Overview of The Hereditary Ataxias

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Overview of the hereditary ataxias

Authors: Puneet Opal, MD, PhD, Huda Y Zoghbi, MD
Section Editors: Marc C Patterson, MD, FRACP, Helen V Firth, DM, FRCP, FMedSci
Deputy Editor: April F Eichler, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2021. | This topic last updated: Sep 30, 2021.
INTRODUCTION AND CLASSIFICATION
The hereditary ataxias are a genetically heterogeneous group of diseases that may be difficult to distinguish clinically because they are
all characterized by motor incoordination resulting from dysfunction of the cerebellum and its connections [1]. With the identification of
the gene defects in many of these disorders, the diagnosis now is made more often by genetic testing.
The hereditary ataxias have traditionally been divided into two main classes:
● Ataxia caused by underlying inborn errors of metabolism; these disorders usually are inherited in an autosomal recessive manner
and typically present in childhood.
● Progressive degenerative ataxias not due to inborn errors of metabolism. These disorders, which are more common, are divided by
their mode of inheritance into autosomal dominant, autosomal recessive, X-linked, and mitochondrial forms.
The hereditary ataxias caused by inborn errors of metabolism and the episodic, X-linked, and mitochondrial ataxias are discussed in this
topic.
The National Ataxia Foundation (www.ataxia.org), the Friedreich's Ataxia Research Alliance (www.curefa.org), and other nonprofit
organizations provide important information for patients and the larger public.
AUTOSOMAL DOMINANT ATAXIAS
The most common autosomal dominant ataxias are the spinocerebellar ataxias (SCAs). Other causes include dentatorubral-
pallidoluysian atrophy (DRPLA), which is common in Japan, and the ataxic variant of the Gerstmann-Sträussler-Scheinker syndrome, a
prion disease. These disorders are briefly reviewed here and discussed in detail separately. (See "The spinocerebellar ataxias".)
More than 40 types of SCA (and the number probably will continue to grow) with characteristic clinical and genetic abnormalities have
been identified. Some of these disorders are caused by trinucleotide (or, in SCA10, pentanucleotide) repeat expansion within the disease-
causing gene rather than by changes to protein function due to sequence alterations ( table 1).
The most common are cytosine-adenine-guanine (CAG) repeats in the coding region that encode for polyglutamine tracts in the protein
products, similar to that seen in Huntington disease. Expansion of CAG repeats is thought to produce a toxic "gain of function" (ie,
disease develops because the mutant form of the protein gains a new function, not because the protein loses its normal function). The
repeats show both somatic and germline instability. As a result, successive generations of affected families experience anticipation, a
phenomenon characterized by earlier onset and a progressively worse phenotype in subsequent generations.
AUTOSOMAL RECESSIVE ATAXIAS
The most common autosomal recessive cerebellar ataxias (ARCAs) are Friedreich ataxia and ataxia-telangiectasia [2]. These are
discussed separately. (See "Friedreich ataxia" and "Ataxia-telangiectasia".)
Less frequent causes are xeroderma pigmentosum and Cockayne syndrome, which, like ataxia-telangiectasia, are caused by defects in
DNA repair mechanisms. (See "Neuropathies associated with hereditary disorders", section on 'DNA repair disorders'.)
All of these disorders at some point have prominent nonneurologic manifestations, but Friedreich ataxia and ataxia-telangiectasia may
be confused in the early stages of the disease. The two disorders can be distinguished by genetic testing [3].
Many ataxias due to underlying inborn errors of metabolism are inherited in an autosomal recessive manner, and some are treatable
with early diagnosis and appropriate therapy. These are discussed below. (See 'Ataxias caused by inborn errors of metabolism' below.)
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X-LINKED ATAXIAS
X-linked progressive ataxias are a heterogeneous group of rare disorders. Some are pure cerebellar syndromes [4,5], while others
encompass additional neurologic abnormalities such as spasticity, deafness, intellectual disability, or dementia [6-9]. The genetic loci
remain unknown in most of these disorders, with the exception of an early-onset X-linked ataxia that is associated with deafness and
loss of vision and links to locus Xq21.2-q24 [8]. Although the X-linked diseases primarily are expressed in males, a small percentage of
females have some symptoms because of skewed inactivation of the X chromosome bearing the normal allele. Other patients have
ataxia combined with systemic abnormalities such as sideroblastic anemia and adrenal insufficiency.
X-linked sideroblastic anemia with ataxia — X-linked sideroblastic anemia with ataxia is a recessive disorder characterized by
relatively mild anemia, unresponsiveness to pyridoxine, and nonprogressive cerebellar ataxia [10,11]. (See "Sideroblastic anemias:
Diagnosis and management", section on 'X-linked sideroblastic anemias'.)
The molecular defect resides at Xq13 in the ATP binding cassette subfamily B member 7 (ABCB7) transporter gene. The role of the ABCB7
protein in erythroid cells and the proposed mechanisms by which ABCB7 mutation causes sideroblastic anemia are discussed in more
detail separately. (See "Causes and pathophysiology of the sideroblastic anemias", section on 'X-linked sideroblastic anemia with ataxia
(ABCB7 mutation)' and "Causes and pathophysiology of the sideroblastic anemias", section on 'Pathophysiology'.)
Adrenoleukodystrophy — Progressive ataxia and incoordination is an atypical presentation of adrenoleukodystrophy, an X-linked

