Sacsinopathies: sacsin-related ataxia.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) was originally found among inhabitants of the Charlevoix-Saguenay region of northeastern Quebec in Canada. This disease is a neurodegenerative disorder characterized by early-onset spastic ataxia, dysarthria, nystagmus, distal muscle wasting, finger and foot deformities, and retinal hypermyelination. The principal neuropathology comprises atrophy of the upper vermis and the loss of Purkinje cells in the cerebellum. The SACS gene was originally reported to consist of a single gigantic exon spanning 12.8 kb with an 11.5-kb open reading frame (ORF), and to encode the protein sacsin. Recently, eight exons upstream from the original gigantic one, however, have been found, and the new ORF has elongated to 13.7 kb. To date, at least 28 mutations have been found in Quebec and non-Quebec patients including ones in Italy, Japan, Spain, Tunisia, and Turkey, and ARSACS thus shows a worldwide occurrence. Although most of the mutations reported have been in the gigantic exon, the genotype is now expanding upstream from this gigantic exon. Therefore, the new exons upstream of the gigantic one should be analyzed when a case is clinically compatible with ARSACS, even without any mutation in the gigantic exon. Although Quebec patients show a homogeneous phenotype, non-Quebec patients exhibit some atypical clinical features, as follows: slightly later onset than that in Quebec patients, absence of retinal hypermyelination, intellectual impairment, and lack of spasticity. Thus, since ARSACS shows the clinical diversity, the SACS gene should be analyzed not only in typical cases as Quebec patients but also in atypical cases as non-Quebec patients. As more SACS mutations are identified worldwide, the clinical spectrum of 'sacsinopathies' will expand, and a finer genotype-phenotype correlation study will become possible and shed light on the molecular mechanism underlying ARSACS.