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  • Updated 06.12.2020
  • Released 03.27.1995
  • Expires For CME 06.12.2023

Autosomal dominant hereditary ataxias



The dominant ataxias continue to be better characterized from a genetic perspective. In this article, the author provides an updated review of the autosomal dominant ataxias, including spinocerebellar ataxia syndromes, dentatorubral-pallidoluysian atrophy, and episodic ataxias. To date, the most recently identified are spinocerebellar ataxia type 48 and episodic ataxia type 8. New mutations, as well as the repeat expansions causing these disorders, are described and reviewed. The exact pathogenesis underlying these disorders is not known, but researchers have continued to elucidate the pathways involved in the syndromes based on the genes and differences between mutations, or the repeat expansions that are involved. There are currently no disease-modifying therapies; however, a goal for the future is to use the known genetic information to generate new effective targeted therapeutics.

Key points

• The autosomal dominant hereditary ataxia syndromes consist of more than 40 known spinocerebellar ataxia syndromes, dentatorubral-pallidoluysian atrophy, and 8 episodic ataxia syndromes. There are likely more genetic etiologies that have yet to be discovered.

• The autosomal dominant spinocerebellar ataxias encompass a wide range of disorders that have a range of phenotypes that can be categorized as ataxia plus nonataxia symptoms, ataxia with vision loss, and almost purely isolated cerebellar ataxia. There is a wide range of age of onset, from childhood to adulthood, for many of the autosomal dominant ataxia syndromes.

• The spinocerebellar ataxia syndromes are currently classified based on their genetic etiology. The main mechanisms of genetic disruption are via repeat expansions of the genome in either coding or noncoding regions and conventional mutations and translocations within the genome.

• The family history is a key area to help distinguish between the acquired and the inherited ataxia syndromes. However, even the inherited ataxias can be caused by a de novo mutation.

• It is difficult to make phenotype/genotype correlations because of the significant overlap of presenting symptoms. However, in general, the spinocerebellar ataxia syndromes caused by repeat polyglutamine expansions have a progressively worse clinical course than the syndromes caused by single mutations.

• Researchers are rapidly learning about the underlying pathophysiology behind the inherited ataxia syndromes. Information based on the genes involved and the pathways they affect are elucidating the basic mechanism of cellular injury in polyglutamine triple repeat expansion disorders versus single mutation disorders.

• There are no disease-modifying therapeutic options. Management consists of symptomatic relief from comorbid conditions and genetic counseling.

Historical note and terminology

Hereditary spinocerebellar degeneration, also referred to as hereditary ataxia, is uncommon. In 1893, Pierre Marie described a clinical condition that he termed “hereditary cerebellar ataxia,” in which cerebellar signs prevailed along with spastic signs. This was later referred to as “Marie’s cerebellar ataxia.” Subsequently, the term was used broadly to describe a variety of hereditary conditions with spinocerebellar manifestations, including the spastic ataxia of Sanger-Brown, Menzel spinocerebellar ataxia with olivopontocerebellar degeneration, the cerebello-olivary degeneration of Holmes, and the olivopontocerebellar degeneration reported by Dejerine and Thomas (46). In 1974, Skre studied the hereditary ataxia diseases in western Norway and chose to consider all these disorders as members of a comprehensive group of diseases called “spinocerebellar ataxias” (210).

Various attempts to classify inherited ataxias have been made. In 1907, Holmes proposed a classification based on pathologic findings, but he did not take into account genetic or clinical features. In 1954, Greenfield classified the inherited ataxias into 3 categories: (1) predominantly spinal, (2) predominantly cerebellar, and (3) combined spinocerebellar (80). The predominantly spinal category included Friedreich ataxia, abetalipoproteinemia, and hereditary spastic paraplegia. The predominantly cerebellar category included ataxia-telangiectasia, late-onset cervical cerebellar atrophy, and Marinesco-Sjogren-Garland disease. The spinocerebellar group consisted of hereditary spastic ataxia, Ramsay Hunt syndrome, hereditary periodic ataxia, and the olivopontocerebellar atrophies.

In 1983, Harding proposed a classification based primarily on the biochemical pathogenesis and age of onset of the ataxia (89). She divided those with a known etiology (eg, abetalipoproteinemia, ataxia telangiectasia) from those whose etiology was unknown (eg, Friedreich ataxia, Ramsay Hunt syndrome, cerebellar ataxia with retinal degeneration). In the latter category, she further subdivided the disorders based on whether the onset was early (before 20 years of age) or late (after 20 years of age). In a subsequent article, she refined the classification for the autosomal dominant forms of spinocerebellar degeneration (90). Autosomal dominant cerebellar ataxia type I presents with ataxia and noncerebellar findings (such as pyramidal or extrapyramidal dysfunction and ophthalmoplegia). Autosomal dominant cerebellar ataxia type II represents cerebellar ataxia with pigmentary retinal degeneration. Autosomal dominant cerebellar ataxia type III produces relatively pure cerebellar signs. However, as more has been learned about these disorders, it has become clear that categorizing the disorders on phenotypic characteristics is simplistic. Each spinocerebellar ataxia manifests significant phenotypic heterogeneity, even within the same family. Furthermore, as Harding intimated in her seminal article, her scheme has been modified as specific genetic mutations have been identified (89; 123). The correlation of clinical disease with the underlying genetic defect is enabling more accurate and rational classification of the spinocerebellar degenerations (99).

Classification of hereditary ataxia is complex, and there is no consensus yet. With advances in genetics, autosomal dominant cerebellar ataxias of Harding are currently termed “spinocerebellar ataxias (SCAs)” with designated numbers from 1 up to almost 50 now in order of genetic discovery. Thus, the spinocerebellar ataxias are referred to as a heterogeneous group of neurodegenerative disorders, primarily affecting cerebellum that have autosomal dominant inheritance. Dentatorubral-pallidoluysian atrophy can be included in the spinocerebellar ataxia category but does not have spinocerebellar ataxia designation. In addition, there are also spinocerebellar ataxias that are inherited in an autosomal recessive manner, and these disorders are grouped under the umbrella of autosomal recessive spinocerebellar ataxias.

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