Disorders In Depth

Spinocerebellar Ataxias

The term Spinocerebellar ataxia (SCA) is used to denote a progressive ataxia related to pathology in the cerebellum and its associated pathways and inherited in an autosomal dominant fashion. SCA is followed by a number that identifies the particular gene locus responsible for the disease; at the moment the HUGO web site lists SCA 1 through SCA 31, indicating the enormous genetic heterogeneity of these diseases. SCA 3 is synonymous with Machado-Joseph disease. Other vagaries that have appeared because of the rapid accumulation of information in the field include the following: SCA 9 is a non-entity at this point in time; SCA 15 and 16 appear to be related to mutations in the same gene; there is a suggestion that is not yet settled that SCA 19 and 22 may also be allelic disorders; and SCA 24 also has been dropped from the list. Dentato-rubral pallid-luysian atrophy (DRPLA) is often classified as an ataxic disease but does not have an SCA designation.

SCA 1,2,3 (Machado-Joseph disease or MJD) and SCA 6 are the first SCA’s in which defined mutations were identified. While the genes responsible appear not to have much in common, the mutations responsible are all unstable expansions of a trinucleotide repeat motif (CAG) within coding regions of the respective genes. The CAG expansion occurs in the ataxin 1,2 and 3 genes for SCA 1,2 and 3 respectively and in the α subunit of neuronal calcium channel gene in SCA 6. Since CAG codes for glutamine, the protein products of these genes have a repetitive stretch of glutamines and these SCA’s are examples of so called “polyglutamine” diseases. The pathogenesis may involve a gain of function of the protein product of the mutated allele; the longer glutamine stretch in the protein leads to conformational changes and misfolding, aggregation of the protein and a variety of secondary changes leading to a cascade of pathogenic events.

Clinically, SCA 1,2,3 and 6 are characterized by wide range of age at onset but typically in the 20’s and 30’s for SCA 1,2 and 3 and even later in SCA 6. Instability of the repeat during intergenerational transmission leads to anticipation in age at onset. Age at onset is inversely correlated with the number of repeats in the expanded allele and the severity of the disease tends to be more with larger repeat sizes as well. SCA 1,2 and 3 are characterized by ataxia in association with a variety of additional neurological signs including upper motor neuron signs, a Parkinosinan phenotype (in SCA 2 and SCA 3), dystonia, peripheral nerve and anterior horn cell signs and signs related to pathology in many brainstem neurons such as oculomotor neurons and ingestion related neurons. These patients also may have a cerebellar type of cognitive deficit (executive dysfunction), sleep disturbances and sphincter problems.  SCA 1,2 and 3 typically result in a shortened life span. SCA 6 in contrast has almost pure cerebellar signs and can be compatible with a  normal life span. The current study is designed to gather detailed natural history data on a large cohort of US patients with SCA 1,2,3 and 6 using standardized rating scales and additional measures of motor function. In addition, genetic modifiers that may influence the course of theses SCA’s will be looked for.

Other degenerative ataxias

Many of the other SCA’s which are not targets of the current study have similar clinical features and only genetic testing can make a definite determination of the genotype. In addition, there are several types of autosomal recessive (AR) ataxias which have a phenotype that is similar to that of the SCA’s. The AR ataxias tend to have onset in childhood (though not always). The most common AR ataxia is Friedreich’s ataxia (FA). There are also patients with progressive ataxia of adult onset with no family history of the disease and who carry no identifiable mutation associated with ataxia; these carry a diagnosis of sporadic or idiopathic ataxia.