Case report: Rare novel MIPEP compound heterozygous variants presenting with hypertrophic cardiomyopathy, severe lactic acidosis and hypotonia in a Chinese infant

Abstract

BackgroundMitochondrial intermediate peptidase, encoded by the MIPEP gene, is involved in the processing of precursor mitochondrial proteins related to oxidative phosphorylation. Only a few studies have shown that mutations in MIPEP can cause combined oxidative phosphorylation deficiency-31 (COXPD31), an autosomal recessive multisystem disorder associated with mitochondrial dysfunction. We report herein a rare case of an 8-month-old boy in China with hypertrophic cardiomyopathy (HCM), severe lactic acidosis, and hypotonia caused by novel MIPEP compound heterozygous variants.MethodsTrio-whole-exome sequencing and copy number variation sequencing were performed to identify mutated genetic loci. Sanger sequencing and quantitative real-time PCR were used to validate the candidate single nucleotide variants and copy number variants, respectively.ResultsThe proband was an 8-month-old boy with HCM, severe lactic acidosis, and hypotonia who died 2 months after his first admission. Two novel compound heterozygous variants, c.1081T > A (p. Tyr361Asn) and a whole deletion (Ex1-19 del), were found in the MIPEP gene, which were inherited from his healthy parents respectively. Additionally, his mitochondria DNA copy number was significantly reduced.ConclusionWe are the first to report a patient with rare MIPEP variants in China. Our findings expand the mutation spectrum of MIPEP, and provide insights into the genotype-phenotype relationship in COXPD31.

Genetic Mutations and Mitochondrial Redox Signaling as Modulating Factors in Hypertrophic Cardiomyopathy: A Scoping Review

“…Early detection of oxidative stress is essential for controlling HCM progression, enabling effective interventions, and identifying potential therapeutic targets. Primary mitochondrial diseases, although rare, often result in oxidative phosphorylation dysfunction due to mtDNA variations, with approximately 40% of affected children developing heart diseases, including heart complications [ 80 ].…”

“…Significant downregulation of mitophagy-related genes has been reported in patients with HCM [ 19 ]. Findings by Nollet et al (2023a) [ 23 ] suggest that deterioration of mitochondrial quality control mechanisms contributes to the accumulation of damaged mitochondria in HCM, exacerbating the mitochondrial injury and continuing a detrimental cycle in its progression [ 1 , 22 , 80 , 83 ].…”

“…Metabolic modifications of HCM, characterized by an altered metabolic profile, abnormal mitochondrial structure, impaired respiratory function, and failure to regulate mitophagy, could guide the development of new therapeutic approaches to restore metabolic function and preserve mitochondrial integrity in the early stages of the disease. Studies have emphasized that cellular oxidative stress is a crucial factor in mitochondrial transformations, leading to structural and functional changes, alterations in cell signaling pathways, and uncontrolled ROS production, suggesting potential therapeutic benefits for various cardiovascular conditions, as shown in Figure 6 [ 9 , 80 , 84 ].…”