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Myotonia congenita (MC) is a rare neuromuscular disease caused by mutations within the CLCN1 gene encoding skeletal muscle chloride channels. MC is characterized by delayed muscle relaxation during contraction, resulting in muscle stiffness. There is a lack of MC case reports and data on the prevalence among Malaysians. We report a clinical case of a 50-year-old woman presents with muscle stiffness and cramp episodes that started in early childhood. She had difficulty initiating muscle movement and presented with transient muscle weakness after rest, which usually improved after repeated contraction (warmup phenomenon). She was diagnosed with MC after myotonic discharge on electromyography (EMG). Her brother had similar symptoms; however, no additional family members showed MC symptoms. Serum creatine kinase levels were elevated in both the proband and her brother with 447 U/L and 228 U/L recorded, respectively. Genetic analysis by whole-exome sequencing (WES) revealed a previously reported pathogenic CLCN1 gene variant c.1667T>A (p.I556N). Genetic screening of all family members revealed that the same variant was observed in the children of both the proband and her brother; however, the children did not present with either clinical or electrophysiological MC symptoms. The multiplex ligation-dependent probe amplification (MLPA) analysis conducted identified neither exon deletion nor duplication in CLCN1. In conclusion, this report describes the first case of MC in Malaysia in which incomplete penetrance observed in this family is caused by a known pathogenic CLCN1 variant. [ABSTRACT FROM AUTHOR]

Background: Hypophosphatemic rickets (HR) is a genetic disease of phosphate wasting that is characterized by defective bone mineralization. The most common cause of the disease is mutations in the phosphate regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene. The aims of this study were to identify the gene variants responsible for HR in three cases of Malaysian origin from three independent families and to describe their clinical, biochemical, and radiological features. Methods: Whole exome sequencing (WES) was performed on all patients and their parents, followed by Sanger sequencing validation. Bioinformatics tools were used to provide supporting evidence for pathogenicity of variants. To confirm that a mutation is de novo, paternity test was carried out. High resolution melting curve analysis was performed to assess the allele frequency in normal controls for mutations that were found in the patients. Results: The patients showed typical characteristics of HR including lower limb deformity, hypophosphatemia, and elevated alkaline phosphatase. WES revealed two variants in the PHEX gene and one variant in the dentin matrix protein 1 (DMP1) gene. Two of the three variants were novel, including c.1946_1954del (p.Gly649_Arg651del) in PHEX and c.54 + 1G > A in DMP1. Our data suggests that the novel p.Gly649_Arg651del variant is likely pathogenic for HR disease. Conclusions: This study extends the variant spectrum of the PHEX and DMP1 genes. Our findings indicate that WES is an advantageous approach for diagnosis of genetic diseases which are heterogeneous. [ABSTRACT FROM AUTHOR]

• SOD1 mutations (3%) and C9orf72 expansion (3%) identified in Malaysian ALS cohort. • Mutations in FUS and TARDBP are absent or rare in this cohort. • First report of the C9orf72 repeat expansion in a patient of Malay ancestry. • Expansion carriers share risk alleles with European, Chinese and Indian ALS cohorts. Recent studies have identified SOD1, FUS, TARDBP and C9orf72 as major ALS-related genes in both European and Asian populations. However, significant differences exist in the mutation frequencies of these genes between various ancestral backgrounds. This study aims to identify the frequency of mutations in the common causative ALS genes in a multi-ethnic Malaysian cohort. We screened 101 Malaysian ALS patients including 3 familial and 98 sporadic cases for mutations in the coding regions of SOD1, FUS , and TARDBP by Sanger sequencing. The C9orf72 hexanucleotide repeat expansion was screened using the repeat-primed polymerase chain reaction assay. Mutations were found in 5.9% (6 of 101) of patients including 3.0% (3 of 101) of patients with the previously reported SOD1 missense mutations (p.V48A and p.N87S) and 3.0% (3 of 101) of patients with the C9orf72 repeat expansion. No mutations were found in the FUS and TARDBP genes. This study is the first to report the mutation frequency in an ethnically diverse Malaysian ALS population and warrants further investigation to reveal novel genes and disease pathways. [ABSTRACT FROM AUTHOR]

Intermediate CAG repeats from 29 to 33 in the ATXN2 gene contributes to the risk of amyotrophic lateral sclerosis (ALS) in European and Asian populations. In this study, 148 ALS patients of multiethnic descent: Chinese (56.1%), Malay (24.3%), Indian (12.8%), others (6.8%) and 100 neurologically normal controls were screened for the ATXN2 CAG repeat expansion. The most common repeat length in both the controls and patients was 22. No familial ALS patients were positive for the intermediate repeat sizes (29-33), while four sporadic patients (2.8%) were positive, with one harbouring a rare ATXN2 homozygous 32 repeat expansion, and a likely pathogenic variant in SPAST. All four patients had limb-onset ALS. Despite representing the smallest ethnic group in our patient cohort, three of the four patients with intermediate repeat sizes were of Indian ancestry. This study, which is the first in Malaysia and Southeast Asia, shows that ATXN2 intermediate risk expansions are relevant to ALS in these populations and will help to inform future genetic testing strategies in the clinic., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Charcot-Marie-Tooth (CMT) disease is a form of inherited peripheral neuropathy that affects motor and sensory neurons. To identify the causative gene in a consanguineous family with autosomal recessive CMT (AR-CMT), we employed a combination of linkage analysis and whole exome sequencing. After excluding known AR-CMT genes, genome-wide linkage analysis mapped the disease locus to a 7.48-Mb interval on chromosome 14q32.11-q32.33, flanked by the markers rs2124843 and rs4983409. Whole exome sequencing identified two non-synonymous variants (p.T40P and p.H915Y) in the AHNAK2 gene that segregated with the disease in the family. Pathogenic predictions indicated that p.T40P is the likely causative allele. Analysis of AHNAK2 expression in the AR-CMT patient fibroblasts showed significantly reduced mRNA and protein levels. AHNAK2 binds directly to periaxin which is encoded by the PRX gene, and PRX mutations are associated with another form of AR-CMT (CMT4F). The altered expression of mutant AHNAK2 may disrupt the AHNAK2-PRX interaction in which one of its known functions is to regulate myelination.