genetic defects. Autosomal recessive inheritance and maternal inheritance (mutations in mitochondrial DNA) patterns exist.
Clinical features: Clinical features include protean manifestations due to multifocal lesions in the brainstem, thalamus, and cerebellum; the most important of these are as follows:
Oculomotor – Nuclear or supranuclear ophthalmoplegia, central nystagmus with rotary and horizontal components
Course – Relapsing-remitting course, rarely progressively fatal
Respiratory – Characterized by unexplained hyperventilation, apnea, and irregular respiration (air hunger)
Neurologic – Truncal ataxia, incoordination, and intention tremor evident as child begins to walk
Laboratory findings
Characteristic symmetric lesions can be demonstrated in the thalamus, putamen, and globus pallidus on T2-weighted MRI sequences. The lesions also are distributed in the brainstem and cerebellum.
Lactate and pyruvate are elevated in the CSF.
Perform enzyme function assays on cultured fibroblasts, muscle, or liver tissue. Frequently, more than one of these tissues should be assayed because of the lack of correlation between enzyme activities in muscle and skin.
Hyperammonemia, hypoglycemia, and organic aciduria are not present.
Multiple mitochondrial enzymes have been demonstrated to be affected in this disorder, particularly the pyruvate dehydrogenase (PDH) complex, cytochrome c oxidase, and the mitochondrial adenosine triphosphatase (ATPase) 6 gene.
Neuropathologic lesions show incomplete necrosis and spongiform changes in the neuropil with relative preservation of the neurons, resulting in a spongiosis. Vascular proliferation also occurs, and white matter changes can be seen.
Treatment: No treatment is known to actually benefit patients. Vitamin B1 (thiamine) supplementation has been administered without documented benefit. Recently, the ketogenic diet has been reported to be useful in treating patients with PDH complex deficiency.
CoQ-10 is involved in facilitation of electron transfer between the various dehydrogenases and cytochromes participating in the respiratory chain and oxidative phosphorylation reaction. Ubiquinone deficiency presents with many different clinical phenotypes ranging from myopathy to Leigh’s disease.
Gene inheritance and pathogenesis: Autosomal recessive, genetic heterogeneity is likely. Mutations (missense) in the CABC1 gene, also called COQ8 or ADCK3, coding for a putative protein kinase in the ubiquinone biosynthesis pathway have recently been shown to be associated with this form of CoQ-10 deficiency. [51]
Clinical features
More than 20 patients have been described with a recessively inherited form of muscle CoQ-10 deficiency who present with a slowly progressive ataxia in childhood, associated with cerebellar atrophy. [52]
Associated features include developmental delay, mental retardation, and seizures.
Laboratory
A few patients demonstrate elevations in plasma lactate.
Decreased CoQ concentration in muscle or fibroblasts.
Treatment
Response to CoQ-10 supplementation is excellent in some patients. [53]
Table 9. Recessively Inherited Chronic/Progressive Ataxias Associated with Mitochondrial Cytopathies (Open Table in a new window)
Disorder/Syndrome
Neurologic Phenotype
Inheritance
Gene Product/Biochemical Defect
NARP syndrome
Progressive ataxia plus
Maternal inheritance
Mitochondrial ATP 6 NARP 8993 mutation causing base substitution T-G or T-C at nucleotide position 8993
Leigh disease
Progressive ataxia plus
Lactic acidosis
Autosomal recessive/maternal inheritance
Multiple biochemical and molecular defects underlie the condition, eg, PDHC deficiency, cytochrome oxidase C deficiency, mitochondrial ATPase 6
CoQ-10 responsive ataxia
Progressive ataxia in childhood
Developmental delay
Seizures
Cerebellar atrophy on MRI
Autosomal recessive
Mutations in the gene CABC1 or ADCK3 are described. The gene codes for a putative protein kinase associated with ubiquinone biosynthesis.
The progressive myoclonic epilepsies (PMEs) constitute a group of seizure disorders with phenotypic features of myoclonic and other generalized seizures, ataxia, and cognitive defects. These features occur in variable combinations that progress over time. These disorders are often difficult to distinguish on purely clinical grounds.
Dodecamer repeat expansions are discussed below.
See the list below:
Gene, inheritance, and pathogenesis: PME of the Unverricht-Lundborg type (EPM1) is autosomal recessive with an approximate age of onset of 10 years. EPM1 mostly has been reported in a genetically homogeneous population, permitting studies using linkage disequilibrium to narrow the gene defect to a small region of sub-band 21q22.3. The gene CST6 codes for a protein called cystatin B, a noncaspase cysteine protease inhibitor. Cystatin B mRNA is reduced markedly in patients with EPM1. The mutation results from an unstable dodecamer repeat expansion in the promoter region of the CST6 gene.
