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The recessive intronic pentanucleotide repeat AAGGG expansion of replication factor complex subunit 1 (RFC1) is associated with cerebellar ataxia, sensory neuropathy, and vestibular areflexia syndrome. And the clinical spectrum has been continuously expanding. We conducted this study to demonstrate the clinical and genetic features of a large-scale case series of Japanese patients with cerebellar ataxia with RFC1 repeat expansions. We examined 1,289 Japanese patients with cerebellar ataxia and analyzed RFC1 repeat expansions in 840 patients, excluding those with genetic diagnoses or an autosomal dominant inheritance pattern. For individuals where no product was obtained by flanking polymerase chain reaction (PCR), repeat-primed PCR was performed using primers specific for the following four repeat motifs: AAAAG, AAAGG, AAGGG, and ACAGG. RFC1 analysis revealed multitype biallelic pathogenic repeat expansions in 15 patients, including (AAGGG)exp/(AAGGG)exp in seven patients, (ACAGG)exp/(ACAGG)exp in three patients, (AAGGG)exp/(ACAGG)exp in four patients, and (AAGGG)exp/(AAAGG)15(AAGGG)exp in one patient. Clinical analysis showed various combinations of cerebellar ataxia, vestibular dysfunction, neuropathy, cognitive decline, autonomic dysfunction, chronic cough, pyramidal tract disorder, parkinsonism, involuntary movement, and muscle fasciculation. Pathological RFC1 repeat expansions account for 1.8% (15/840) of undiagnosed patients with cerebellar ataxia and sporadic/recessive/unclassified inheritance. Screening of RFC1 repeat expansions should be considered in patients with cerebellar ataxia, irrespective of their subtype and onset age.

We report a patient with myelin oligodendrocyte glycoprotein (MOG) antibody positivity who manifested myelitis with right optic perineuritis (OPN) 6 years following left OPN. A 45-year-old man treated 6 years previously for left OPN developed ascending numbness in both legs, urinary dysfunctions, and constipation. Neurologic examination disclosed bilateral hypesthesia extending downward over the chest from the T8 level. No motor weakness was evident. Visual field testing showed dense peripheral constriction with intact central vision on the right and a smaller superior scotoma on the left. Visual acuity and funduscopic findings were normal. Results of routine serologic investigations and autoimmune antibody titers, including those of anti-aquaporin 4 antibody, were within normal limits, except that both serum and cerebrospinal fluid were positive for anti-MOG antibody. MRI displayed a longitudinal cord lesion extending from T2 to T9, as well as optic nerve sheath enhancement characteristic of OPN. The patient was diagnosed with myelitis in addition to OPN, both resulting from MOG antibody-associated demyelination. Patients with myelitis, require careful assessment of visual acuity and visual fields to detect possible accompanying OPN and ON. We suspect that OPN in some other patients may likewise be caused by anti-MOG antibody.

BackgroundNOTCH2NLCGGC repeat expansions have been associated with various neurogenerative disorders, including neuronal intranuclear inclusion disease and inherited peripheral neuropathies (IPNs). However, only a fewNOTCH2NLC-related disease studies in IPN have been reported, and the clinical and genetic spectra remain unclear. Thus, this study aimed to describe the clinical and genetic manifestations ofNOTCH2NLC-related IPNs.MethodAmong 2692 Japanese patients clinically diagnosed with IPN/Charcot–Marie–Tooth disease (CMT), we analysedNOTCH2NLCrepeat expansion in 1783 unrelated patients without a genetic diagnosis. Screening and repeat size determination ofNOTCH2NLCrepeat expansion were performed using repeat-primed PCR and fluorescence amplicon length analysis-PCR.ResultsNOTCH2NLCrepeat expansions were identified in 26 cases of IPN/CMT from 22 unrelated families. The mean median motor nerve conduction velocity was 41 m/s (range, 30.8–59.4), and 18 cases (69%) were classified as intermediate CMT. The mean age of onset was 32.7 (range, 7–61) years. In addition to motor sensory neuropathy symptoms, dysautonomia and involuntary movements were common (44% and 29%). Furthermore, the correlation between the age of onset or clinical symptoms and the repeat size remains unclear.ConclusionsThese findings of this study help us understand the clinical heterogeneity ofNOTCH2NLC-related disease, such as non-length-dependent motor dominant phenotype and prominent autonomic involvement. This study also emphasise the importance of genetic screening, regardless of the age of onset and type of CMT, particularly in patients of Asian origin, presenting with intermediate conduction velocities and dysautonomia.

This study aimed to evaluate genotype-phenotype correlations of Parkinson’s disease (PD) patients with phospholipase A2 group V (PLA2G6) variants. We analyzed the DNA of 798 patients with PD, including 78 PD patients reported previously, and 336 in-house controls. We screened the exons and exon-intron boundaries of PLA2G6 using the Ion Torrent system and Sanger method. We identified 21 patients with 18 rare variants, such that 1, 9, and 11 patients were homozygous, heterozygous, and compound heterozygous, respectively, with respect to PLA2G6 variants. The allele frequency was approximately equal between patients with familial PD and those with sporadic PD. The PLA2G6 variants detected frequently were identified in the early-onset sporadic PD group. Patients who were homozygous for a variant showed more severe symptoms than those who were heterozygous for the variant. The most common variant was p.R635Q in our cohort, which was considered a risk variant for PD. Thus, the variants of PLA2G6 may play a role in familial PD and early-onset sporadic PD.