Hexanucleotide repeat expansion in SCA36 reduces the expression of genes involved in ribosome biosynthesis and protein translation.

Hereditary spinocerebellar ataxia (SCA) is a group of clinically and genetically heterogeneous inherited disorders characterized by slowly progressive cerebellar ataxia. We ascertained a Japanese pedigree with autosomal dominant SCA comprising four family members, including two patients. We identified a GGCCTG repeat expansion of intron 1 in the NOP56 gene by Southern blotting, resulting in a molecular diagnosis of SCA36. RNA sequencing using peripheral blood revealed that the expression of genes involved in ribosomal organization and translation was decreased in patients carrying the GGCCTG repeat expansion. Genes involved in pathways associated with ribosomal organization and translation were enriched and differentially expressed in the patients. We propose a novel hypothesis that the GGCCTG repeat expansion contributes to the pathogenesis of SCA36 by causing a global disruption of translation resulting from ribosomal dysfunction.

Episodic ataxia type 2 with a novel missense variant (Leu602Arg) in CACNA1A.

Autosomal dominant episodic ataxia type 2 (EA2) is caused by variants in CACNA1A. We examined a 20-year-old male with EA symptoms from a Japanese family with hereditary EA. Cerebellar atrophy was not evident, but single photon emission computed tomography showed cerebellar hypoperfusion. We identified a novel nonsynonymous variant in CACNA1A, NM_001127222.2:c.1805T>G (p.Leu602Arg), which is predicted to be functionally deleterious; therefore, this variant is likely responsible for EA2 in this pedigree.

Case report: Frontotemporal dementia and amyotrophic lateral sclerosis caused by a missense variant (p.Arg89Trp) in the valosin-containing protein gene.

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6, also known as amyotrophic lateral sclerosis 14, is an autosomal dominant, progressive neurodegenerative disorder caused by various mutations in the valosin-containing protein gene. In this report, we examined a 51-year-old female Japanese patient with frontotemporal dementia and amyotrophic lateral sclerosis. The patient began noticing gait disturbances at the age of 45 years. Neurological examination at the age of 46 years met the Awaji criteria for clinically probable amyotrophic lateral sclerosis. At the age of 49 years, she tended to have poor mood and an aversion to activity. Her symptoms gradually worsened. She required a wheelchair for transport and had difficulty communicating with others because of poor comprehension. She then began to frequently exhibit irritability. Eventually, she was admitted to the psychiatric hospital because uncontrollable violent behavior throughout the day. Longitudinal brain magnetic resonance imaging revealed progressive brain atrophy with temporal dominance, non-progressive cerebellar atrophy, and some non-specific white matter intensities. Brain single photon emission computed tomography showed hypoperfusion in the bilateral temporal lobes and cerebellar hemispheres. Clinical exome sequencing revealed the presence of a heterozygous nonsynonymous variant (NM_007126.5, c.265C>T; p.Arg89Trp) in the valosin-containing protein gene, which was absent in the 1000 Genomes Project, the Exome Aggregation Consortium Database, and the Genome Aggregation Database, and was predicted to be "damaging" by PolyPhen-2 and "deleterious" using SIFT with a Combined Annotation Dependent Depletion score of 35. We also confirmed the absence of this variant in 505 Japanese control subjects. Therefore, we concluded that the variant in the valosin-containing protein gene was responsible for the symptoms of this patient.