IMPORTANCE Although mutations in 26 causative genes have been identified in the spinocerebellar ataxias (SCAs), the causative genes in a substantial number of families with SCA remain unidentified.OBJECTIVE To identify the causative gene of SCA in 2 Japanese families with distinct neurological symptoms and radiological presentations.
DESIGN, SETTING, AND PARTICIPANTSClinical genetic study at a referral center of 11 members from 2 Japanese families, which started in 1997.
MAIN OUTCOMES AND MEASURESResults of neurological examinations and radiological evaluations. The causative mutation was identified using genome-wide linkage analysis and next-generation sequencing.RESULTS Affected members (9 of 11 members [81.8%]) showed slowly progressive cerebellar ataxia (all 9 members [100%]), ocular movement disturbance (all 9 members [100%]), and pyramidal tract signs (8 of 9 members [88.9%]) with an age at onset between the second and sixth decades of life. Besides cerebellar and pontine atrophy, magnetic resonance imaging of the brain revealed the hot cross bun sign (4 of 6 members [66.7%]), pontine midline linear hyperintensity (2 of 6 members [33.3%]), or high intensity in the middle cerebellar peduncle (1 of 6 members [16.7%]), which are all reminiscent of multiple system atrophy in tested patients. Using linkage analysis combined with exome and whole-genome sequencing, we identified a novel heterozygous mutation in the ELOVL fatty acid elongase 4 (ELOVL4) gene (c.736T>G, p.W246G) in both families. Haplotype analysis indicated that it was unlikely that these 2 Japanese families shared a common ancestor. Although a missense mutation in ELOVL4 (c.504G>C, p.L168F) was recently reported to be associated with SCA with erythrokeratodermia variabilis (SCA34) in a French-Canadian family, signs of erythrokeratodermia variabilis were absent in our families.
CONCLUSIONS AND RELEVANCECombined with the results of the family with SCA34 reported previously, this report confirms that mutations in ELOVL4 can cause dominantly inherited neurodegeneration severely affecting the cerebellum and brainstem. We should be aware that the presence of multiple system atrophy-like features on magnetic resonance imaging scans, together with cerebellar and brainstem atrophy, suggests SCA34, even when erythrokeratodermia variabilis is absent. The present study further broadened the spectrum of the clinical presentations of SCA34 associated with mutations in ELOVL4, which is involved in the biosynthesis of very long-chain fatty acids.
Leukoencephalopathies comprise a broad spectrum of disorders, but the genetic background of adult leukoencephalopathies has rarely been assessed. In this study, we analyzed 101 Japanese patients with genetically unresolved adult leukoencephalopathy using whole‐exome sequencing and repeat‐primed polymerase chain reaction for detecting GGC expansion in NOTCH2NLC. NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease. We found 12 patients with GGC expansion in NOTCH2NLC as the most frequent cause of adult leukoencephalopathy followed by NOTCH3 variants in our cohort. Furthermore, we found 1 case with de novo GGC expansion, which might explain the underlying pathogenesis of sporadic cases. ANN NEUROL 2019;86:962–968
Hereditary spastic paraplegia (HSP) is one of the most genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity and pyramidal weakness of lower limbs. Because >30 causative genes have been identified, screening of multiple genes is required for establishing molecular diagnosis of individual patients with HSP. To elucidate molecular epidemiology of HSP in the Japanese population, we have conducted mutational analyses of 16 causative genes of HSP (L1CAM, PLP1, ATL1, SPAST, CYP7B1, NIPA1, SPG7, KIAA0196, KIF5A, HSPD1, BSCL2, SPG11, SPG20, SPG21, REEP1 and ZFYVE27) using resequencing microarrays, array-based comparative genomic hybridization and Sanger sequencing. The mutational analysis of 129 Japanese patients revealed 49 mutations in 46 patients, 32 of which were novel. Molecular diagnosis was accomplished for 67.3% (33/49) of autosomal dominant HSP patients. Even among sporadic HSP patients, mutations were identified in 11.1% (7/63) of them. The present study elucidated the molecular epidemiology of HSP in the Japanese population and further broadened the mutational and clinical spectra of HSP.
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