Spinocerebellar Ataxia 11

A number sign (#) is used with this entry because of evidence that this form of spinocerebellar ataxia, SCA11, is caused by mutations in the gene encoding tau tubulin kinase-2 (TTBK2; 611695).

Pure autosomal dominant cerebellar ataxia is a relatively benign, late-onset, slowly progressive neurologic disorder characterized by an uncomplicated cerebellar syndrome (see SCA1; 164400).

For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Clinical Features

Worth et al. (1999) identified 2 British families with a relatively pure form of autosomal dominant cerebellar ataxia in which affected individuals did not have the CAG expansion in the CACNA1A gene (601011), excluding a diagnosis of SCA6 (183086), and in which the disease was not linked to the SCA5 (600224) or SCA10 (603516) loci.

Houlden et al. (2007) described an affected family from Devon, on the southwest coast of England, which stretched over 8 generations. Affected individuals had progressive cerebellar ataxia, abnormal eye signs and pyramidal features, as well as cerebellar atrophy visible upon magnetic resonance imaging.

Mapping

Using a genomewide searching strategy in one of the British families described by them with autosomal dominant cerebellar ataxia, Worth et al. (1999) found linkage to marker D15S1039. Construction of haplotypes defined a 7.6-cM interval between the flanking markers D15S146 and D15S1016, thereby assigning the disease locus, designated SCA11, to chromosome 15q14-q21.3. They excluded linkage of the disease phenotype to this region in the second family.

Houlden et al. (2007) further localized the SCA11 locus to a 5.6-cM region containing 134 genes.

Molecular Genetics

After screening 54 genes in the linked region identified on chromosome 15q15-q21, none of which had a pathogenic mutation, Houlden et al. (2007) analyzed the gene encoding tau tubulin kinase-2 (TTBK2; 611695) and found a 1-base insertion of an adenosine in exon 13 at nucleotide 1329, codon 444 (611695.0001). In a second family with pure ataxia, they found a frameshift deletion of 2 bases (GA) in exon 13 of TTBK2 (611695.0002).