recessive disorder characterized by progressive neurologic dysfunction and primary adrenal insufficiency. This disorder is discussed in
detail elsewhere. (See "X-linked adrenoleukodystrophy and adrenomyeloneuropathy", section on 'Other presentations'.)
MITOCHONDRIAL ATAXIAS
Certain mitochondrial disorders can present with a progressive or intermittent ataxia.
Leigh syndrome — Leigh syndrome (subacute necrotizing encephalomyelopathy) is an inherited neurodegenerative disorder of infancy
or childhood that is discussed in detail elsewhere. (See "Neuropathies associated with hereditary disorders", section on 'Leigh
syndrome'.)
Summarized briefly, this disorder is characterized by developmental delay or psychomotor regression, signs of brainstem dysfunction,
ataxia, dystonia, external ophthalmoplegia, seizures, lactic acidosis, vomiting, and weakness. Peripheral neuropathy with reduced nerve
conduction velocity and demyelination also are frequent findings. The prognosis is poor, with survival often being a matter of months
after disease onset. Histologic examination reveals bilateral, symmetric necrotizing lesions in the basal ganglia, thalamus, brainstem,
and spinal cord. Magnetic resonance imaging shows abnormal white matter signal in the putamen, basal ganglia, and brainstem with T2
images.
The Leigh syndrome phenotype appears to be related to altered mitochondrial metabolism. Alterations in the mitochondrial respiratory
chain complex I, pyruvate dehydrogenase complex (PDHC), or mitochondrial DNA (mtDNA) have been associated with autosomal, X-
linked, or mtDNA mutations (maternally inherited Leigh syndrome). A deficiency in cytochrome c oxidase (COX), the fourth multisubunit
complex of the respiratory chain, is a common finding that is inherited as an autosomal recessive trait. Mutations in SURF1, a gene
located on chromosome 9q34, have been identified in many COX-deficient patients with Leigh syndrome. (See "Neuropathies associated
with hereditary disorders", section on 'Leigh syndrome'.)
Ataxia and myoclonus — Ataxia and myoclonus can be produced by a variety of mitochondrial lesions. They include large deletions and
duplications characteristic of Kearns-Sayre syndrome and maternally inherited point mutations in mitochondrial genes encoding
transfer RNA (tRNA), the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), and the
MERRF syndrome (myoclonic epilepsy with ragged red fibers) [12-17]. In MELAS, for example, the genetic defect alters amino acid
incorporation into the subunits of the oxidative phosphorylation system that are synthesized in the mitochondria, resulting in altered
function [12]. In MERRF, on the other hand, an impairment in mitochondrial calcium homeostasis occurs [16].
ATAXIAS CAUSED BY INBORN ERRORS OF METABOLISM
Numerous hereditary ataxias appear to be caused by inborn errors of metabolism. These ataxias tend to have recessive inheritance, as
enzymatic activity of 50 percent in heterozygotes is sufficient for most metabolic pathways to proceed.
The metabolic pathways involved in these disorders typically have numerous functions. As a result, ataxia is just one component of the
clinical phenotype, which, taken as a whole, often points toward the underlying defect. The clinical phenotype can be divided into two
general groups: the intermittent ataxias that occur with exacerbations of the underlying biochemical abnormality and the chronic
progressive ataxias that are induced by specific enzyme deficiencies ( table 2). A review of the individual disorders is beyond the scope
of this discussion. Approximately 200 gene defects are recognized in the spectrum of autosomal recessive cerebellar ataxias (ARCAs) [2].
Intermittent ataxias — The most common causes of intermittent ataxias are the aminoacidurias resulting from mutations in urea cycle
enzymes, which lead to hyperammonemia and disorders of pyruvate and lactate metabolism ( table 2). Affected infants with all of
these conditions typically display intellectual disability and developmental delay. Nevertheless, establishing the correct diagnosis is
important because supportive measures differ.
Urea cycle enzyme deficiencies — Neonates with urea cycle enzyme deficiencies typically present with acute neurologic deterioration
and hypotonia. Older children may have clumsiness, vomiting, and headaches. In addition, seizures, involuntary movements, and ptosis
can occur at the peaks of hyperammonemia, usually induced by stress or ingestion of protein. Inheritance of urea cycle deficits is
autosomal recessive, with the important exception of the relatively common ornithine transcarbamylase (OTC) deficiency, which is X-
linked. However, some female carriers with OTC convert less ammonia nitrogen to urea and are symptomatic [18-20]. (See "Urea cycle
disorders: Clinical features and diagnosis".)
Aminoacidurias — Ataxia may be seen in children with aminoaciduria, such as intermittent branched-chain ketoaciduria and isovaleric
acidemia. This ataxic picture often is combined with seizures, episodic vomiting, and lethargy, similar to that seen in children with urea
cycle deficits. The urine usually has a characteristic odor.
Hartnup disease is a pathogenetically different cause of ataxia, resulting from a defect in renal and intestinal transport of neutral amino
acids rather than a metabolic defect. This disorder also is associated with niacin deficiency, often leading to symptoms of pellagra (such
as rash and confusion). Hartnup disease results from mutations in the solute carrier family 6 member 19 (SLC6A19) gene, which encodes
for a sodium-dependent neutral amino acid transporter that is primarily expressed in the kidney and intestine [21,22].
Disorders of pyruvate and lactate metabolism — Pyruvate dehydrogenase (PDH) deficiency, a less common cause of metabolic
intermittent ataxia, is characterized by lactic acidosis, seizures, intellectual disability, ataxia, and spasticity [23]. This condition typically is
caused by a mutation in PDHA1, the gene for the E1 alpha subunit of the PDH enzyme complex (Xp22.2-p22.1) [24]. Other less common
genetic defects associated with PDH deficiency have been reported, including mutations in the E1 beta [25], E2 [26], and E3 [27]
subunits; the E3 binding protein [28]; and the PDH phosphatase enzyme that regulates the PDH complex [29].
Biotin-responsive multiple carboxylase deficiency is an autosomal recessive ataxia, characterized by ketoacidosis, dermatitis, seizures,