Clinical features
Ataxia developing late in the disease course
Mild mental deterioration
Progressive disability from stimulus-sensitive myoclonus and generalized tonic-clonic (GTC) seizures
Laboratory findings
EEG findings are nonspecific, showing background slowing and paroxysmal bursts of generalized spike-wave abnormalities.
Giant somatosensory evoked potentials can be elicited.
Treatment
N-acetylcysteine has been found effective in an open trial in 4 patients. A marked decrease in myoclonus and some normalization of somatosensory evoked potentials with N -acetylcysteine treatment has been documented.
Phenytoin aggravates symptoms.
Piracetam has been useful in the treatment of myoclonus.
Inherited enzyme defects are discussed below.
See the list below:
Gene, inheritance, and pathogenesis: PME of the Lafora type (EPM2/MELF) resembles EPM1 clinically. EPM2 is linked to 6q24, where the gene EPM2A encodes a protein tyrosine phosphatase termed laforin. Phosphatases are involved in many aspects of neuronal function, including glycogen metabolism and regulation of ionic channels and synaptic transmission. The disorder is fatal. Symptomatic treatment for seizures and myoclonus may be tried.
Clinical features
Ataxia
Progressively worsening myoclonic and occipital seizures with visual signs
Presentation in late childhood or adolescence, leading to a fatal outcome within a decade
Laboratory findings
MRI shows cerebellar atrophy.
Periodic acid-Schiff–positive cytoplasmic inclusion bodies are found in the brain, muscle, liver, and skin. These findings are considered diagnostic.
See the list below:
Gene, inheritance, and pathogenesis: Neuronal ceroid lipofuscinosis (NCL) describes autosomal recessive disorders in which characteristic storage material is identified within neurons, resulting in their degeneration. NCLs are a group of progressive neurodegenerative disorders that share several clinical features, particularly the presence of seizures and progressive dementia. Several genetically distinct subgroups have been determined based on age at presentation. Each subgroup has a characteristic ultrastructural appearance of the intracellular lipopigment. The gene for the classic late infantile form (LINCL CLN2) maps to band 11p15. Mutations in the gene encoding a pepstatin-insensitive lysosomal peptidase have been identified in patients with CLN2, and assays demonstrate that this enzyme is deficient in CLN2 autopsy specimens. The disorders are progressive and fatal. Symptomatic treatment and supportive measures may help improve the quality of life.
Clinical features
Ataxia
Dementia
Myoclonic seizures, atypical absence seizures, GTC seizures, other seizure types
Visual impairment
Laboratory findings
CT scanning and MRI show predominantly cerebellar atrophy. See image below.
Electron microscopic examination of skin or conjunctival biopsy shows typical intralysosomal curvilinear inclusions.
Giant visual evoked potentials and large somatosensory visual evoked potentials can be elicited.
Driving responses on the EEG to photic stimulation are abnormal (ie, high-amplitude spike at low rates of stimulation).
Lysosomal palmitoyl protein thioesterase and tripeptidyl peptidase 1 enzyme analysis may be performed.
DNA may be examined for mutation analysis.
Mitochondrial cytopathies are discussed below.
See the list below:
Gene, inheritance, and pathogenesis: MERRF is the prototype disorder in which epilepsy results from deficient mitochondrial energy production. An A-to-G transition mutation at nucleotide pair 8344 in human mitochondrial DNA has been identified in most patients. The mutation creates a specific restriction site on the tRNALys gene, producing defects in complex I and IV enzymes of the oxidative phosphorylation system. Myriad cell functions are involved in the control of excitability and are energy dependent. Thus, deficient energy production or utilization can lead to neurologic dysfunction in a variety of ways.
Clinical features
Ataxia
Impaired deep sensations (similar to FRDA)
Myopathy
Sensorineural deafness
Short stature
Myoclonic and GTC seizures that are often photosensitive and exaggerated by voluntary movements
Laboratory findings
CT scanning may show basal ganglia calcification.
Ragged red fibers in muscle biopsy specimens result from the subsarcolemmal aggregation of mitochondria.
EEG shows paroxysmal irregular generalized spike-wave complexes with background abnormalities.
Lactic acidosis may be present.
The pathogenic mutation may be undetectable in leukocytes and may only be detected in other tissues, such as cultured skin fibroblasts, urinary sediment, oral mucosa (from mouthwash), hair follicles, or most reliably, skeletal muscle.
Treatment
The seizure disorder can be treated with conventional anticonvulsant therapy.
No treatment for the genetic defect is currently available. Coenzyme Q10 and L-carnitine have been proposed to stabilize mitochondrial dysfunction.
