INTRODUCTION — 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. Autosomal dominant ataxias are reviewed separately. (See "Autosomal dominant spinocerebellar ataxias".)
An approach to the initial evaluation of an adult with ataxia is presented separately. (See "Overview of cerebellar ataxia in adults".)
AUTOSOMAL DOMINANT ATAXIAS — The most common autosomal dominant ataxias are the spinocerebellar ataxias (SCAs) (table 1). 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 reviewed in detail separately. (See "Autosomal dominant spinocerebellar ataxias".)
AUTOSOMAL RECESSIVE ATAXIAS — Approximately 200 gene defects are recognized in the spectrum of autosomal recessive cerebellar ataxias (ARCAs) [2]. Nomenclature is heterogeneous and has evolved to accommodate the primacy of specific genetic diagnoses. Disorders are named based on their order of identification, prominent clinical features, and/or the causative gene (table 2 and table 3 and table 4 and table 5 and table 6 and table 7).
The most common ARCAs are Friedreich ataxia and ataxia-telangiectasia [2]. These are discussed separately (see "Friedreich ataxia" and "Ataxia-telangiectasia"). In adults, another important genetic cause of ataxia is CANVAS (cerebellar ataxia, neuropathy, and vestibular areflexia syndrome), caused by intronic repeat expansions of the RFC1 gene. (See "Overview of cerebellar ataxia in adults", section on 'Autosomal recessive ataxias'.)
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.)
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 (table 8), 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 "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy".)
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 9).
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 9). 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 9). 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 9). 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 "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Myeloneuropathy'.)
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 "Ocular gaze disorders" 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 involvement'). 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: Management".)
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.
●SCA27B due to repeat expansions in the first intron of the fibroblast growth factor 14 (FGF14) gene can present initially with episodic ataxia that evolves over time to become constant and progressive. (See "Autosomal dominant spinocerebellar ataxias", section on 'SCA27B'.)
Disturbances of neuronal excitability may be the underlying mechanism causing these different clinical manifestations. (See "Hemiplegic migraine", section on 'Familial hemiplegic migraine' and "Autosomal dominant 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.
HEREDITARY SPASTIC PARAPLEGIAS — Other familial genetic syndromes have ataxia as a common associated symptom and, in some instances, phenocopy the familial ataxias. The hereditary spastic paraplegias are the most notable example. (See "Hereditary spastic paraplegia".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Friedreich ataxia (The Basics)")
The National Ataxia Foundation, the Friedreich's Ataxia Research Alliance, and other nonprofit organizations provide important information for patients and the larger public.
SUMMARY AND RECOMMENDATIONS
●Classification – 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) (table 9) and progressive ataxias not due to inborn errors of metabolism. (See 'Introduction' above.)
●Autosomal dominant progressive ataxias – 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 "Autosomal dominant spinocerebellar ataxias".)
●Autosomal recessive ataxias – The most common autosomal recessive ataxias are Friedreich ataxia and ataxia-telangiectasia (table 6). 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 ataxias – 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.)
●Mitochondrial ataxias – Certain mitochondrial disorders can present with a progressive or intermittent ataxia. (See 'Mitochondrial ataxias' above.)
●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 (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 9). (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 9). (See 'Progressive ataxias' above.)
●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. 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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