myoclonus, and nystagmus [30]. The infantile form can be caused by a variety of mutations in the holocarboxylase synthetase gene at
locus 21q22 [30-32]. This enzyme catalyzes the fixation of biotin to inactive apocarboxylases, producing four active carboxylases
(including pyruvate carboxylase). In children with late-onset (usually juvenile) disease, the defect appears to lie in biotinidase, which
catalyzes the removal of biotin from the carboxylases, thereby generating biotin for reutilization [33,34]. The biotinidase gene is located
on chromosome 3p25 [35].
Diagnosis — Metabolic ataxias usually are diagnosed by screening biochemical tests when the neurologic abnormalities are first
noticed. Based on a positive family history, OTC deficiency and several of the hyperammonemias can be diagnosed from blood samples
taken in utero. PDH deficiency can, in addition, be corroborated by a relatively simple biochemical assay on cultured fibroblasts. Despite
the identification of individual gene defects, genetic testing, at least at present, is impractical because of the numerous mutations in the
relevant genes.
Therapy — Although the underlying defect usually cannot be corrected, many of the intermittent ataxias can be indirectly treated:
● Supportive therapy for the urea cycle disorders consists of hydration and dietary protein restriction. No treatment exists for the
underlying enzyme deficiency in these disorders except for liver transplantation or, perhaps in the future, hepatocyte
transplantation [36,37]. (See "Hepatocyte transplantation".)
● Treatment of the aminoacidurias consists of a high-protein diet. In addition, children with Hartnup disease are given niacin
(nicotinamide) supplementation.
● Among the disorders of pyruvate and lactate metabolism, PDH deficiency can be treated with a ketogenic diet [38] and
dichloroacetate, which increases the activity of PDH by stabilizing the mutant subunit [39,40]. Both infantile [41,42] and late-onset
multiple carboxylase deficiency can be treated with pharmacologic doses of biotin [34,43,44]. (See "Overview of water-soluble
vitamins", section on 'Biotin'.)
● Possible gene therapies are still experimental [45].
Progressive ataxias — Progressive ataxias induced by enzymatic or transporter deficiency can be seen in a variety of genetic diseases (
table 2). These disorders typically present in later childhood or adolescence, unlike the intermittent ataxias [2]. The probable
explanation for this difference is that cumulative damage must reach a threshold before the clinical signs appear.
Neurometabolic diseases predominate in this group, which includes Niemann-Pick disease type C, Wilson disease, metachromatic
leukodystrophy, neuronal ceroid lipofuscinosis, hexosaminidase deficiencies (eg, juvenile or late-onset Tay-Sachs disease), and
adrenoleukodystrophy/adrenomyeloneuropathy ( table 2). Some of these disorders are discussed in detail elsewhere. (See "Overview
of Niemann-Pick disease" and "Wilson disease: Epidemiology and pathogenesis" and "Metachromatic leukodystrophy" and "Neuronal
ceroid lipofuscinosis" and "X-linked adrenoleukodystrophy and adrenomyeloneuropathy", section on 'Adrenomyeloneuropathy'.)
The diagnosis of a particular neurometabolic disease is usually made from the clinical picture in conjunction with histopathologic
findings or biochemical tests. In adrenoleukodystrophy/adrenomyeloneuropathy, for example, the disease is suspected from the X-
linked inheritance and confirmed by elevated serum very long-chain fatty acid concentrations.
In Niemann-Pick disease type C, the diagnosis may be suspected based upon the finding of vertical supranuclear gaze palsy, which is
virtually always present in patients with Niemann-Pick disease type C and ataxia. Additional features include splenomegaly and large,
lipid-laden foam cells in bone marrow. In Wilson disease, important findings include hepatomegaly and Kayser-Fleischer rings on slit
lamp examination ( picture 1). (See "Overview of Niemann-Pick disease" and "Supranuclear disorders of gaze in children" and "Wilson
disease: Epidemiology and pathogenesis".)
Treatable diseases — No cure has been found for the ataxias induced by neurometabolic defects, but specific measures can at least
halt progression in a variety of disorders. Some examples are ataxia with vitamin E deficiency, cerebrotendinous xanthomatosis, Refsum
disease, and Wilson disease.
Ataxia with vitamin E deficiency — Vitamin E deficiency from a variety of causes (eg, malabsorption) can lead to ataxia [46,47].
Several hereditary ataxias also are associated with vitamin E deficiency. The neurologic injury in these disorders may be related to low
vitamin E content [48]. Ataxia with vitamin E deficiency is an autosomal recessive disease caused by mutations in the alpha tocopherol
transfer protein gene on chromosome 8q13.1 [49-51]. It can present as a slowly progressive ataxia syndrome with neuropathy that can
resemble Friedreich ataxia. In addition, some patients develop retinitis pigmentosa [52,53]. High doses of vitamin E typically lead to
neurologic improvement, although recovery may be slow and incomplete [54]. Heterozygotes are phenotypically normal but have serum
vitamin E concentrations 25 percent lower than normal [50].
Hypovitaminosis E results from fat malabsorption in patients with abetalipoproteinemia, an autosomal recessive disorder also known as
Bassen-Kornzweig disease. The disease is caused by mutations in the microsomal triglyceride transfer protein gene [55]. Defective
assembly and secretion of apolipoprotein B (apo B) and apo-B-containing lipoproteins leads to impaired fat absorption, very low serum
concentrations of cholesterol and triglyceride, and absent serum beta lipoprotein. The neurologic manifestations include progressive
retinal degeneration (caused by coexisting vitamin A deficiency), peripheral neuropathy, and ataxia. Supplementation with vitamin E and
the other fat-soluble vitamins early in the clinical course may improve the neuropathy and retinopathy. (See "Neuroacanthocytosis",
section on 'Abetalipoproteinemia'.)
A similar autosomal recessive ataxic syndrome with vitamin E deficiency occurs in patients with familial hypobetalipoproteinemia in
which a mutation in the apo B gene is present [56,57]. Interestingly, some mutations produce no symptoms and are associated with
normal serum vitamin E concentrations [57].
Cerebrotendinous xanthomatosis — Cerebrotendinous xanthomatosis is a relatively rare autosomal recessive cause of

