Review
Hereditary Ataxias

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There are many causes of hereditary ataxia. These can be grouped into categories of autosomal recessive, autosomal dominant, and X-linked. Molecularly, many of them are due to trinucleotide repeat expansions. In Friedreich ataxia, the trinucleotide repeat expansions lead to a “loss of function.” In the dominant ataxias, the expanded repeats lead to a “gain of function,” most likely through accumulation of intranuclear (and less commonly cytoplasmic) polyglutamine inclusions. Channelopathies can also lead to ataxia, especially episodic ataxia. Although phenotypic characteristics are an aid to the clinician, a definitive diagnosis is usually made only through genotypic or molecular studies. Genetic counseling is necessary for the testing of symptomatic and asymptomatic individuals. No effective treatment is yet available for most ataxic syndromes, except for ataxia with isolated vitamin E deficiency and the episodic ataxias.

Section snippets

Friedreich Ataxia

Friedreich ataxia is the most common cause of hereditary ataxia, with an estimated incidence of 1 in 20,000 and a prevalence of 1 in 50,000 persons.3, 4 The cardinal features include gait and limb ataxia, dysarthria, absent muscle stretch reflexes in the lower limbs, sensory loss, and signs of corticospinal tract disease. Skeletal abnormalities, cardiomyopathy, and impaired glucose tolerance or diabetes are often encountered. The onset is usually before a patient is 20 years old, and

X-LINKED SCAs

The X-linked SCAs are a heterogeneous group of disorders that are less common and less well characterized than the autosomal dominant and recessive ataxias. Considerable phenotypic variability occurs. Molecular characterization of these disorders remains to be determined. A referenced summary of clinical data is presented in Table 2.

AUTOSOMAL DOMINANT CEREBELLAR ATAXIAS

The estimated incidence of ADCAs in the general population is 5 in 100,000.84.85 Most classifications of the ADCAs have emphasized clinical features.85, 86 The ADCAs are classified genotypically by using the terminology of SCA types 1 through 8, SCA type 10, dentatorubropallidoluysian atrophy (DRPLA), and EA-1 and EA-2. A clinicogenetic classification combining the classic clinical schemes with the current genetic information on the ADCAs is outlined in Table 3. For the clinician, such a

SUMMARY

The many causes of hereditary ataxia can be categorized both genotypically and phenotypically. In this review, we offer a summary of the major features of the more common hereditary ataxias. (The clinical and molecular features and several of the more rare recessive ataxias that were not discussed in the text are included in Table 1, Table 2, Table 3. Additional syndromes listed in Table 2 but not discussed in the text are included in references 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83

ACKNOWLEDGMENT

We thank John Hardy, PhD, and Beth M. Marten for their valuable comments and contributions to the submitted manuscript.

REFERENCES (177)

  • KA Henning et al.

    The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA potymerase II TFIIH

    Cell

    (1995)
  • LA Bindoff et al.

    Familial intermittent ataxia due to a defect of the El component of pyruvate dehydrogenase complex

    J Neurol Sci

    (1989)
  • V Campuzano et al.

    Friedrcich's ataxia: autosomal recessive disease caused by an imronic GAA triplei repeal expansion

    Science

    (1996)
  • A Durr et al.

    Clinical and genetic abnormalities in patients with Friedreich's ataxia

    N Engl J Med

    (1996)
  • G Geoffroy et al.

    Clinical description and rocntgcnologic evaluation of patients with Friedreich's ataxia

    Can J Neural Sci

    (1976)
  • A Filla et al.

    Friedreich's ataxia after gene cloning: the sensitivity and specificity of clinical diagnosis [abstract]

    Neurology

    (1997)
  • S Gilman et al.

    Cerebral glucose hypermclabolism in Friedreich's ataxia detected with positron emission tomography

    Ann Neurol

    (1990)
  • L Junck et al.

    Structural and functional brain imaging in Friedreich's ataxia

    Arch Neurol

    (1994)
  • C Epplen et al.

    Differential stability of the (GAA)n tract in the Friedreich ataxia (STM7) gene

    Hum Genet

    (1997)
  • G De Michele et al.

    Laie onset Friedreich's disease: clinical features and mapping of mutation to the FRDA locus

    J Neurol Neurosurg Psychiatry

    (1994)
  • AE Harding

    Early onset cerebellar ataxia with retained tendon reflexes: a clinical and genetic study of a disorder distinct from Friedreich's ataxia

    J Neurol Neurosurg Psychiatry

    (1981)
  • M Ragno et al.

    Broadened Friedreich's ataxia phenotype after gene cloning: minimal GAA expansion causes late-onset spastic ataxia

    Neurology

    (1997)
  • F Palau et al.

