Autosomal dominant cerebellar ataxia type I: A review of the phenotypic and genotypic characteristics

Abstract

Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds.

Autosomal dominant cerebellar ataxia with slow ocular saccades, neuropathy and orthostatism: A novel entity?

“…The disorder described here presented with a combination of cerebellar ataxia and additional neurological symptoms, similar to the majority of the already characterized ADCAs [2,4,10].…”

“…Autosomal dominant cerebellar ataxias (ADCA) include a wide variety of subtypes, ranging from pure cerebellar syndromes to combinations of ataxia with pyramidal or extrapyramidal signs, cognitive impairment, bulbar, spinal or peripheral neurological dysfunction, or retinal degeneration [1][2][3][4][5]. The broad spectrum of clinical phenotypes reflects the genetic heterogeneity of the various ADCA subtypes.…”

“…Known genetic causes include expansions of polyglutamine repeats or non-coding regions and conventional mutations. For a substantial number of ADCA subtypes the underlying genetic causes remain to be identified [4,6].…”

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

“…This classification system was introduced by AE Harding in 1982 to account for the varying degree of heterogeneity between the dominantly inherited ataxias [42]. Although, the classification is somewhat out-dated due to the genetically classified SCA system used in the present day, it is of some benefit to mention, as the system broadly classifies all ADCA into three discrete categories [43,44]. These categories were created on the basis of separating dominant ataxias by their complex phenotypes of ataxic and non-ataxic clinical manifestations; termed ADCA type I, II and III (Table 1) [42,45].…”

Spinocerebellar ataxia 1: case and cohort-based studies in India

“…Age of onset of symptoms is typically between 20 and 50 years, and the disease culminates with the death of the individual within 10-20 years after its onset 8 . Currently, no treatment is available either for curing SCA1 or delaying the onset of the disease 9 . Majority of SCA1 studies in India are hospital-based [10][11][12][13][14][15] and hence cross-sectional; thus they fail to reveal characteristic clinical features of disease progression.…”