progressive ataxia. It is characterized by a block in bile acid synthesis caused by mutations in the mitochondrial sterol 27-hydroxylase
gene on chromosome 2q33. The clinical manifestations include ataxia, neuropathy, cataracts, Achilles tendon xanthomas, and
accelerated atherosclerosis. The diagnosis is suggested by elevated serum cholestanol in the presence of normal serum cholesterol and
can be confirmed by genetic testing. Cholestanol is thought to be responsible for the neurologic toxicity. Treatment with
chenodeoxycholic acid can markedly reduce both serum and cerebrospinal fluid cholestanol and appears to halt progression of the
disease. It should be started early because improvement in established disease is uncommon. (See "Cerebrotendinous xanthomatosis".)
Refsum disease — Refsum disease is another treatable progressive ataxia. It should be suspected when a patient with autosomal
recessive ataxia presents with the additional triad of ichthyosis, retinitis pigmentosa, and neuropathy. Patients with classic Refsum
disease are unable to degrade phytanic acid due to deficient activity of phytanoyl-CoA hydroxylase (PhyH) caused by mutations in the
PHYH gene. Strict reduction in dietary phytanic acid intake may be associated with a significant improvement in both the peripheral
neuropathy and ataxia. (See "Peroxisomal disorders", section on 'Refsum disease'.)
Wilson disease — The majority of patients with neurologic Wilson disease have symptoms that fall into one of several categories:
dysarthric, dystonic, tremulous, pseudosclerotic (tremor with or without dysarthria), or parkinsonian (see "Wilson disease: Clinical
manifestations, diagnosis, and natural history", section on 'Neurologic manifestations'). Initially, only one symptom may be present
(often unilaterally), but as the disease progresses, complex combinations of neurologic signs and symptoms may develop. Cerebellar
ataxia is generally not the sole neurologic manifestation of Wilson disease. The ataxia is typically not clinically relevant, and frank limb
ataxia is uncommon.
Wilson disease is associated with tissue copper accumulation caused by mutations in the gene for ATP7B, a copper transporting ATPase
(see "Wilson disease: Epidemiology and pathogenesis"). Symptomatic patients are treated with a chelating agent (penicillamine or
trientine) until stable. Trientine may be preferred in patients with neurologic symptoms, since it appears to be less likely to exacerbate
them. (See "Wilson disease: Treatment and prognosis".)
EPISODIC ATAXIAS
There are seven varieties of dominantly inherited episodic ataxias (EAs), called EA1 through EA7. Of these, EA1 and EA2 account for the
majority of reported cases [58]. The diagnosis of EA is typically made based upon the history and clinical features. Molecular genetic
testing is clinically available for some of these disorders [59]. Both EA1 and EA2 respond to treatment with acetazolamide (250 to 750
mg/day) [60-64], and EA2 responds to dalfampridine as discussed below.
Episodic ataxia type 1 — EA1 is characterized by persistent myokymia (rippling of muscles) with brief episodes of cerebellar dysfunction
consisting of gait unsteadiness, limb ataxia, dysarthria, titubation, nystagmus, or tremor lasting for only a few minutes [10,65-67]. These
spells can be induced by triggers that include physical activity or exercise, stress, environmental temperature, startle, postural change,
emotion, hunger, alcohol, intercurrent illness, or caffeine [68]. Most affected individuals have normal or near-normal neurologic function
between attacks. However, persistent cerebellar dysfunction and hearing impairment have been reported [65,66]. Disease onset is
usually in childhood or adolescence.
The genetic basis for EA1 is the presence of point mutations in a voltage-gated potassium channel gene, KCNA1, located on chromosome
12p13 [69,70]. Molecular genetic testing for KCNA1 mutations is clinically available [67,71]. Typically, the only pathological correlate is
minimal atrophy of the anterior cerebellar vermis.
Episodic ataxia type 2 — Patients with EA2 have prolonged attacks of ataxia that can last from a few hours to a few days [72]. Severe
vertigo, nausea, and vomiting often are part of the attacks, and gaze-evoked, rebound, or downbeat nystagmus may be evident not only
during but also between attacks [62]. These episodes appear to produce cumulative cerebellar injury, as patients often develop
persistent cerebellar symptoms and cerebellar atrophy [73]. Thus, subtle cerebellar signs, such as nystagmus and mild clumsiness, and
the longer duration of episodes suggest EA2 rather than EA1. The manifestations and rate of progression are variable but usually
relatively uniform within a kindred [62]. As with EA1, disease onset is usually late childhood or adolescence.
EA2 is caused by mutations in the CACNA1A gene that encodes the alpha-1A subunit of a brain-specific P/Q-type calcium channel [74-77]
or, in one family, in the gene for the beta-4 subunit of this channel [78]. The alpha-1A subunit mutation also can occur de novo [63].
Mutations in the P/Q calcium channel may cause episodic ataxia in EA2 by reducing calcium-dependent neurotransmitter release in
cerebellar Purkinje cells [79]. Molecular genetic testing for CACNA1A mutations is clinically available [80].
As noted above, acetazolamide is often effective for reducing the frequency of attacks. In addition, the potassium channel blocker
dalfampridine (4-aminopyridine) is beneficial, as shown in a randomized controlled trial of 10 patients with EA, including 7 patients with
CACNA1A mutations; dalfampridine (5 mg three times a day) was significantly more effective for reducing attack frequency than placebo
[81]. In an earlier pilot study, dalfampridine completely prevented attacks of ataxia in two patients and markedly reduced attacks in one
[82]. Two of these patients had previously developed an increased frequency of attacks despite treatment with acetazolamide. The
proposed mechanism of dalfampridine is increased excitability of cerebellar Purkinje cells with subsequent increased release of the
inhibitory neurotransmitter gamma-aminobutyric acid (GABA) [82]. No trials have compared dalfampridine with acetazolamide in EA2.
Episodic ataxia types 3 to 7
● Episodic ataxia type 3 – Patients with EA3 (originally designated as EA4) have recurrent, brief (minutes long) attacks of vestibular
ataxia, vertigo, tinnitus, and interictal myokymia [64]. The age of onset is variable. The attacks appear to be responsive to
