Journal of Neurology

, Volume 259, Issue 5, pp 862–868 | Cite as

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations

  • Sha Tang
  • Elliot L. Dimberg
  • Margherita Milone
  • Lee-Jun C. Wong
Original Communication

Abstract

The aim of the study was to determine the prevalence of MNGIE-like phenotype in patients with recessive POLG1 mutations. Mutations in the POLG1 gene, which encodes for the catalytic subunit of the mitochondrial DNA polymerase gamma essential for mitochondrial DNA replication, cause a wide spectrum of mitochondrial disorders. Common phenotypes associated with POLG1 mutations include Alpers syndrome, ataxia-neuropathy syndrome, and progressive external ophthalmoplegia (PEO). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by severe gastrointestinal dysmotility, cachexia, PEO and/or ptosis, peripheral neuropathy, and leukoencephalopathy. MNGIE is caused by TYMP mutations. Rare cases of MNGIE-like phenotype have been linked to RRM2B mutations. Recently, POLG1 mutations were identified in a family with clinical features of MNGIE but no leukoencephalopathy. The coding regions and exon–intron boundaries of POLG1 were sequence analyzed in patients suspected of POLG1 related disorders. Clinical features of 92 unrelated patients with two pathogenic POLG1 alleles were carefully reviewed. Three patients, accounting for 3.3% of all patients with two pathogenic POLG1 mutations, were found to have clinical features consistent with MNGIE but no leukoencephalopathy. Patient 1 carries p.W748S and p.R953C; patient 2 is homozygous for p.W748S, and patient 3 is homozygous for p.A467T. In addition, patient 2 has a similarly affected sibling with the same POLG1 genotype. POLG1 mutations may cause MNGIE-like syndrome, but the lack of leukoencephalopathy and the normal plasma thymidine favor POLG1 mutations as responsible molecular defect.

Keywords

POLG1 MNGIE Mitochondrial DNA Pseudo-obstruction Leukoencephalopathy 

Notes

Acknowledgments

We thank Drs. Laurence Walsh and Fernando Kok for referring patients 2 and 3 for the study.

Conflict of Interest

None.