Table 10. Progressive Ataxias with Myoclonus and Epileptic Seizures (Open Table in a new window)
Type
Unverricht-Lundborg syndrome
Neurologic Phenotype
Inheritance
Locus
Gene Product/Biochemical Defect
Dodecamer repeat expansion
Unverricht-Lundborg syndrome
Myoclonus
Ataxia
Seizures
Autosomal recessive
21q22.2
Dodecamer repeat expansions affects gene for cystatin B
Inherited enzyme defect
Lafora body disease
Myoclonus
Ataxia
Seizures
Autosomal recessive
6q24
Mutation affects a gene encoding for a protein tyrosine phosphatase (laforin) that may disrupt glycogen metabolism
Inherited enzyme defect
Late infantile neuronal ceroid lipofuscinosis
Myoclonus
Ataxia
Seizures
Autosomal recessive
11p15.5
Gene codes for a lysosomal pepstatin insensitive protease
Mitochondrial cytopathy
MERRF
Myoclonus
Ataxia
Maternal inheritance
N/A
mt-DNA mutations affecting tRNALys
Defective oxidative phosphorylation
See the list below:
Gene, inheritance, and pathogenesis: This is a disorder caused by abnormalities of imprinting. It manifests with significant gait abnormalities and ataxia with characteristic pattern, identified earlier as happy puppet syndrome (this term is no longer used). A number of different pathogenetic mechanisms such as loss of maternal allele, paternal uniparental disomy, mutation of the ubiquitin protein ligase E3A gene (UBE3A) account for different subsets of Angelman syndrome.
Clinical features
Microcephaly
Prognathia
Hypopigmentation of the skin
Significant seizures
Happy disposition and paroxysmal laughter
Poor speech
Severe mental retardation
Ataxia with jerky arm movements and hyperreflexia
Characteristic arm position with wrist and elbow flexion
Laboratory findings
DNA methylation abnormalities in the 15q11-13 region
Deletions in 15q11-13 region using fluorescent in situ hybridization (FISH)
Uniparental disomy studies
UBE3A mutation on DNA analysis
Mild cortical atrophy on CT scanning or MRI
EEG abnormalities that are considered as highly characteristic
See the list below:
Gene, inheritance, and pathogenesis: Carriers of premutation alleles (55-200 CGG repeats) of fragile X mental retardation 1 (FMR1) are now being identified with one (or more) distinct clinical disorders, including mild cognitive delay and/or behavioral deficits on the fragile X spectrum and a neurodegenerative disorder among older adult carriers. This is known as the fragile X–associated tremor/ataxia syndrome (FXTAS). Awareness of these clinical presentations is important for physicians involved in the care of patients with fragile X syndrome but also more broadly for neurologists caring for adults with tremor, gait ataxia, and parkinsonism. Female carriers of the FMR1 premutation who present with symptoms of tremor and ataxia do not develop features of dementia, unlike males with FXTAS. This protective effect in female carriers remains unexplained at present.
In the fragile X tremor ataxia syndrome, up to 40% of males and 4-8% of females carrying the premutation can be symptomatic. In the premutation states, the degree of FMR protein (FMRP) amounts are not decreased. The levels may be near normal; however, the amount of mRNA expression is noted to be 8-10 times elevated. This is not seen with the full mutation. The tremor ataxia syndrome is thought to be related to mRNA accumulation and resultant toxicity.
The assessment of such a patient involves obtaining a detailed clinical history complemented by an appropriate neurologic examination that delineates the following information:
Age of onset
Mode of onset (ie, acute, subacute, chronic)
Sex
Natural history (ie, nonprogressive/static, episodic, progressive)
Associated symptoms/signs that provide localizing information
Presence of dystonia or chorea suggesting involvement of the striatum
Proprioceptive dysfunction suggesting involvement of spinocerebellar pathways
Visual deficits (retinitis pigmentosa), auditory involvement (Refsum disease)
Cognitive dysfunction possible early and/or late
Other systemic features
Dysmorphic features and associated congenital malformation may suggest a specific association or clinical syndrome.
Cardiac (Friedreich ataxia), renal (NPCA), and cutaneous (xeroderma pigmentosa) features are examples.
Family history and pedigree analysis provides diagnostic clues and information on possible patterns of inheritance, which are useful for planning investigations and genetic counseling.
Once a specific clinical phenotype is delineated, the investigative process can be initiated based on the clinical features. The initial step involves obtaining specific neuroimaging studies; MRI is often preferable because it can provide detailed information helpful in anatomic localization (ie, signal changes in the cortex, white matter, cerebellum, striatum, and brainstem), and patterns of involvement in some conditions can be diagnostic. In mitochondrial cytopathies, magnetic resonance (MR) spectroscopy (ProtonMRS) can demonstrate an elevated lactate peak and can complement the findings on MRI. A karyotype (demonstrating deletions, duplications, and chromosomal rearrangements), specialized cytogenetic studies (as in Angelman syndrome), and DNA-based molecular diagnostics (as in SCAs, fragile X syndrome, and Angelman syndrome) can be utilized to provide rapid turnaround times for diagnosis.
