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Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and
Pegah Beheshti1, Fahimeh Akbarian1, Emran Esmaeilzadeh2
1Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
Clinical Genetics
|September 3, 2025
Summary
Myopathy with extrapyramidal signs (MPXPS) is a rare genetic disorder caused by MICU1 gene variants. This study details 62 cases, revealing common symptoms like learning difficulties and myopathy, and suggests MCU modulation for potential therapies.
Area of Science:
- Genetics
- Neurology
- Mitochondrial Biology
Background:
- Myopathy with extrapyramidal signs (MPXPS) is a rare, autosomal-recessive, multisystem disorder.
- It is caused by biallelic loss-of-function (LOF) variants in the MICU1 gene, which regulates mitochondrial calcium uptake.
Purpose of the Study:
- To clinically and genetically characterize individuals with MPXPS.
- To identify pathogenic MICU1 variants and understand the genotype-phenotype correlation.
- To explore potential therapeutic avenues targeting MCU modulation.
Main Methods:
- Clinical and genetic characterization of seven affected individuals from six Iranian-Turkish families.
- Exome sequencing to identify MICU1 variants.
- Combined data with 54 previously published cases for a cohort of 62 patients.
- Deep phenotyping and analysis of age at onset and common symptoms.
Main Results:
- Six pathogenic MICU1 variants were identified: 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*).
- The mean age at onset was 5.9 years, with 61.5% presenting before age 5.
- Common symptoms included learning difficulties (72%), myopathy (51%), and speech impairments (51%).
- An adult-onset case showed rapid progression, and monozygotic twins had indistinguishable clinical courses.
Conclusions:
- MICU1 variants are a significant cause of MPXPS, with a consistent genotype-driven phenotype.
- MPXPS presents with a spectrum of symptoms, including neurological and muscular deficits.
- Further research into MCU modulation may offer future therapeutic strategies for MPXPS.
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