MPV17-related mitochondrial DNA maintenance defect

New cases and review of clinical, biochemical, and molecular aspects

Ayman W. El-Hattab, Julia Wang, Hongzheng Dai, Mohammed Almannai, Christian Staufner, Majid Alfadhel, Michael J. Gambello, Pankaj Prasun, Saleem Raza, Hernando J. Lyons, Manal Afqi, Mohammed A.M. Saleh, Eissa A. Faqeih, Hamad I. Alzaidan, Abduljabbar Alshenqiti, Leigh Anne Flore, Jozef Hertecant, Stephanie Sacharow, Deborah S Barbouth, Kei Murayama & 3 others Amit A. Shah, Henry C. Lin, Lee Jun C. Wong

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
JournalHuman Mutation
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Mitochondrial DNA
Maintenance
Liver
Mitochondrial Dynamics
Deficiency Diseases
Protein Deficiency
Failure to Thrive
Peripheral Nervous System Diseases
Muscular Diseases
Neurologic Manifestations
Mitochondria
Membrane Proteins
Milk
Nucleotides
Genotype
Proteins

Keywords

  • Mitochondrial DNA (mtDNA)
  • MPV17
  • MtDNA depletion
  • MtDNA maintenance
  • Multiple mtDNA deletions

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

El-Hattab, A. W., Wang, J., Dai, H., Almannai, M., Staufner, C., Alfadhel, M., ... Wong, L. J. C. (Accepted/In press). MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects. Human Mutation. https://doi.org/10.1002/humu.23387

MPV17-related mitochondrial DNA maintenance defect : New cases and review of clinical, biochemical, and molecular aspects. / El-Hattab, Ayman W.; Wang, Julia; Dai, Hongzheng; Almannai, Mohammed; Staufner, Christian; Alfadhel, Majid; Gambello, Michael J.; Prasun, Pankaj; Raza, Saleem; Lyons, Hernando J.; Afqi, Manal; Saleh, Mohammed A.M.; Faqeih, Eissa A.; Alzaidan, Hamad I.; Alshenqiti, Abduljabbar; Flore, Leigh Anne; Hertecant, Jozef; Sacharow, Stephanie; Barbouth, Deborah S; Murayama, Kei; Shah, Amit A.; Lin, Henry C.; Wong, Lee Jun C.

In: Human Mutation, 01.01.2018.

Research output: Contribution to journalArticle

El-Hattab, AW, Wang, J, Dai, H, Almannai, M, Staufner, C, Alfadhel, M, Gambello, MJ, Prasun, P, Raza, S, Lyons, HJ, Afqi, M, Saleh, MAM, Faqeih, EA, Alzaidan, HI, Alshenqiti, A, Flore, LA, Hertecant, J, Sacharow, S, Barbouth, DS, Murayama, K, Shah, AA, Lin, HC & Wong, LJC 2018, 'MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects', Human Mutation. https://doi.org/10.1002/humu.23387
El-Hattab, Ayman W. ; Wang, Julia ; Dai, Hongzheng ; Almannai, Mohammed ; Staufner, Christian ; Alfadhel, Majid ; Gambello, Michael J. ; Prasun, Pankaj ; Raza, Saleem ; Lyons, Hernando J. ; Afqi, Manal ; Saleh, Mohammed A.M. ; Faqeih, Eissa A. ; Alzaidan, Hamad I. ; Alshenqiti, Abduljabbar ; Flore, Leigh Anne ; Hertecant, Jozef ; Sacharow, Stephanie ; Barbouth, Deborah S ; Murayama, Kei ; Shah, Amit A. ; Lin, Henry C. ; Wong, Lee Jun C. / MPV17-related mitochondrial DNA maintenance defect : New cases and review of clinical, biochemical, and molecular aspects. In: Human Mutation. 2018.
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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.

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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.

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