Metabolic screening involves tests such as quantitative studies for plasma lactate, ammonia, carnitine levels, amino acids in blood and urine, urine analysis for organic acid and acylglycines (stable isotope dilution gas chromatography–mass spectrometry [GC/MS]), plasma acylcarnitines (tandem mass spectrometry [MS/MS]), and assays for sialotransferrins (isoelectric focusing of serum transferrins) should be used selectively after consultation with a metabolic geneticist. A schematic approach is suggested (see image below).
With the recent completion of the Human Genome Project, newer gene discoveries have ushered in an era where making diagnoses is not limited to clinical aspects but also relies on establishing a molecular basis. The identification of gene-protein links to specific cellular pathways will add to the understanding and eventually guide the way for future therapeutic advances. When approaching the child or adult with ataxia, the differential diagnosis always must include biochemical defects. The age of onset, mode of presentation, family history, and presence or absence of other neurologic signs are involved heavily in determining the screening and specific tests used in the evaluation (see image below).
Many of these conditions are progressive and neurodegenerative, with no treatment currently available. Identification of specific defects, such as ataxia with selective vitamin deficiency, provides treatment options for disorders that are eminently treatable. For other incurable disorders, such as Friedreich ataxia, treatment approaches such as antioxidant therapy may prolong life and lead to reduction in morbidity. Idebenone, a synthetic analogue of coenzyme Q has been tried with beneficial effects on ADL scores on both cardiac hypertrophy as well as neurologic symptoms in preliminary trials. Suitable doses have to be determined to optimize benefits. Supportive therapy, management of associated complications, and the role of support groups cannot be overemphasized for families who have to deal with truly challenging medical needs.
International Network of Ataxia Friends (INTERNAF)
2600 Fernbrook Lane; Suite 119
Minneapolis, MN 55447
Phone: 763-553-0020
Fax: 763-553-0167
Email: naf@ataxia.org
Spinocerebellar Ataxia: Making an Informed Choice about Genetic Testing
Euro-ataxia (European Federation of Hereditary Ataxias)
Boherboy, Dunlavin
Co Wicklow, Ireland
Phone: +353 45 401218
Fax: +353 45 401371
Email: mary.kearneyl@euro-ataxia.org
NCBI Genes and Disease – Spinocerebellar ataxia
WE MOVE (Worldwide Education and Awareness for Movement Disorders)
204 West 84th Street
New York, NY 10024
Phone: 800-437-MOV2 (800-437-6683)
Fax: 212-875-8389
Email: wemove@wemove.org
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Disorder/Syndrome
Phenotype*
Inheritance
NPCA with or without cerebellar hypoplasia
Early hypotonia
Delayed motor and speech development
Autosomal recessive
Autosomal dominant
X linked recessive
Sporadic
NPCA with posterior fossa malformations (eg, Dandy Walker syndrome)
Variable association with hydrocephalus
Delays in motor development
Cognitive delay
N/A
Ataxia syndromes, multiple congenital anomalies, and cerebellar hypoplasia (eg, Joubert syndrome, Varadi syndrome, COACH syndrome)
Encephalo-oculo-hepato-renal anomalies with recognized association patterns of anomalies
Autosomal recessive
Autosomal dominant
X linked
Ataxia syndromes with cerebellar hypoplasia (eg, Gillespie syndrome)
Partial aniridia
Hypogonadotrophic hypogonadism
External exophthalmoplegia
Autosomal recessive
*Gait ataxia is a constant feature.