    Early-onset ataxia with cardiomyopathy and retained tendon reflexes maps to the Friedreich's ataxia locus on chromosome 9q

    Ann Neurol

    (1995)
  • A Barbeau et al.

    Recessive ataxia in Acadians and “Cajuns.”

    Can J Neural Sci

    (1984)
  • BJ Keats et al.

    “Acadian” and “classical” forms of Friedreich ataxia are most probably caused by mutations at the same locus

    Am J Med Genet.

    (1989)
  • L Montermini et al.

    Phcnotypic variability in Friedreich ataxia: role of the associated GAA triplet repeal expansion

    Ann Neurol

    (1997)
  • V Campuzalo et al.

    Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes

    Hum Mol Genet

    (1997)
  • M Babcock et al.

    Regulation of mitochondrial iron accumulation by Yfhlp, a putative homolog of frataxin

    Science

    (1997)
  • J Priller et al.

    Frataxin gene of Friedreich's ataxia is targeted to mitochondria

    Ann Neurol

    (1997)
  • K Eder et al.

    Brain phospholipids and fatty acids in Friedreich's ataxia and spinoccrebellar atrophy type-I

    Mov Disord

    (1998)
  • AE Harding et al.

    Spinoccrebellar degeneration associated with a selective defect of vitamin E absorption

    N Engl J Med

    (1985)
  • C Ben Hamida et al.

    Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping

    Nat Genet

    (1993)
  • T Yokola et al.

    Friedreich-like ataxia with retinitis pigmentosa caused by the HislolGln mutation of the alpha-tocopherol transfer protein gene

    Ann Neurol

    (1997)
  • F Hentati et al.

    Exclusion of genetic linkage between autosomal recessive hereditary ataxia with brisk knee and absent ankle reflexes and Friedreich's ataxia phenotypes loci [abstract]

    Newrology

    (1997)
  • JJ Higgins et al.

    An aulosomal recessive disorder with posterior column ataxia and retinitis pigmentosa

    Neurology

    (1997)
  • K Nikali et al.

    Infantile onset spinocerebellar ataxia represents an allelic disease distinct from olher hereditary ataxias

    Pediatr Rcs

    (1994)
  • T Koskinen et al.

    Infantile-onset spinocerebellar ataxia: MR and CT findings

    AJNR Am J Neuroradial

    (1995)
  • K Nikali et al.

    Random search for shared chromosomal regions in four affected individuals: the assignment of a new hereditary ataxia locus

    Am J Hum Genet

    (1995)
  • S Leber

    Progressive myoclonus epilepsy

  • K Virtaneva et al.

    Unstable minisaiellile expansion causing recessively inherited myoclonus epilepsy, EPM1

    Nat Genet

    (1997)
  • MD Lalioli et al.

    Identification of mutations in cystatin B. the gene responsible for the Unvemcht-Lundborg type of progressive myoclonus epilepsy (EPM1)

    Am J Hum Genet

    (1997)
  • LA Pennacchio et al.

    Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EOM1)

    Scienee

    (1996)
  • RG Lafreniere et al.

    Unstable insertion in the 5′ flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM)

    Nat Genet

    (1997)
  • G Holmes

    A form of familial degeneration of the cerebellum

    Brain

    (1907)
  • AC Fok et al.

    Syndrome of cerebellar ataxia and hypogonadolrophic hypogonadism: evidence for pituitary gonadotrophin deficiency

    J Neurol Neurosurg Psychiatry

    (1989)
  • A Malandrini et al.

    Ultrastruciural sperm abnormalities and cerebellar atrophy; docs a correlation exist? report of two cases without endocrine hypogonadism

    J Submicrosc Cytol Paihol

    (1993)
  • K Tojo et al.

    A new family of Boucher-Neuhauscr syndrome: coexistence of Holmes type cerebellar atrophy, hypogonadotropic hypogonadism and retino-choroidal degeneration: case reports and review of literaturc

    EndocrJ

    (1995)
  • G Marinesco et al.

    Nouvelle maladie familiale caractérisée par une cataracte congénitale et un arrêt du développement somato-neuropsychique

    Encephale

    (1931)
  • MB Bromberg et al.

    The Marinesco-Sjögren syndrome examined by computed tomography, magnetic resonance, and 18F-2-fIuoro-2-deoxy-D-glucose and positron emission tomography

    Arch Neurol

    (1990)
  • A Todorov

    Le syndrôme de Marinesco-Sjögren: premiêre étude analomo-clinjque

    J Gener Hum

    (1965)

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    Dr Evidente is now at St Luke's Philippine Movement Disorders Center, Quezon City, Philippines.

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