Submission Details

The relationship between MPC1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 20, 2023. This gene encodes mitochondrial pyruvate carrier 1 that mediates the uptake of pyruvate into the mitochondria.

MPC1 was first reported in relation to autosomal recessive primary mitochondrial disease in 2012 (PMID: 22628558) although the first reported family was described in 2003 (PMID: 12649063), in three families with a defect in mitochondrial pyruvate oxidation. The first family, initially described in 2003, had the most severely affected individuals with neonatal encephalopathy and elevated lactate while the other two families were less severely affected and had variable developmental delay and cognitive impairment. While various names have been given to the constellation of features seen in those with MPC1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MPC1 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included seven unique missense variants identified in 14 affected individuals from nine kindreds from three publications (PMIDs: 22628558, 36079864, 34873722). Age of onset was early in life, ranging from the prenatal period to the first couple months of life. Outcomes were also variable, ranging from death at 19 months of age to an individual being alive at 20-years-old at the time of report. Of note, one individual was treated with the ketogenic diet (PMID: 36079864) and another with L-glutamine (PMID: 34873722), with clinical improvement reported. Features in affected individuals include intrauterine growth restriction, encephalopathy, severe developmental delay, hypotonia, infantile spasms, refractory epilepsy, peripheral neuropathy, microcephaly, diabetes, hearing loss, and growth failure, and there is one report of Leigh-like syndrome (PMID: 34873722). Muscle biopsy showed decreased pyruvate oxidation. Brain imaging ranged from normal to cerebral atrophy and features of the Leigh syndrome spectrum. Metabolic labs showed elevated pyruvate (blood), lactate (blood/cerebrospinal fluid); and 3-OH-butyric, alpha-ketoglutaric, 4-OH-phenylactic, and 4-OH-phenylpyruvic acids in urine.

This gene-disease association is also supported by its known biochemical function (PMID: 33340416), functional alteration in non-patient cells (PMID: 34873722), and yeast, drosophila, and mouse embryonic fibroblasts (PMID: 22628558).

In summary, there is definitive evidence to support the relationship between MPC1 and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 20, 2023 (SOP Version 10).