acetazolamide. Genome-wide screening suggests linkage to chromosome 1q42 [83].
● Episodic ataxia type 4 – Patients with EA4 (previously designated as EA3 and also known as periodic vestibulocerebellar ataxia) have
recurrent attacks of vertigo, diplopia, tinnitus, and ataxia beginning in early adulthood [64,84]. Ocular manifestations include
defective smooth pursuit and gaze-evoked nystagmus [85]. Unlike the other EAs, this form appears to be unresponsive to
acetazolamide.
● Episodic ataxia type 5 – EA5 has clinical features similar to those of EA2, with attacks lasting hours [86]. EA5 is caused by a mutation
in the calcium voltage-gated channel auxiliary subunit beta 4 (CACNB4) gene on chromosome 2q22-23; the same mutation was
identified in another family with generalized epilepsy but no ataxia [78].
● Episodic ataxia type 6 – EA6 is caused by a heterozygous mutation in the SLC1A3 gene, a member of the solute carrier family that
encodes excitatory amino acid transporter 1 (EAAT1), and was identified in an adolescent patient with EA, seizures, migraine, and
alternating hemiplegia [87]. Another SLC1A3 mutation was found in three family members who had EA but no seizures, migraine, or
alternating hemiplegia [88].
● Episodic ataxia type 7 – EA7 was identified in a single family and has clinical features similar to those of EA2, with the exception that
neurologic examination is normal between attacks [89]. Linkage analysis suggested chromosome 19q13 as the gene locus.
Overlap with other paroxysmal neurologic disorders — Mutations in genes encoding ion channels, ion pumps, and glutamate
transporters have been associated with EAs, familial hemiplegic migraine (FHM), seizures, and spinocerebellar ataxia (SCA). The following
observations have been made:
● Different mutations in the CACNA1A gene encoding the alpha-1A subunit of the P/Q type calcium channel have been identified in
EA2, FHM type 1, and SCA type 6.
● Some patients with EA2 have episodic hemiplegia that may be associated with migraine headaches [90].
● Co-occurrence of FHM with childhood epilepsy and cerebellar ataxia in a single family with a CACNA1A mutation has been reported
[91].
● As mentioned above in the discussion of EA6, a heterozygous mutation in the SLC1A3 gene was identified in a single adolescent
patient with EA, seizures, migraine, and alternating hemiplegia [87]
● EA, FHM, and SCA are often associated with cerebellar atrophy.
Disturbances of neuronal excitability may be the underlying mechanism causing these different clinical manifestations. (See "Hemiplegic
migraine", section on 'Familial hemiplegic migraine' and "The spinocerebellar ataxias".)
OTHER DISORDERS WITH ATAXIA AND MYOCLONUS
Unverricht-Lundborg disease — Unverricht-Lundborg disease (ULD) is one form of progressive myoclonus epilepsy that is
characterized by myoclonic seizures and progressive ataxia. ULD is discussed separately. (See "Hyperkinetic movement disorders in
children", section on 'Unverricht-Lundborg disease'.)
Sialidosis — Sialidosis (neuraminidase deficiency, mucolipidosis type I) is an autosomal recessive disorder characterized by a defect in
the sialidase (neuraminidase) gene on chromosome 6p21.3 [92]. Two main clinical variants of sialidosis have been described:
● Sialidosis type I is characterized by late onset with myoclonus and bilateral macular cherry-red spots.
● Sialidosis type II is characterized by infantile onset with skeletal dysplasia, intellectual disability, and hepatosplenomegaly.
SUMMARY
● The hereditary ataxias are a genetically heterogeneous group of diseases that are characterized by motor incoordination resulting
from dysfunction of the cerebellum and its connections. The hereditary ataxias have traditionally been divided into those caused by
underlying inborn errors of metabolism (generally autosomal recessive) and progressive ataxias not due to inborn errors of
metabolism. (See 'Introduction and classification' above.)
● The most common autosomal dominant ataxias are the spinocerebellar ataxias (SCAs) ( table 1). Other causes include
dentatorubral-pallidoluysian atrophy (DRPLA) and the ataxic variant of the Gerstmann-Sträussler-Scheinker syndrome. (See
'Autosomal dominant ataxias' above and "The spinocerebellar ataxias".)
● The most common autosomal recessive ataxias are Friedreich ataxia and ataxia-telangiectasia. Less frequent causes are xeroderma
pigmentosum and Cockayne syndrome, which, like ataxia-telangiectasia, are caused by defects in DNA repair mechanisms. (See
'Autosomal recessive ataxias' above.)
● X-linked progressive ataxias are a heterogeneous group of rare disorders. Some are pure cerebellar syndromes, while others
encompass additional neurologic abnormalities such as spasticity, deafness, intellectual disability, or dementia. (See 'X-linked
ataxias' above.)
● Certain mitochondrial disorders can present with a progressive or intermittent ataxia. (See 'Mitochondrial ataxias' above.)
● Numerous hereditary ataxias appear to be caused by inborn errors of metabolism. These ataxias tend to have recessive
inheritance, as enzymatic activity of 50 percent in heterozygotes is sufficient for most metabolic pathways to proceed (see 'Ataxias
caused by inborn errors of metabolism' above):
• The most common causes of intermittent ataxias are the aminoacidurias resulting from mutations in urea cycle enzymes, which
lead to hyperammonemia, and disorders of pyruvate and lactate metabolism ( table 2). (See 'Intermittent ataxias' above.)
• Progressive ataxias induced by catalytic deficiency can be seen in a variety of diseases. Storage diseases predominate in this
group and include Niemann-Pick disease type C, Wilson disease, metachromatic leukodystrophy, the heterogeneous ceroid
lipofuscinosis and hexosaminidase deficiencies, and adrenoleukodystrophy/adrenomyeloneuropathy ( table 2). (See
'Progressive ataxias' above.)
● There are seven varieties of dominantly inherited episodic ataxias (EAs), called EA1 through EA7. Of these, EA1 and EA2 account for
the majority of reported cases. The diagnosis of EA is typically made based upon the history and clinical features. Molecular genetic
testing is clinically available for some of these disorders. Both EA1 and EA2 respond to treatment with acetazolamide (250 to 750
mg/day). (See 'Episodic ataxias' above.)
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Topic 6234 Version 28.0
GRAPHICS
Characteristics of the autosomal dominant spinocerebellar ataxias
Disorder Distinguishing features Gene locus and protein

