Kishin Koh

A Japanese SCA5 family with a novel three-nucleotide in-frame deletion mutation in the SPTBN2 gene: a clinical and genetic study

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.

Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.This study identifies TTTCA- and TTTTA-repeat expansions in benign adult familial myoclonic epilepsy. Cortical neurons from affected people exhibit RNA foci containing these expanded repeats, suggesting RNA toxicity as the mechanism underlying disease pathogenesis.

Novel mutations in the PNPLA6 gene in Boucher-Neuhäuser syndrome.

On whole-exome sequencing, a novel compound heterozygous mutation (c.2923A>G/c.3523_3524insTGTCCG, p.T975A/p.1175_1176insVS) and a novel homozygous one (c.3534G>C, p.W1178C) in the PNPLA6 gene were identified in sporadic and familial Japanese patients with Boucher-Neuhäuser syndrome (BNS), respectively. However, we did not find any mutations in the PNPLA6 gene in 88 patients with autosomal recessive hereditary spastic paraplegia (ARHSP). Our study confirmed the earlier report that a PNPLA6 mutation causes BNS. This is the first report on PNPLA6 mutations in non-Caucasian patients. Meanwhile, PNPLA6 mutations might be extremely rare in Japanese ARHSP patients. Moreover, we first found hypersegmented neutrophils in two BNS patients with PNPLA6 mutations.

A de novo mutation in the NALCN gene in an adult patient with cerebellar ataxia associated with intellectual disability and arthrogryposis

To the Editor: Mutations in NALCN cause either a recessive or dominant condition. Recessive mutations predominantly cause hypotonia and severe intellectual disabilities like infantile neuroaxonal dystrophy (1, 2). Meanwhile, dominant mutations are all de novo, and cause congenital contractures of the limbs and face, hypotonia, and global developmental delay syndrome, or intellectual disability, ataxia and arthrogryposis (3–5). Thus, both recessive and dominant mutations might cause a severe phenotype in childhood. In contrast, we report here the first adult patient with a relatively mild phenotype with a de novo NALCN mutation. A 33-year-old Japanese woman presented with cerebellar ataxia associated with intellectual disability and

Exome sequencing reveals a novel missense mutation in the KIAA0196 gene in a Japanese patient with SPG8.

Exome sequencing revealed a novel missense mutation (c.2152G>A, p.E713K) in the KIAA0196 gene in a Japanese patient with SPG8. To date, only 10 mutations in the KIAA0196 gene have been reported in the world. We describe the clinical and genetic findings in our patient with SPG8, which is a rare dominant hereditary spastic paraplegia. Notably, our patient showed mild upper limb ataxia, which is a relatively atypical symptom of SPG8. Thus, our patient showed a wide clinical spectrum of SPG8.

Novel mutations in the ALDH18A1 gene in complicated hereditary spastic paraplegia with cerebellar ataxia and cognitive impairment

Hereditary spastic paraplegias (HSPs) are characterized by various inherited disorders in which weakness and spasticity of the lower extremities are the predominant symptoms. Recently, HSP caused by ALDH18A1 mutations has been reported as SPG9 with autosomal dominant (SPG9A) and autosomal recessive (SPG9B) transmission. In this study, we obtained clinical and genetic findings in two Japanese families with SPG9B. One family had a novel compound heterozygous mutation (c.1321 C > T/c.1994G > A) in the ALDH18A1 gene. The other family had a homozygous mutation (c.383 G > A/c.383 G > A) in the ALDH18A1 gene. To date, only two SPG9B families with ALDH18A1 mutations have been reported. This is the first report of SPG9 in non-Caucasians. Furthermore, we found cerebellar ataxia in one family, although cerebellar ataxia has not been reported in SPG9B so far. SPG9B might involve a complicated HSP including cerebellar ataxia and cognitive impairment. This study expands the clinical and genetic spectrum of ALDH18A1-related disorders.

プリオン蛋白遺伝子のコドン180と232にdouble mutationをみとめたCreutzfeldt-Jakob病の1例

Creutzfeldt-Jakob disease (CJD) presents with rapidly progressive dementia associated with several symptoms including pyramidal, extrapyramidal, and cerebellar signs. In Japan, patients with PRNP gene mutations comprise 18.3% of CJD cases. In the present study, we report a 74-year-old man with a double mutation in the PRNP gene. He showed dysarthria, gait disturbance, and cognitive impairment. High signal intensity was observed in the bilateral cortex on brain MRI in diffusion-weighted images. There were high total Tau protein and 14-3-3 protein levels in the cerebrospinal fluid. We diagnosed him as having CJD clinically, and analyzed the PRNP gene, which revealed a V180I mutation and a M232R one, i.e., a compound heterozygous status. In our patient, the disease has very slowly progressive (total disease course, 37 months). The V180I and M232R mutations are specific mutations to Japanese CJD patients. For patients with a double PRNP gene mutation, only V180I and M232R have been known. Patients with a double mutation (V180I /M232R) in the PRNP gene might show an atypical disease course with a slow progression.

Whole‐exome sequencing reveals a missense mutation in the KCND3 gene in a patient with SCA19/22

We report a 45‐year‐old Japanese man with SCA19/22. Whole‐exome sequencing revealed a heterozygous missense mutation (c.1169G>A, p.S390N) in the KCND3 gene. Although this mutation has been reported to cause SCA19 in a Dutch patient, a co‐segregation study of the mutation has not been carried out. In the present family, since the S390M mutation was found in the patient but not in the unaffected siblings, we suspected co‐segregation of this mutation with the disease in our family. Our patient presented with juvenile‐onset pure cerebellar ataxia associated with pes cavus, which has not been previously described in SCA19/22. Thus, our patient would expand the clinical spectrum of SCA19/22. In the case of juvenile‐onset pure cerebellar ataxia with autosomal dominant transmission, SCA19/22 should be considered.

Japanese amyotrophic lateral sclerosis patient with learning disabilities with a deletion mutation in the C‐terminal of the FUS/TLS gene

We report a 19‐year‐old Japanese man with a heterozygous deletion mutation (c.1485delA, p.G497AfsX527) in the fused in sarcoma/translated in liposarcoma gene. His mother and aunt were diagnosed with amyotrophic lateral sclerosis. He and his mother had learning disabilities. He noted muscle weakness of the right arm at age 18 years and 9 months. His respiratory function worsened rapidly, and he died of respiratory failure 11 months after onset. To date, the fused in sarcoma/translated in liposarcoma c.1485delA mutation has only been reported in three patients in a Caucasian family, and all those patients had a short disease course (12–18 months) and learning disabilities or slowness in school, similar to our patients. Thus, the fused in sarcoma/translated in liposarcoma c.1485delA mutation might cause a rapid disease course and affect the learning function. This is the first non‐Caucasian patient with a heterozygous mutation, c.1485delA, in the fused in sarcoma/translated in liposarcoma gene.

Exome sequencing shows a novel de novo mutation in ATL1

We experienced treating a male patient born to healthy parents, who presented with spastic gait from childhood, and his son and daughter similarly presented with spastic gait, raising the possibility of a de novo mutation in the patient. With the hypothesis of a de novo mutation in the patient, we carried out exome sequencing of the patient and his parents to identify the gene with a disease‐causative mutation in the patient.