LETTER TO JMG A new locus for a childhood onset, slowly progressive autosomal recessive spinocerebellar ataxia maps to chromosome 11p15

T he cerebellar ataxias are a heterogeneous group of neurodegenerative disorders, characterised by symptoms and signs of cerebellar degeneration, pyramidal and extrapyramidal features, and variable polyneuropathy. Prominent clinical features are signs of cerebellar ataxia, such as uncoordinated gait and uncontrolled co-ordination of hand, speech, and eye movements, while (extra) pyramidal signs, such as retinal, cardiac, muscle and/or neuronal involvement, are less common. The clinical picture shows a large variation in age at onset and disease progression. Sporadic ataxias may be attributed to various toxic, inflammatory, paraneoplastic, metabolic, endocrinal, or malabsorption conditions. Hereditary ataxias consist of a large number of autosomal dominant ataxias and ataxias with an autosomal recessive and X-linked mode of inheritance. The remaining ataxias of unknown cause are referred to as idiopathic sporadic cerebellar ataxias. Most symptomatic ataxias can be diagnosed on the basis of a typical history or by simple laboratory tests. In hereditary ataxias family history is important. However, a negative family history cannot rule out autosomal recessive or X-linked ataxia and even autosomal dominantly inherited ataxia may be missed because of reduced penetrance, the early death of gene carriers before the onset of symptoms, imprinting effects, variable expression, adoption, or nonpaternity. Gene defects have been identified for several hereditary forms. Autosomal dominant ataxias are often associated with genes containing unstable expanded trinucleotide repeats, such as polyglutamine-coding CAG repeat expansions in SCA 1, 2, 3, 6, 7, 17 and DRPLA, or trinucleotide or pentanucleotide repeat expansions in (non-) coding regions in SCA 8, 10, and 12. Other mutations have been identified, such as point mutations in FGF14 and SCA14, and several loci, such as SCA 4, 5, 11, 13, 15, 16, 18, 19, 21, 22, 23, and 25 have been mapped. 3 Some autosomal recessive ataxias have been clinically characterised, their genes localised, or their genes and their proteins identified (table 1). The most common form (11–38%) of autosomal recessive ataxia is Friedreich’s ataxia (FRDA), which shows a large variation in clinical presentation, that is age at onset and severity of clinical symptoms. Other forms of autosomal recessive ataxia are ataxia teleangiectasia (AT) or AT-like disorders, ataxia with isolated vitamin E deficiency (AVED), abetalipoproteinaemia (ABL), spastic ataxia of Charlevoix-Saguenay (ARSACS), 14 infantile onset spinocerebellar ataxia (IOSCA), ataxia with oculomotor apraxia (AOA1 and 2), 17 and Refsum’s disease (RD). 19 Furthermore, inherited metabolic disorders can cause ataxia-like carbohydrate deficient glycoconjugate syndrome, 21 GM2 gangliosidosis, 22