SCA1 Pyramidal signs, peripheral neuropathy ATXN1 CAG repeat, ataxin-1
SCA2 Slow saccades; less often myoclonus, areflexia ATXN2 CAG repeat, ataxin-2
SCA3 (MJD) Slow saccades, persistent stare, extrapyramidal ATXN3 CAG repeat, ataxin-3 (MJD1)
signs, peripheral neuropathy
SCA4 Sensory neuropathy 16q22.1
SCA5 Early onset but slow progression SPTBN2 Beta III spectrin
SCA6 May have very late onset, mild, may lack family CACNA1A CAG repeat, alpha 1A P/Q calcium channel subunit
history, nystagmus
SCA7 Macular degeneration ATXN7 CAG repeat, ataxin-7
SCA8 Mild disease ATXN8 CTG*CAG repeat
ATXN8OS
SCA9 Not assigned
SCA10 Generalized or complex partial seizures ATXN10 ATTCT repeat, ataxin-10
SCA11 Mild disease TTBK2 Tau tubulin kinase-2
SCA12 Tremor, dementia PPP2R2B CAG repeat in 5' region, protein phosphatase 2A
SCA13 Intellectual disability KCNC3 Voltage gated potassium channel KCNC3
SCA14 Intermittent myoclonus with early onset disease PRKCG Protein kinase C gamma
SCA15/16 Slowly progressive ITPR1 Inositol 1,4,5-triphosphate receptor 1
SCA17 Gait ataxia, dementia TBP CAG repeats, TATA binding protein
SCA18 Pyramidal signs, weakness, sensory axonal 7q22-q32

