MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects

Abstract

Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early-onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late-onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis.

MPV17 mutations in juvenile‐ and adult‐onset axonal sensorimotor polyneuropathy

“…We describe five patients from two unrelated families with homozygous MPV17 mutations with isolated, juvenile‐onset peripheral neuropathy. MPV17 ‐related disease generally presents with peripheral nerve dysfunction, but neuropathy is rarely the predominant feature, as infantile‐ or early‐childhood‐onset chronic liver failure and progressive CNS involvement usually cause severe morbidity and early mortality . This constellation is similar in other mitochondrial conditions in which a peripheral neuropathy is part of the clinical picture, for example, ataxia‐neuropathy spectrum ( POLG1 mutations), mitochondrial neurogastrointestinal encephalopathy ( TYMP mutations) or neuropathy, ataxia, and retinitis pigmentosa ( MTATP6 mutations) .…”

“…MPV17-related disease generally presents with peripheral nerve dysfunction, but neuropathy is rarely the predominant feature, as infantile-or early-childhood-onset chronic liver failure and progressive CNS involvement usually cause severe morbidity and early mortality. 4,9 This constellation is similar in other mitochondrial conditions in which a peripheral neuropathy is part of the clinical picture, for example, ataxia-neuropathy spectrum (POLG1 mutations), mitochondrial neurogastrointestinal encephalopathy (TYMP mutations) or neuropathy, ataxia, and retinitis pigmentosa (MTATP6 mutations). 10 Mitochondrial neuropathies presenting as isolated Charcot-Marie-Tooth disease arise from MFN2 (CMT2A2), GDAP1 (CMT2K, CMT4A, CMTRIA) and-in few families-MTATP6 mutations.…”

“…Patients F2.1, F2.2 and F2.3 carry a newly described homozygous splice‐region mutation (c.376‐9T>G), leading to an in‐frame deletion due to skipping of exon 6 in a considerable proportion of MPV17 mRNA. Notably, similar c.376‐1G>A and c.376‐2A>C variants were recently reported in cases with neurohepatopathy . Although no mRNA studies were presented for these variants, it is conceivable that they have more serious effects on splicing, probably resulting in skipping of exon 6 in all transcripts, which may explain the more severe phenotype.…”

“…These findings are most similar to those in two patients reported by Choi et al, who were diagnosed with neuropathy at age 9 and 13 years and have remained without signs of liver or brain involvement until age 22 and 34 years, respectively (Table S1). 8 9 Although no mRNA studies were presented for these variants, it is conceivable that they have more serious effects on splicing, probably resulting in skipping of exon 6 in all transcripts, which may explain the more severe phenotype. On the other hand, the c.122G>A (Table S1).…”

First cases of MPV17 related mitochondrial DNA depletion syndrome with compound heterozygous mutations in p.R50Q/p.R50W: a case report

“…To date, MPV17-related hepatocerebral MTDPS has been reported in 96 patients [4,5, . Disease prognosis is severe, given that ~80% of patients die from liver failure during early childhood [30] . Hepatic cirrhosis has been diagnosed in 20 patients, while three patients had hepatocellular carcinoma (HCC) [10,15,25] .…”