Disorder/Syndrome
Phenotype*
Inheritance
Gene Locus
Gene Product/Biochemical Defect
EA1
Intermittent ataxia
Autosomal dominant
12q13
Missense point mutations affecting the voltage-gated potassium channel (KCNA1)
EA2
Intermittent ataxia
Autosomal dominant
19q13
Point mutations or deletions allelic with SCA6 and familial hemiplegic migraine
Altered calcium channel function
EA2
Intermittent ataxia
Autosomal dominant
2q22-q23
Voltage-dependent L-type calcium channel, beta subunit
EA3
Intermittent ataxia with vertigo and tinnitus
Autosomal dominant
1q42
Not identified
Disorder/Syndrome
Phenotype*
Inheritance
Gene Locus
Gene Product/Biochemical Defect
Maple syrup urine disease
Intermittent ataxia
Autosomal recessive
19q13.2
Mutations affect the E1 alpha subunit of branched-chain alpha-keto dehydrogenase complex that catalyzes the conversion of alpha keto acids to acyl-CoA and carbon dioxide
Hartnup disease
Intermittent ataxia
Autosomal recessive
11q13
Abnormality in the intestinal and renal transport of neutral alpha amino acids
Pyruvate dehydrogenase deficiency
Intermittent ataxia
Lactic acidosis
X-linked recessive
Xp22.2-p22.1
Defective E1 component of the PDH complex
Pyruvate carboxylase deficiency
Intermittent ataxia
Lactic acidosis
Autosomal recessive
11q13.4-q13.5
N/A
Defects of mitochondrial fatty acid beta-oxidation
Intermittent ataxia
Metabolic acidosis
Elevated ammonia
Autosomal recessive
N/A
Multiple defects affecting different acyl-CoA dehydrogenases
Late-onset urea cycle defects
Argininosuccinic acidemia
Carbamyl phosphate synthetase deficiency
Citrullinemia
Ornithine transcarbamoylase deficiency
Argininemia
Intermittent ataxia
Episodic encephalopathy
Autosomal recessive
7q21.3-q22 (arginosuccinate lyase)
2q33-q36 (carbamoyl-phosphate synthetase I)
9q34 (arginosuccinate synthetase)
Xp21.1 (ornithine carbamoyltransferase)
6q23 (arginase)
N/A
Autosomal Dominant Ataxias
Neurologic Phenotype
(Gait ataxia is a constant feature)
Triplet Repeat Size
Gene Locus/Gene Product
Spinocerebellar ataxia
(SCA1)
Peripheral neuropathy
Pyramidal signs
Ophthalmoparesis
CAG expansion 39-83 (6-36 normal range)
6p23
Ataxin-1
(ATXN1)
Spinocerebellar ataxia
(SCA2)
Abnormal ocular saccades
Hyporeflexia
Dementia
Peripheral neuropathy, less frequent
Extrapyramidal findings
CAG expansion 34-400 (15-31 normal range)
12q24.1
Ataxin-2
(ATXN2)
Spinocerebellar ataxia
(SCA3/MJ disease)
Pyramidal, extrapyramidal, and ocular movement abnormalities
Amyotrophy
Sensory neuropathy
“Bulging eyes” (eyelid retraction)
CAG expansion 53-86 (≤47 normal range)
14q21
Ataxin-3
(ATXN3)
Spinocerebellar ataxia
(SCA4)
Sensory axonal neuropathy
Pyramidal signs
—
16q22.1
Secretory carrier-associated membrane protein 4 (SCA4)
Spinocerebellar ataxia
(SCA5)
Early onset, relatively pure cerebellar ataxia with dysarthria
Slow progression
—
11p13
Mutation in SPTBN2 gene
Spinocerebellar ataxia
(SCA6)
Slowly progressive, pure cerebellar ataxia with dysarthria, nystagmus
Occasional mild sensory loss
CAG expansion 20-33 (≤18 normal range)
19p13
Altered a1A subunit of the voltage-dependent calcium channel (CACNA1A)
Spinocerebellar ataxia
(SCA7)
Visual loss, retinal degeneration
Dysarthria
Variable pyramidal signs
CAG expansion 37->300 (4-35 normal range)
3p14.1-p12
Ataxin-7
Spinocerebellar ataxia
(SCA8)
Hyperreflexia, spasticity
Impaired vibration sense
CTG expansion 100-250 (15-52 normal range)
13q21
KLHL1AS
Spinocerebellar ataxia
(SCA9)
SCA9 has not yet been characterized.
—
—
Spinocerebellar ataxia
(SCA10)
Frequent seizures
Neuropathy
ATTCT expansion
280->4500 (10-22 normal range)
22q13
Ataxin-10
(ATXN10)
Spinocerebellar ataxia
(SCA11)
Rare
Slowly progressive mild ataxia
—
15q14-q21.3
SCA11
Spinocerebellar ataxia
(SCA12)
Tremor at onset
Late dementia
Noncoding CAG expansion 51-78 (7-31 normal range)
5q31
Serine
Threonine
Protein phosphatase 2A (PPP2R2B)
Spinocerebellar ataxia
(SCA13)
Childhood onset
Associated cognitive delay
Short stature
—
19q13.3- q14.4
KCNC3 gene
Spinocerebellar ataxia (SCA14)
Facial myokymia
Eye movement abnormalities
Axial myoclonus, dystonia, vibratory loss
