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Background: Mutations in the PRRT2 gene have recently been identified in patients with familial paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) and patients with sporadic PKD/IC from several ethnic groups. To extend these recent genetic reports, we investigated the frequency and identities of PRRT2 mutations in a cohort of Taiwanese patients with PKD/IC. Methodology and Principal Findings: We screened all 3 coding exons of PRRT2 for mutations in 28 Taiwanese patients with PKD/IC. Among them, 13 had familial PKD/IC and 15 were apparently sporadic cases. In total, 7 disparate mutations were identified in 13 patients, including 8 familial cases and 5 apparently sporadic cases. The mutations were not present in 500 healthy controls. Four mutations were novel. One patient had a missense mutation and all other patients carried PRRT2 mutations putatively resulting in a protein truncation. Haplotype analysis revealed that 5 of the 7 patients with the PRRT2 p.R217Pfs*8 mutation shared the same haplotype linked to the mutation. Conclusions and Significance: PRRT2 mutations account for 61.5% (8 out of 13) of familial PKD/IC and 33.3% (5 out of 15) of apparently sporadic PKD/IC in the Taiwanese cohort. Most patients with the PRRT2 p.R217Pfs*8 mutation in Taiwan likely descend from a single common ancestor. This study expands the spectrum of PKD/IC-associated PRRT2 mutations, highlights the pathogenic role of PRRT2 mutations in PKD/IC, and suggests genetic heterogeneity within idiopathic PKD. [ABSTRACT FROM AUTHOR]

Background: Charcot-Marie-Tooth disease type 2 (CMT2) is a clinically and genetically heterogeneous group of inherited axonal neuropathies. The aim of this study was to extensively investigate the mutational spectrum of CMT2 in a cohort of patients of Han Chinese. Methodology and Principal Findings Genomic DNA from 36 unrelated Taiwanese CMT2 patients of Han Chinese descent was screened for mutations in the coding regions of the MFN2, RAB7, TRPV4, GARS, NEFL, HSPB1, MPZ, GDAP1, HSPB8, DNM2, AARS and YARS genes. Ten disparate mutations were identified in 14 patients (38.9% of the cohort), including p.N71Y in AARS (2.8%), p.T164A in HSPB1 (2.8%), and p.[H256R]+[R282H] in GDAP1 (2.8%) in one patient each, three NEFL mutations in six patients (16.7%) and four MFN2 mutations in five patients (13.9%). The following six mutations were novel: the individual AARS, HSPB1 and GDAP1 mutations and c.475-1G>T, p.L233V and p.E744M mutations in MFN2. An in vitro splicing assay revealed that the MFN2 c.475-1G>T mutation causes a 4 amino acid deletion (p.T159_Q162del). Despite an extensive survey, the genetic causes of CMT2 remained elusive in the remaining 22 CMT2 patients (61.1%). Conclusions and Significance This study illustrates the spectrum of CMT2 mutations in a Taiwanese CMT2 cohort and expands the number of CMT2-associated mutations. The relevance of the AARS and HSPB1 mutations in the pathogenesis of CMT2 is further highlighted. Moreover, the frequency of the NEFL mutations in this study cohort was unexpectedly high. Genetic testing for NEFL and MFN2 mutations should, therefore, be the first step in the molecular diagnosis of CMT2 in ethnic Chinese. [ABSTRACT FROM AUTHOR]

Introduction. Familial amyloid polyneuropathy (FAP) is a rare autosomal dominant peripheral neuropathy. We report a case series of Malaysian FAP patients. Methods. Patients with definite (genetically confirmed) FAP seen at the University of Malaya Medical Centre between 2008 till 2019 were included in the series. The patients' demographic and clinical features and investigations including nerve conduction studies and electromyography (NCS/EMG), echocardiography, sural nerve biopsy and hATTR mutation are reported. Results. A total 21 index cases were seen. Nineteen (90%) were ethnic Chinese, one ethnic (5%) Malay and one (5%) ethnic Indian; Fourteen (67%) were men. Mean age of onset of symptoms was 56.1 ± 10.5 years (range: 31-73). Nineteen (90%) patients presented with numbness and weakness of the limbs while two had postural hypotension. Fifteen (71%) patients had positive family history. NCS/EMG showed sensorimotor polyneuropathy in 19 (90%) patients; fifteen (71%) showing axonal neuropathy. Amyloid deposits were seen on nerve biopsy in ten patients and rectal, leptomeningeal and endomyocardial biopsies in 1 patient respectively. The latter was diagnosed as familial amyloid cardiomyopathy (FAC). Sixteen patients (76%) had abnormal cardiac echocardiogram with amyloid deposits. Fifteen Chinese patients (71%) carried the Ala97Ser hATTR mutation while the FAC patient has Asp39Val mutation. Our Malay patient had Glu54Lys mutation and Indian patient had Gly67Val mutation. Two patients carried Val30Met mutation. Autonomic function test was abnormal in all 7 patients in whom they were carried out. Conclusion. FAP in Malaysians is seen mainly among ethnic Chinese, in whom Ala97Ser may be a common mutation. This is also the reported "hotspot" mutation for FAP reported in Taiwan but not in China. Similar to Taiwan, Chinese-Malaysians are descended from immigrants from Southern China. Similar to Taiwanese patients, our FAP patients with Ala97Ser mutation, present with late-onset progressive sensorimotor polyneuropathy and cardiac involvement was common. [ABSTRACT FROM AUTHOR]