TY - JOUR
T1 - MPV17-related mitochondrial DNA maintenance defect
T2 - New cases and review of clinical, biochemical, and molecular aspects
AU - El-Hattab, Ayman W.
AU - Wang, Julia
AU - Dai, Hongzheng
AU - Almannai, Mohammed
AU - Staufner, Christian
AU - Alfadhel, Majid
AU - Gambello, Michael J.
AU - Prasun, Pankaj
AU - Raza, Saleem
AU - Lyons, Hernando J.
AU - Afqi, Manal
AU - Saleh, Mohammed A.M.
AU - Faqeih, Eissa A.
AU - Alzaidan, Hamad I.
AU - Alshenqiti, Abduljabbar
AU - Flore, Leigh Anne
AU - Hertecant, Jozef
AU - Sacharow, Stephanie
AU - Barbouth, Deborah S.
AU - Murayama, Kei
AU - Shah, Amit A.
AU - Lin, Henry C.
AU - Wong, Lee Jun C.
N1 - Publisher Copyright:
© 2017 Wiley Periodicals, Inc.
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
KW - MPV17
KW - mitochondrial DNA (mtDNA)
KW - mtDNA depletion
KW - mtDNA maintenance
KW - multiple mtDNA deletions
UR - http://www.scopus.com/inward/record.url?scp=85040600092&partnerID=8YFLogxK
U2 - 10.1002/humu.23387
DO - 10.1002/humu.23387
M3 - Article
C2 - 29282788
AN - SCOPUS:85040600092
VL - 39
SP - 461
EP - 470
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 4
ER -