Elsevier

The Lancet Neurology

Volume 6, Issue 3, March 2007, Pages 245-257
The Lancet Neurology

Review
Clinical features and molecular genetics of autosomal recessive cerebellar ataxias

https://doi.org/10.1016/S1474-4422(07)70054-6Get rights and content

Summary

Among the hereditary ataxias, autosomal recessive spinocerebellar ataxias comprise a diverse group of neurodegenerative disorders. Clinical phenotypes vary from predominantly cerebellar syndromes to sensorimotor neuropathy, ophthalmological disturbances, involuntary movements, seizures, cognitive dysfunction, skeletal anomalies, and cutaneous disorders, among others. Molecular pathogenesis also ranges from disorders of mitochondrial or cellular metabolism to impairments of DNA repair or RNA processing functions. Diagnosis can be improved by a systematic approach to the categorisation of these disorders, which is used to direct further, more specific, biochemical and genetic investigations. In this Review, we discuss the clinical characteristics and molecular genetics of the more common autosomal recessive ataxias and provide a framework for assessment and differential diagnosis of patients with these disorders.

Section snippets

Clinical features of autosomal recessive ataxias

Insidious loss of balance and coordination can be debilitating for patients and a diagnostic dilemma for clinicians. The phenotype of progressive cerebellar ataxia can result from both acquired and hereditary disorders. For these reasons, a systematic approach to the diagnosis of patients with ataxia is essential. Hereditary ataxias can be divided into autosomal dominant, autosomal recessive, X-linked, and mitochondrial on the basis of mode of inheritance. This Review will focus on the clinical

Friedreich's ataxia and phenotypically related disorders

Friedreich's ataxia is an important consideration in all assessments of autosomal recessive ataxic syndromes. However, several other ataxic disorders strongly mimic this phenotype. Therefore, the initial characterisation of a patient as having Friedreich's ataxia phenotype is a useful first step in differentiation. Despite their clinical similarity, these disorders are easily differentiated by laboratory testing and, ultimately, through genetic analysis.

Friedreich's ataxia phenotype with cerebellar atrophy

As with the disorders described above, the following disorders can mimic the Friedreich's ataxia phenotype; however, they can be readily distinguished by the presence of cerebellar atrophy or other findings on neuroimaging. Furthermore, the presence of clinical neurological findings not typically seen in Friedreich's ataxia, such as epilepsy or cognitive or psychiatric symptoms, should also alert physicians to consider these disorders in the differential diagnosis.

Early-onset ataxia with cerebellar atrophy

This final class of disorders differs from those previous in that the age at onset is typically much younger than seen in Friedreich's ataxia and phenotypically similar disorders. Cerebellar atrophy is also a prominent feature. Ataxia telangiectasia is the prototypical disorder in this group. Although they may present in the teenage years, ataxia with oculomotor apraxia types 1 and 2 are also included in this category due to their notable similarities to ataxia telangiectasia. This category is

Conclusion

Among the hereditary ataxias, those with autosomal recessive inheritance form a heterogeneous population. The major disorders can be effectively grouped into three categories. The first two of these are best represented clinically by Friedreich's ataxia, while the last category is exemplified by ataxia telangiectasia. Although additional clinical assessment can aid in further differentiation within these categories (table 2), ancillary testing with simple laboratory studies and neuroimaging can

Search strategy and selection criteria

References for this review were identified by searches of PubMed from 1966 until June 2006 with the terms “cerebellar ataxia”, “recessive cerebellar ataxia”, “Friedreich ataxia”, “AVED”, “abetalipoproteinemia”, “Refsum disease”, “late onset Tay-Sachs”, “cerebrotendinous xanthomatosis”, “POLG ataxia”, “SCAN1”, “ataxia telangiectasia”, “AOA1”, “AOA2”, “ARSACS”, “IOSCA”, “Cayman ataxia”, and “Marinesco-Sjogren”. Due to space limitations, emphasis was placed on comprehensive reviews and

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