Late onset can be pure ataxia
—
19q13.4
Protein kinase C gamma type (PRKC)
Spinocerebellar ataxia
(SCA15/SCA 16)
Pure ataxia with slow progression
Tremor
Mutations or deletions on ITPR1 gene
3p26.1
Spinocerebellar ataxia (SCA17)
Ataxia
Pyramidal and extrapyramidal signs
Dementia
Widespread cerebellar and cerebral atrophy
CAG expansion 45-63 (25-42 repeats normal range)
6q27
TATA-box binding protein
Spinocerebellar ataxia (SCA18)
Ataxia
Sensorimotor neuropathy
—
7q22-q32
Spinocerebellar ataxia
(SCA19)
Slowly progressive ataxia
Hyporeflexia
Cognitive decline
Myoclonus tremor
—
1p21-q21
Spinocerebellar ataxia (SCA20)
Dysarthria
Dystonia
Calcification of dentate nucleus
Palatal tremor
—
11p13-q11
Spinocerebellar ataxia
(SCA21)
Mild ataxia
Cognitive delay
Extrapyramidal features
Hyporeflexia
—
7p21-p15.1
Spinocerebellar ataxia (SCA22)
Gradual onset, slow progression pure ataxia, nystagmus, and dysarthria
—
1p21-q23
Spinocerebellar ataxia (SCA23)
Ataxia of late onset, slow progression
Sensory loss
Vibration loss
—
20p13-p12.3
Spinocerebellar ataxia(SCA24)
Renamed autosomal recessive cerebellar ataxia 4 (SCAR4)
—
—
Spinocerebellar ataxia (SCA25)
Severe sensory neuropathy
Gastrointestinal symptoms
—
2p21-q15
Spinocerebellar ataxia
(SCA26)
Dysarthria
Ocular pursuit abnormalities
—
19p13.3
Spinocerebellar ataxia (SCA27)
Gait and limb ataxia, tremors
Orofacial dyskinesias
Behavioral outbursts
Fibroblast growth factor 14–related truncating mutations
13q34
Spinocerebellar ataxia (SCA28)
Ophthalmoparesis
Hyperreflexia
—
18p11.22-q11.2
Spinocerebellar ataxia (SCA29)
Early onset, nonprogressive ataxia
Vermian hypoplasia
—
18p11.22-q11.2
Spinocerebellar ataxia(SCA30)
Dysarthria
Lower limb hyperreflexia
Hypermetric saccades
—
4q34.3-q35.1
Spinocerebellar ataxia (SCA31)
Late-onset ataxia
Hearing loss
Slowly progressive gait and limb ataxia
Cerebellar dysarthria,
Decreased muscle tone
Horizontal gaze nystagmus
Cerebellar atrophy
2.5-kb to 3.8-kb insertion containing pentanucleotide repeats including (TGGAA)n within an intron of the BEAN gene (612051)
16q21-q22
Spinocerebellar ataxia (SCA32)
Variable cognitive impairment, and azoospermia in males
—
7q32-q33
Spinocerebellar ataxia (SCA34)
Ichthyosiform skin lesions
—
6p12.3-q16.2
Spinocerebellar ataxia (SCA35)
Upper limb involvement and torticollis
—
20p13
Mutation in the TGM6 gene
Spinocerebellar ataxia (SCA36)
Truncal instability
Dysarthria
Dysdiadochokinesis
Hyperreflexia
Impaired smooth pursuit and horizontal gaze nystagmus,
Dysphagia
GGCCTG hexanucleotide repeat. affected individuals carry 1,500-2,000 repeats
NOP56 gene on chromosome 20p13
Dentatorubropallidoluysian atrophy (DRPLA)
Chorea
Seizures
Myoclonus
Dementia
Triplet repeat expansion leads to altered protein product
12p13.31
Atrophin-1 with toxic gain of function
*Gait ataxia is a constant feature
Disorder/Syndrome
Neurologic Phenotype
Inheritance
Gene Locus
Gene Product/Biochemical Defect
Ataxia with selective vitamin E deficiency
Chronic ataxia
Autosomal recessive
8q13.1-q13.3
Mutated alpha-tocopherol transfer protein (ATTP) binds alpha-tocopherol, enhancing its transfer between separate membranes
Vitamin E likely has a role in preventing modification of lipoproteins by oxidative stress
Friedreich ataxia
Progressive ataxia plus
Autosomal recessive
9q13-q21.1
Expansion of GAA triplet repeats leads to a defective protein frataxin, abnormal mitochondrial function, oxidative stress, and accumulation of iron
Abetalipoproteinemia
Progressive ataxia plus
Autosomal recessive
4q24
MTP catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces and is also required for the secretion of plasma lipoproteins that contain Apo-B
Defects in the transfer protein result in loss of ability to produce Apo-B–containing lipoproteins with secondary malabsorption of vitamin E
Hypobetalipoproteinemia*
Chronic ataxia
Autosomal dominant
2q24
In the homozygous state, affected individuals are indistinguishable from those with abetalipoproteinemia
Defective Apo-B, VLDL, and LDL result in hypocholesterolemia
*Listed here due to overlap of clinical features with abetalipoproteinemia.
