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  • Updated 04.30.2023
  • Released 10.21.2003
  • Expires For CME 04.30.2026

Nondominant hereditary ataxias



The autosomal recessive cerebellar ataxias comprise a large group of rare diseases, the most common forms being Friedreich ataxia, ataxia-telangiectasia, and early-onset cerebellar ataxia with retained tendon reflexes. This is a large and expanding group of disorders characterized by degeneration or developmental anomalies of the cerebellum and spinal cord, age of onset prior to 20 years, and autosomal recessive inheritance. The author provides an updated comprehensive review of this disorder and its classifications. The disorders of X-linked inheritance are also described here. The “Differential diagnosis” section describes the utility of using associated symptoms as a clinical tool to investigate etiologies. Methods such as in proteomics, molecular and genetic studies, and high-throughput drug screening are allowing researchers to better understand the mechanisms of this group of disorders and arrive at targeted therapy.

Key points

• Nondominant hereditary ataxias are a group of heterogeneous, rare neurologic disorders characterized by degeneration or developmental abnormality of the cerebellum and spinal cord.

• The most common of these is Friedreich ataxia, mapped to genetic locus 9q13-q21 and caused by GAA triplet repeat expansion.

• The list of diseases comprising this group is extensive and continues to grow as genome analysis has become more widespread and accessible.

• Because of an increased knowledge of underlying molecular mechanisms, management and targeted therapy has advanced to trial phases in certain disorders, including Friedreich ataxia.

Historical note and terminology

Autosomal recessive cerebellar ataxias are a group of heterogeneous rare neurologic disorders characterized by degeneration or developmental abnormality of the cerebellum and spinal cord, with onset prior to 20 years of age. Among the hereditary cerebellar ataxias, there are at least 36 different forms of autosomal dominant cerebellar ataxia, 20 autosomal recessive cerebellar ataxias, two X-linked ataxias, and several forms of ataxia associated with mitochondrial defects (94). They are characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements (06).

In 1893 Pierre Marie described a clinical condition that he termed “hereditary cerebellar ataxia,” in which cerebellar signs and spasticity prevailed. This disorder 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 (24). In 1974, Skre of Norway studied the hereditary ataxias such as Friedreich ataxia and pioneered the term “spinocerebellar ataxias” (137; 138).

The most well-known and the most common hereditary ataxia is Friedreich ataxia. Nikolaus Friedreich (1825-1882) first described the disorder in a series of five articles, starting in 1863. Although nystagmus was not a consistent finding, he initially used the term “ataxic nystagmus” (40). After ataxic nystagmus was found to be a distinct entity and not just a part of the natural history of progressive locomotor ataxia and disseminated sclerosis, Brousse coined the term “maladie de Friedreich” in 1882. He was the first to describe the diagnostic criteria for Friedreich ataxia, which remain applicable today. In 1988, Chamberlain and colleagues mapped the genetic locus for Friedrich ataxia to chromosome 9q13-q21 (15). The causative GAA triplet repeat expansion was discovered in 1996 (13).

The first description of patients with ataxia-telangiectasia was published in 1926 by French investigators Syllaba and Henner (142). They reported three adolescent siblings with progressive choreoathetosis and ocular telangiectasia. In 1957, the clinical and pathological description became clearer, and the disorder was given the name “ataxia-telangiectasia” by Boder and Sedgwick (07).

Dejerine and Thomas introduced the term “olivopontocerebellar atrophy” in 1900. They described two patients with a chronic progressive cerebellar degeneration appearing in middle-age (24). The characteristic presentation of olivopontocerebellar atrophy is progressive, symmetric cerebellar dysfunction in childhood, followed by dysarthria, spasticity, and hyperreflexia. However, in 1970 Konigsmark and Weiner published a paper in which they recognized the heterogeneity of olivopontocerebellar atrophy and proposed a classification based on clinical, genetic, and anatomic features (76). Familial cases of olivopontocerebellar atrophy are now included within the spinocerebellar ataxia rubric (117).

Multiple attempts to classify inherited ataxias have been proposed. In 1907, Holmes suggested a classification based on pathologic findings, but this did not take into account genetic or clinical features of the disorders. In 1954, Greenfield classified the inherited ataxias into three categories: (1) predominantly spinal, (2) predominantly cerebellar, and (3) combined spinocerebellar (45). In 1983, Harding proposed a classification based primarily on the biochemical pathogenesis and age of onset of the ataxia (52). She divided those with a known etiology (eg, abetalipoproteinemia, ataxia-telangiectasia) from those whose etiology was unknown (eg, Friedreich ataxia). In the latter category, she further subdivided the disorders based on whether the onset was before the age of 20 years or later. As genetic mutations were identified in a number of disorders, newer classification schemes were suggested (26). The correlation of clinical disease with the underlying genetic defect has enabled more complete classification of these ataxias (60).

The autosomal recessive ataxias are now subdivided as shown in Table 1.

Table 1. Current Categorization of Autosomal Recessive Ataxias

Degenerative ataxias

• Friedreich ataxia
• Mitochondrial recessive ataxia syndrome (MIRAS)
• Charlevoix-Saguenay spastic ataxia
• Early-onset cerebellar ataxia with retained tendon reflexes (EOCARR)
• Infantile onset spinocerebellar ataxia
• Marinesco-Sjogren syndrome
• Coenzyme Q10 deficiency with cerebellar ataxia
• Posterior column ataxia and retinitis pigmentosa (PCARP)

DNA repair defects

• Ataxia-telangiectasia
• Ataxia with oculomotor apraxia 1 (AOA 1)
• Ataxia with oculomotor apraxia 2 (AOA 2)
• Ataxia-telangiectasia–like disorder (ATLD)
• Spinocerebellar ataxia with axonal neuropathy (SCAN 1)
• Xeroderma pigmentosum (XP)

Congenital ataxias

• Joubert syndrome (JBTS 1-5)
• Cayman ataxia

Metabolic ataxias

• Ataxia with isolated vitamin E deficiency (AVED)
• Abetalipoproteinemia
• Cerebrotendinous xanthomatosis
• Refsum’s disease
• Others : urea cycle disorders, lysosomal storage disorders

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