Akademik Veri Yönetim Sistemi
Clinical Genetics, 2025 (SCI-Expanded)
Myopathy with extrapyramidal signs (MPXPS) is a rare, autosomal-recessive, multisystem disorder caused by biallelic loss-of-function (LOF) variants in MICU1, the calcium-sensing gatekeeper of the mitochondrial calcium uniporter. We clinically and genetically characterized seven affected individuals from six Iranian-Turkish consanguineous families and combined these data with 54 previously published cases (total of 62). The targeted neuromuscular assessment, along with muscle biopsy and exome sequencing, identified six pathogenic MICU1 variants, including c.355C>T; p.Arg119*, c.493 + 1G>A, c.508C>T; p.Gln170*, c.547C>T; p.Gln183*, c.1226C>G; p.Ser409*, and c.553C>T; p.Arg185*. Notably, we report one adult-onset patient whose symptoms began at age 29 and progressed more rapidly than those in childhood-onset cases. A separate pedigree contained monozygotic twins who exhibited an indistinguishable clinical course, emphasizing the consistency of the genotype-driven phenotype. Across the combined cohort, the mean age at onset was 5.9 ± 7.3 years (median = 3 years); 61.5% presented before age 5, while 9.5% manifested after 15 years. Deep phenotyping of 61 patients from different ethnic backgrounds revealed that common symptoms included learning difficulties (72%), myopathy (51%), and speech impairments (51%). Functional studies targeting MCU modulation may provide future therapeutic options.