Disorder/Syndrome
Neurologic Phenotype
Inheritance
Gene Locus
Gene Product/Biochemical Defect
Cockayne syndrome type A
Progressive ataxia plus
Early onset severe syndrome
Autosomal recessive
5q11
ERCC8
Cockayne syndrome type B
Progressive ataxia plus
Classical type
Autosomal dominant
10q11-q21
ERCC6
Xeroderma pigmentosum
Progressive ataxia plus
Autosomal recessive
Genetically heterogeneous with several complementation groups identified
9q34 locus (A)
Other complementation groups involved are 2q21 (B & CS); 3p25.1 (C); 19q13.2(D); Unknown (E); 16p13 (F); 13q32-33 (G & CS)
Mutations result in either defective damage-specific DNA-binding protein or defective excision repair (ERCC)
Neurologic manifestations beginning in childhood relate to complementation group
Ataxia
Telangiectasia
Progressive ataxia plus
Autosomal recessive
11q22-q23
ATM gene
Product belongs to the P-13 kinase family of proteins involved in DNA damage recognition
Ataxia with oculomotor apraxia type 1 (AOA1)
FRDA-like hypoalbuminemia
Autosomal recessive
9p13.3
Aprataxin (APTX)
Role in single-stranded DNA repair
Ataxia with oculomotor apraxia type 2 (AOA2)
Changed to autosomal recessive cerebellar ataxia (SCAR1)
Ocular apraxia is an inconsistent feature.
Ataxia
Distal amyotrophy
Peripheral neuropathy
Autosomal recessive
9q34
Senataxin (SETX)
Protein involved in RNA maturation and termination
Disorder/Syndrome
Neurologic Phenotype
Inheritance
Gene Locus
Gene Product/Biochemical Defect
Autosomal recessive spastic ataxia of Charlevoix-Saguenay
Chronic ataxia
Spasticity
Retinal
abnormalities
Autosomal recessive
13q11
SACS gene codes for sacsin, which is involved in chaperone-mediated protein folding
Leukoencephalopathy with VWM
Progressive ataxia
Spasticity
Optic atrophy
Seizures
Autosomal recessive
3q27
Mutations affect eIF2B
4H syndrome
Short stature
Slowly progressive ataxia
Hypogonadism
Hypomyelination
hypodontia
Autosomal recessive
Not known
Not known
Disorder/Syndrome
Neurologic Phenotype
Inheritance
Gene Locus
Gene Product/Biochemical Defect
Refsum disease
Progressive ataxia plus
Autosomal recessive
10pter-p11.2
Mutations affecting the gene coding for phytanoyl-CoA hydroxylase
Cerebrotendinous xanthomatosis
Chronic progressive ataxia
Autosomal recessive
2q3-qter
Defective mitochondrial cytochrome-P450 sterol27-hydroxylase CYP-27A1 leading to accumulation of plasma cholestanol
Biotinidase deficiency
Progressive ataxia plus
Autosomal recessive
3q25
Deletions resulting in multiple carboxylase deficiency and impaired release of biotin from biocytin, the product of biotin-dependent carboxylase degradation
L-2 hydroxyglutaric acidemia
Chronic progressive ataxia
Autosomal recessive
Unknown locus
Deficiency of hepatic hydroxyglutaric acid dehydrogenase
Succinic-semialdehyde dehydrogenase deficiency
Progressive ataxia plus
Autosomal recessive
6p22
Deficiency of succinic semialdehyde dehydrogenase
Accumulation of 4-hydroxybutyric acid in plasma and urine
Late infantile and juvenile sphingolipidoses
1. Metachromatic leukodystrophy
2. Krabbe globoid cell leukodystrophy
3. Gaucher type III
4. Niemann-Pick C disease
5. GM2 gangliosidosis
Progressive ataxia plus
Seizures
Psychomotor regression
Spasticity
Extrapyramidal features
Supranuclear gaze palsies
Autosomal recessive
1. 22q13.3-qter/
2. 14q31
3. 1q21 18q11-q12
4. 15q23-q24
1. Deficiency of arylsulfatase A/sphingolipid activator Protein (SAP)
2. Deficiency of galactosylceramide beta-galactosidase
3. Deficiency of beta-glucocerebrosidase
4. Abnormal uptake of cholesterol and defective esterification leading abnormal cholesterol ester storage
5. Defect in hexoaminidase A or of the GM2 protein activator
Congenital disorders of glycosylation type Ia
Progressive ataxia plus
Autosomal recessive
16p13.3-p13.2
Mutations in the gene encoding for phosphomannomutase
Marinesco-Sjögren syndrome
Chronic ataxia
Cataract
Hypotonia
Myopathy
Autosomal recessive
5q31
Disturbed SIL1 and HSP70 chaperone HSPA5 protein folding interaction
Disorder/Syndrome
Neurologic Phenotype
Inheritance
Gene Product/Biochemical Defect
NARP syndrome
Progressive ataxia plus
Maternal inheritance
Mitochondrial ATP 6 NARP 8993 mutation causing base substitution T-G or T-C at nucleotide position 8993
Leigh disease
Progressive ataxia plus
Lactic acidosis
Autosomal recessive/maternal inheritance
Multiple biochemical and molecular defects underlie the condition, eg, PDHC deficiency, cytochrome oxidase C deficiency, mitochondrial ATPase 6
CoQ-10 responsive ataxia
Progressive ataxia in childhood
Developmental delay
Seizures
Cerebellar atrophy on MRI
Autosomal recessive
Mutations in the gene CABC1 or ADCK3 are described. The gene codes for a putative protein kinase associated with ubiquinone biosynthesis.
