Objective:

We report the genotype and phenotype in three patients with an ultra-rare autosomal recessive myopathy caused by biallelic pathogenic or likely pathogenic variants in MSTO1.

Background:

MSTO1 is a nuclear DNA gene which encodes misato homolog 1 (MSTO1), a mitochondrial membrane protein involved in maintaining the mitochondrial network and promoting mitochondrial fusion. Pathogenic variants in MSTO1 have been reported as a cause of myopathy and ataxia, with fewer than 40 reported cases to date. Recent reports have expanded the clinical phenotype beyond myopathy and cerebellar ataxia. The literature currently describes the phenotype to include myopathy, cerebellar atrophy and ataxia, dysphagia, skeletal abnormalities, short stature, cognitive deficits, corticospinal tract dysfunction, optic atrophy, and retinopathy.

Design/Methods:

Exome or genome sequencing was used to identify genetic variants in patients with suspected hereditary myopathy who had negative results on initial targeted screening. 

Results:

Two patients (Patient 1 and 3) were 13 years old at diagnosis and one (Patient 2) was 30 years old at diagnosis. All patients presented with myopathy of varying severity and elevated creatine kinase levels. Two patients had hypotonia since birth, while one had weakness beginning at age 2. Cerebellar atrophy was noted in one of 2 patients that underwent brain MRI at age 15. Restrictive pulmonary function testing (PFT) was noted in 2 patients. Additionally, Patient 1 had tremor and ADHD; Patient 2 had autism, developmental delay, and skeletal abnormalities; Patient 3 had developmental delay, nystagmus, tremor, and skeletal abnormalities.  

Conclusions:

The phenotype of MSTO1-related syndrome includes early-onset myopathy, and less consistently cerebellar atrophy with or without later-onset ataxia. Other features may include restrictive PFTs, dysphagia, skeletal abnormalities, short stature, cognitive deficits, corticospinal tract dysfunction, optic atrophy, and retinopathy. As genome and exome sequencing becomes more accessible, further characterization of the phenotypic spectrum is likely.