To date, four families with spinocerebellar ataxia type 5 (SCA5) with four distinct mutations in the spectrin, beta, nonerythrocytic 2 gene (SPTBN2) have been reported worldwide. In the present study, we identified the first Japanese family with SCA5, and analyzed this family clinically and genetically. The clinical features of the five patients in this family revealed late-onset autosomal-dominant pure cerebellar ataxia. We collected DNA samples from the majority of the family members across two generations, and exome sequencing combined with Sanger sequencing revealed a novel heterozygous three-nucleotide in-frame deletion mutation (c.2608_2610delGAG) in exon 14 of the SPTBN2 gene. This mutation cosegregated with the disease in the family and resulted in a glutamic acid deletion (p.E870del) in the sixth spectrin repeat, which is highly conserved in the SPTBN2 gene. This is the first three-nucleotide in-frame deletion mutation in this region of the beta-3 spectrin protein highly likely to be pathogenic based on exome and bioinformatic data.

A 31-year-old woman presented with severe dystonia-parkinsonism. She had nonprogressive psychomotor retardation and cognitive dysfunction from childhood without evidence of dystonia or parkinsonism. At age 30, she then developed severe dystonia and gait disturbance. There was neither dystonia nor parkinsonism before age 30. MRI revealed cerebral atrophy and iron accumulation in the globus pallidus and substantia nigra ( figure 1, A-D). The characteristic MRI findings were hyperintensity of the substantia nigra with a central band of hypointensity in T1-weighted axial slices ( figure 1, B). Beta-propeller proteinassociated neurodegeneration (BPAN) was diagnosed based on MRI findings and identification of a novel heterozygous mutation in the WDR45 gene (NM_007075.3: c.51911_51913del) (figure 2). This is a neurodegeneration involving brain iron accumulation (NBIA) characterized by psychomotor retardation from childhood and dystonia-parkinsonism in midadulthood.

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