Type
Unverricht-Lundborg syndrome
Neurologic Phenotype
Inheritance
Locus
Gene Product/Biochemical Defect
Dodecamer repeat expansion
Unverricht-Lundborg syndrome
Myoclonus
Ataxia
Seizures
Autosomal recessive
21q22.2
Dodecamer repeat expansions affects gene for cystatin B
Inherited enzyme defect
Lafora body disease
Myoclonus
Ataxia
Seizures
Autosomal recessive
6q24
Mutation affects a gene encoding for a protein tyrosine phosphatase (laforin) that may disrupt glycogen metabolism
Inherited enzyme defect
Late infantile neuronal ceroid lipofuscinosis
Myoclonus
Ataxia
Seizures
Autosomal recessive
11p15.5
Gene codes for a lysosomal pepstatin insensitive protease
Mitochondrial cytopathy
MERRF
Myoclonus
Ataxia
Maternal inheritance
N/A
mt-DNA mutations affecting tRNALys
Defective oxidative phosphorylation
Fredy J Revilla, MD Neuroscience Associates, Greenville Health System
Fredy J Revilla, MD is a member of the following medical societies: American Academy of Neurology, International Parkinson and Movement Disorder Society, Society for Neuroscience
Disclosure: Nothing to disclose.
Ramya Raghavan Co-op Student, University of Cincinnati
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Florian P Thomas, MD, PhD, MA, MS Chair, Neuroscience Institute and Department of Neurology, Director, Multiple Sclerosis Center and Hereditary Neuropathy Centers, Hackensack University Medical Center; Founding Chair and Professor, Department of Neurology, Hackensack Meridian School of Medicine at Seton Hall University; Professor Emeritus, Department of Neurology, St Louis University School of Medicine; Editor-in-Chief, Journal of Spinal Cord Medicine
Florian P Thomas, MD, PhD, MA, MS is a member of the following medical societies: Academy of Spinal Cord Injury Professionals, American Academy of Neurology, American Neurological Association, Consortium of Multiple Sclerosis Centers, National Multiple Sclerosis Society, Sigma Xi
Disclosure: Nothing to disclose.
Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Acorda, Livanova, Eisai, Greenwich, Lundbeck, Neuropace, Sunovion, Upsher-Smith.<br/>Serve(d) as a speaker or a member of a speakers bureau for: Livanova, Eisai, Greenwich, Lundbeck, Neuropace, Sunovion.<br/>Received research grant from: Acorda, Livanova, Greenwich, Lundbeck, Sepracor, Sunovion, UCB, Upsher-Smith.
Rodrigo O Kuljis, MD Esther Lichtenstein Professor of Psychiatry and Neurology, Director, Division of Cognitive and Behavioral Neurology, Department of Neurology, University of Miami School of Medicine
Rodrigo O Kuljis, MD is a member of the following medical societies: American Academy of Neurology, Society for Neuroscience
Disclosure: Nothing to disclose.
Cheryl R Greenberg, MD Professor,Department of Pediatrics, Section of Medical Genetics, Children’s Hospital of Winnipeg, University of Manitoba Faculty of Medicine, Canada
Disclosure: Nothing to disclose.
Mandar S Jog MD Professor, Department of Neurology, University of Western Ontario; Director of Movement Disorders Program, London Health Sciences Centre, London, Ontario, Canada
Mandar S Jog is a member of the following medical societies: Movement Disorders Society, Royal College of Physicians and Surgeons of Canada, and Society for Neuroscience
Disclosure: Nothing to disclose.
Asuri Prasad, MBBS, MD, FRCPE, FRCPC Associate Professor, Department of Pediatrics and Clinical Neurosciences, Faculty of Medicine, University of Western Ontario; Consulting Staff, Children’s Hospital of Western Ontario
Asuri Prasad, MBBS, MD, FRCPE, FRCPC is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, Child Neurology Society, Royal College of Physicians, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.
Chitra Prasad, MD, FRCPC, FCCMG, FACMG Director of Metabolic Services, Children’s Hospital, London Health Sciences Centre; Associate Professor, Departments of Genetics, Metabolism and Pediatrics, University of Western Ontario School of Medicine, Canada
Chitra Prasad, MD, FRCPC, FCCMG, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Society of Human Genetics, Canadian Paediatric Society, Royal College of Physicians and Surgeons of Canada, and Society for Inherited Metabolic Disorders
Disclosure: no financial interest None None
Ataxia with Identified Genetic and Biochemical Defects
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