Novel Homozygous Mitochondrial Calcium Uptake Protein 1 Variant (c.38T>C, p.Leu13Pro) in a 7-year-old Girl with Congenital Ptosis and Proximal Myopathy: Expanding the Phenotypic Spectrum.

Abstract

ABSTRACT Myopathy with extrapyramidal signs (OMIM #615673) is a rare autosomal recessive mitochondrial disorder caused by biallelic loss-of-function variants in Mitochondrial calcium uptake protein 1 (MICU1), which encodes the gatekeeper of the mitochondrial calcium uniporter complex. We report a 7-year-old Indian girl with global developmental delay, congenital nonfatiguable right ptosis, proximal-predominant myopathy without calf hypertrophy, multi-system dysmorphism (elongated facies, baggy cheeks, large prominent ears, partial webbed neck, bilateral clinodactyly, fetal finger pads, pes planus, and sandal gap), and thickened corpus callosum on magnetic resonance imaging. Creatine kinase ranged between 4068 and 4732 U/L; electromyography demonstrated a myogenic pattern with normal nerve conduction and nondecremental repetitive nerve stimulation. Whole-exome sequencing identified a novel homozygous missense variant, c.38T>C (p.Leu13Pro), in exon 1 of MICU1, classified as a variant of uncertain significance. To our knowledge, this is the first reported pediatric MICU1 case with congenital ptosis, absence of calf hypertrophy, and a structural corpus callosum abnormality, substantially broadening the phenotypic spectrum of MICU1-related myopathy.