neuropathy
SCA19/22 Predominantly cerebellar syndrome, sometimes KCND3 gene Voltage-gated potassium channel Kv4.3
with cognitive impairment or myoclonus
SCA20 Palatal tremor and dysphonia 11q12
SCA21 Mild to severe cognitive impairment TMEM240 Transmembrane protein 240
SCA23 Distal sensory deficits PDYN Prodynorphin
SCA24 Recessive inheritance; redesignated as SCAR4 1p36
SCA25 Sensory neuropathy, facial tics, gastrointestinal 2p21-p13

symptoms
SCA26 Pure cerebellar ataxia EEF2 Eukaryotic translation elongation factor 2
SCA27 Cognitive impairment FGF14 Fibroblast growth factor 14
SCA28 Ophthalmoparesis and ptosis AFG3L2 Catalytic subunit of the mitochondrial AAA protease
SCA29 Early onset, nonprogressive ataxia; may be an 3p26

allelic variant of SCA15
SCA30 Slowly progressive, relatively pure ataxia 4q34.3-q35.1
SCA31 Decreased muscle tone BEAN (TGGAA)n repeat
SCA32 Cognitive impairment, affected males with 7q32-q33

azoospermia and testicular atrophy
SCA33 Not assigned
SCA34 Skin lesions consisting of papulosquamous ELOVL4 ELOVL fatty acid elongase 4
erythematous ichthyosiform plaques
SCA35 Late onset, slowly progressive gait and limb ataxia TGM6 Transglutaminase 6
SCA36 Late onset, truncal ataxia, dysarthria, variable NOP56 GGCCTG repeat
motor neuron disease and sensorineural hearing
loss
SCA37 Late onset, falls, dysarthria, clumsiness, abnormal 1p32

vertical eye movements
SCA38 Slowly progressive pure cerebellar phenotype ELOVL5 ELOVL fatty acid elongase 5
SCA39 Not assigned
SCA40 Hyperreflexia and spasticity CCDC88 Coiled-coil domain-containing 88C
SCA42 Early motor delay, hypotonia, speech delay, severe CACNA1G Voltage-gated calcium channel subunit alpha 1G
intellectual disability, ataxia
SCA44 Ataxia, dysarthria, dysmetria, dysphagia GRM1 Metabotropic glutamate receptor 1
SCA45 Limb and gait ataxia, downbeat nystagmus, FAT2 Protocadherin Fat 2
dysarthria
SCA46 Neuropathy and sensory ataxia affecting lower PLD3 5'-3' exonuclease PLD3
limbs more than upper limbs, cerebellar atrophy
SCA47 Early-onset developmental disability, ataxia, PUM1 Pumilio homolog 1

seizure; later-onset ataxia, dysarthria, dysmetria
SCA48 Gait ataxia, cognitive dysfunction in adulthood STUB1 CHIP, an E3 ubiquitin-protein ligase
DRPLA Chorea, seizures, myoclonus, dementia ATN1 CAG repeat, atrophin-1
SCA: spinocerebellar ataxia; MJD: Machado-Joseph disease; DRPLA: dentatorubral pallidoluysian atrophy.
Data from: Online Mendelian Inheritance in Man and Neuromuscular Disease Center, Washington University.
Graphic 74269 Version 12.0
Major causes of hereditary ataxias due to known enzymatic defects
Disorder Gene locus and protein
Intermittent ataxias
Hyperammonemias and aminoacidurias
Ornithine transcarbamylase deficiency Xp21.1 Ornithine transcarbamylase
Citrullinemia 9q34 Arginosuccinate synthetase
Arginase deficiency 6q23 Arginase
Argininosuccinic aciduria 7cen-q11 Arginosuccinate lyase
Hyperornithemia-hyperammonemia- homocitrullinuria syndrome 13q14 Mitochondrial ornithine transporter
Hartnup disease 5p15.33 Neutral amino acid transporter
Isovaleric acidemia 15q14 Isovaleric acid CoA dehydrogenase
Disorders of pyruvate and lactate metabolism
Pyruvate dehydrogenase complex Xp22.2 (most common) E1-alpha subunit (most common)
Multiple carboxylase deficiency 21q22 Holocarboxylase synthetase
Progressive ataxias
Tay-Sachs disease 15q23-q24 Alpha subunit of hexosaminidase A
Sandhoff disease 15q13 Beta subunit of hexosaminidase A and B
Niemann-Pick type A and B 11p15.4-p15.1 Acid sphingomyelinase
Niemann-Pick type C 18q11-q12 NPC1
14q24.3 NPC2
Metachromatic leukodystrophy 22q13 Arylsulfatase A
Adrenomyeloneuropathy Xq28 Adrenoleukodystrophy protein
Abetalipoproteinemia 4q22 Microsomal triglyceride transfer protein
Hypobetalipoproteinemia 2p24 Apolipoprotein B
Cerebrotendinous xanthomatosis 2q33 Mitochondrial sterol 27-hydroxylase
Ataxia with vitamin E deficiency 8q13 Alpha-tocopherol transfer protein
Lesch-Nyhan syndrome Xq26 Hypoxanthine-guanine phosphoribosyl- transferase
Wilson disease 13q14 ATP7B (copper transporting ATPase)
Ceroid lipofuscinosis Several variants Multiple gene products
Refsum disease 10pter Phytanoyl CoA hydroxylase
X-linked ataxia, ichthyosis, and tapetoretinal dystrophy Xpter-p22 Arylsulfatase C
Kayser-Fleischer ring
Kayser-Fleischer ring (arrow) in a patient with advanced

neuropsychiatric Wilson disease. The dense brown copper deposits
encircle the iris. It is rare to see Kayser-Fleischer rings without the
aid of a slit lamp examination because Wilson disease is usually
recognized at an earlier stage when the rings are not as prominent.
Courtesy of Marshall M Kaplan, MD.
Contributor Disclosures
Puneet Opal, MD, PhD Grant/Research/Clinical Trial Support: Biohaven [Spinocerebellar ataxia]. All of the relevant financial relationships listed have
been mitigated. Huda Y Zoghbi, MD Equity Ownership/Stock Options: Cajal Neuroscience [Alzheimer's, Parkinson's]; Regeneron [Macular
degeneration, cancer, dermatitis, COVID-19]. Grant/Research/Clinical Trial Support: UCB [Research support]; Ionis [RNA-targeted therapeutics].
Consultant/Advisory Boards: Regeneron [Macular degeneration, cancer, dermatitis, COVID-19]; The Column Group [Healthcare venture capital]; VIB
Belgium [Institutional Advisory Board]. All of the relevant financial relationships listed have been mitigated. Marc C Patterson, MD, FRACP Equity
Ownership/Stock Options: IntraBio [General lysosomal diseases and ataxic disorders]. Grant/Research/Clinical Trial Support: Orphazyme [Niemann-Pick
disease, type C]; Shire [Metachromatic leukodystrophy]; Amicus [Late-onset Pompe disease]; Glycomine [Congenital disorders of glycosylation].
Consultant/Advisory Boards: Actelion [Niemann-Pick C]; Amicus [Fabry disease, Gaucher disease, Pompe disease]; Cerecor [Congenital disorders of
glycosylation]; IntraBio [General lysosomal diseases and ataxic disorders]; Novartis [Multiple sclerosis]; Orphazyme [Niemann-Pick disease, type C];
Shire [Metachromatic leukodystrophy]. Other Financial Interest: Sage [Child neurology]; Wiley [JIMD]. All of the relevant financial relationships listed
have been mitigated. Helen V Firth, DM, FRCP, FMedSci No relevant financial relationship(s) with ineligible companies to disclose. April F Eichler, MD,
MPH No relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level
review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
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INTRODUCTION AND CLASSIFICATION

AUTOSOMAL DOMINANT ATAXIAS

AUTOSOMAL RECESSIVE ATAXIAS

Adrenoleukodystrophy — Progressive ataxia and incoordination is an atypical presentation of adrenoleukodystrophy, an X-linked

Certain mitochondrial disorders can present with a progressive or intermittent ataxia.

ATAXIAS CAUSED BY INBORN ERRORS OF METABOLISM

● Possible gene therapies are still experimental [45].

Cerebrotendinous xanthomatosis — Cerebrotendinous xanthomatosis is a relatively rare autosomal recessive cause of

Episodic ataxia types 3 to 7

OTHER DISORDERS WITH ATAXIA AND MYOCLONUS

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Characteristics of the autosomal dominant spinocerebellar ataxias

Disorder Distinguishing features Gene locus and protein

SCA4 Sensory neuropathy 16q22.1

SCA7 Macular degeneration ATXN7 CAG repeat, ataxin-7

SCA8 Mild disease ATXN8 CTG*CAG repeat

SCA9 Not assigned

SCA10 Generalized or complex partial seizures ATXN10 ATTCT repeat, ataxin-10

SCA11 Mild disease TTBK2 Tau tubulin kinase-2

SCA13 Intellectual disability KCNC3 Voltage gated potassium channel KCNC3

SCA15/16 Slowly progressive ITPR1 Inositol 1,4,5-triphosphate receptor 1

SCA18 Pyramidal signs, weakness, sensory axonal 7q22-q32

SCA20 Palatal tremor and dysphonia 11q12

SCA21 Mild to severe cognitive impairment TMEM240 Transmembrane protein 240

SCA23 Distal sensory deficits PDYN Prodynorphin

SCA24 Recessive inheritance; redesignated as SCAR4 1p36

SCA25 Sensory neuropathy, facial tics, gastrointestinal 2p21-p13

SCA26 Pure cerebellar ataxia EEF2 Eukaryotic translation elongation factor 2

SCA27 Cognitive impairment FGF14 Fibroblast growth factor 14

SCA29 Early onset, nonprogressive ataxia; may be an 3p26

SCA30 Slowly progressive, relatively pure ataxia 4q34.3-q35.1

SCA31 Decreased muscle tone BEAN (TGGAA)n repeat

SCA32 Cognitive impairment, affected males with 7q32-q33

SCA33 Not assigned

SCA37 Late onset, falls, dysarthria, clumsiness, abnormal 1p32

SCA39 Not assigned

SCA40 Hyperreflexia and spasticity CCDC88 Coiled-coil domain-containing 88C

SCA44 Ataxia, dysarthria, dysmetria, dysphagia GRM1 Metabotropic glutamate receptor 1

SCA47 Early-onset developmental disability, ataxia, PUM1 Pumilio homolog 1

DRPLA Chorea, seizures, myoclonus, dementia ATN1 CAG repeat, atrophin-1

Graphic 74269 Version 12.0

Major causes of hereditary ataxias due to known enzymatic defects

Disorder Gene locus and protein

Hyperammonemias and aminoacidurias

Ornithine transcarbamylase deficiency Xp21.1 Ornithine transcarbamylase

Citrullinemia 9q34 Arginosuccinate synthetase

Arginase deficiency 6q23 Arginase

Argininosuccinic aciduria 7cen-q11 Arginosuccinate lyase

Hyperornithemia-hyperammonemia- homocitrullinuria syndrome 13q14 Mitochondrial ornithine transporter

Hartnup disease 5p15.33 Neutral amino acid transporter

Isovaleric acidemia 15q14 Isovaleric acid CoA dehydrogenase

Disorders of pyruvate and lactate metabolism

Multiple carboxylase deficiency 21q22 Holocarboxylase synthetase

Tay-Sachs disease 15q23-q24 Alpha subunit of hexosaminidase A

Sandhoff disease 15q13 Beta subunit of hexosaminidase A and B

Niemann-Pick type A and B 11p15.4-p15.1 Acid sphingomyelinase

Niemann-Pick type C 18q11-q12 NPC1

Metachromatic leukodystrophy 22q13 Arylsulfatase A

Adrenomyeloneuropathy Xq28 Adrenoleukodystrophy protein

Abetalipoproteinemia 4q22 Microsomal triglyceride transfer protein