References

  1. 1.
    Nishino I, Spinazzola A, Papadimitriou A et al (2000) Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol 47(6):792–800PubMedCrossRefGoogle Scholar
  2. 2.
    Nishino I, Spinazzola A, Hirano M (1999) Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283(5402):689–692PubMedCrossRefGoogle Scholar
  3. 3.
    Shaibani A, Shchelochkov OA, Zhang S et al (2009) Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B. Arch Neurol 66(8):1028–1032PubMedCrossRefGoogle Scholar
  4. 4.
    Van Goethem G, Schwartz M, Lofgren A et al (2003) Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. Eur J Hum Genet 11(7):547–549PubMedCrossRefGoogle Scholar
  5. 5.
    Tang S, Wang J, Lee N, Milone M, Halberg MC, Schmitt ES, Craigen WJ, Zhang W, Wong LC (2011) Mitochondrial DNA polymerase γ mutations: an ever expanding molecular and clinical spectrum. J Med Genet 48(10):669–681PubMedCrossRefGoogle Scholar
  6. 6.
    Wong LJ, Naviaux RK, Brunetti-Pierri N et al (2008) Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat 29(9):E150–E172PubMedCrossRefGoogle Scholar
  7. 7.
    Chinault AC, Shaw CA, Brundage EK et al (2009) Application of dual-genome oligonucleotide array-based comparative genomic hybridization to the molecular diagnosis of mitochondrial DNA deletion and depletion syndromes. Genet Med 11(7):518–526PubMedCrossRefGoogle Scholar
  8. 8.
    Wong LJ, Dimmock D, Geraghty MT et al (2008) Utility of oligonucleotide array-based comparative genomic hybridization for detection of target gene deletions. Clin Chem 54(7):1141–1148PubMedCrossRefGoogle Scholar
  9. 9.
    Shanske S, Wong LJ (2004) Molecular analysis for mitochondrial DNA disorders. Mitochondrion 4(5–6):403–415PubMedCrossRefGoogle Scholar
  10. 10.
    Bai RK, Wong LJ (2005) Simultaneous detection and quantification of mitochondrial DNA deletion(s), depletion, and over-replication in patients with mitochondrial disease. J Mol Diagn 7(5):613–622PubMedCrossRefGoogle Scholar
  11. 11.
    Dimmock D, Tang LY, Schmitt ES et al (2010) Quantitative evaluation of the mitochondrial DNA depletion syndrome. Clin Chem 56(7):1119–1127PubMedCrossRefGoogle Scholar
  12. 12.
    Venegas V, Wang J, Dimmock D, et al. (2011) Real-time quantitative PCR analysis of mitochondrial DNA content. Curr Protoc Hum Genet Chapter 19:Unit 19.7Google Scholar
  13. 13.
    Luoma P, Melberg A, Rinne JO et al (2004) Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 364(9437):875–882PubMedCrossRefGoogle Scholar
  14. 14.
    Milone M, Massie R (2010) Polymerase gamma 1 mutations: clinical correlations. Neurologist 16(2):84–91PubMedCrossRefGoogle Scholar
  15. 15.
    Cohen BH, Naviaux RK (2010) The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders. Methods 51(4):364–373PubMedCrossRefGoogle Scholar
  16. 16.
    Taanman JW, Rahman S, Pagnamenta AT et al (2009) Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion. Hum Mutat 30(2):248–254PubMedCrossRefGoogle Scholar
  17. 17.
    Deschauer M, Tennant S, Rokicka A et al (2007) MELAS associated with mutations in the POLG1 gene. Neurology 68(20):1741–1742PubMedCrossRefGoogle Scholar
  18. 18.
    Milone M, Wang J, Liewluck T et al (2011) Novel POLG splice site mutation and optic atrophy. Arch Neurol 68(6):806–811PubMedCrossRefGoogle Scholar
  19. 19.
    Santoro L, Manganelli F, Lanzillo R et al (2006) A new POLG1 mutation with peo and severe axonal and demyelinating sensory-motor neuropathy. J Neurol 253(7):869–874PubMedCrossRefGoogle Scholar
  20. 20.
    Nishigaki Y, Marti R, Copeland WC et al (2003) Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency. J Clin Invest 111(12):1913–1921PubMedGoogle Scholar
  21. 21.
    Giordano C, Sebastiani M, De Giorgio R et al (2008) Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion. Am J Pathol 173(4):1120–1128PubMedCrossRefGoogle Scholar
  22. 22.
    Vissing J, Ravn K, Danielsen ER et al (2002) Multiple mtDNA deletions with features of MNGIE. Neurology 59(6):926–929PubMedCrossRefGoogle Scholar
  23. 23.
    Hirano M, Lagier-Tourenne C, Valentino ML et al (2005) Thymidine phosphorylase mutations cause instability of mitochondrial DNA. Gene 354:152–156PubMedCrossRefGoogle Scholar
  24. 24.
    Pontarin G, Fijolek A, Pizzo P et al (2008) Ribonucleotide reduction is a cytosolic process in mammalian cells independently of DNA damage. Proc Natl Acad Sci USA 105(46):17801–17806PubMedCrossRefGoogle Scholar
  25. 25.
    Bourdon A, Minai L, Serre V et al (2007) Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet 39(6):776–780PubMedCrossRefGoogle Scholar
  26. 26.
    Tyynismaa H, Ylikallio E, Patel M et al (2009) A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions. Am J Hum Genet 85(2):290–295PubMedCrossRefGoogle Scholar
  27. 27.
    Spelbrink JN, Toivonen JM, Hakkaart GA et al (2000) In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells. J Biol Chem 275(32):24818–24828PubMedCrossRefGoogle Scholar
  28. 28.
    Milone M, Brunetti-Pierri N, Tang LY et al (2008) Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations. Neuromuscul Disord 18(8):626–632PubMedCrossRefGoogle Scholar
  29. 29.
    Szigeti K, Sule N, Adesina AM et al (2004) Increased blood-brain barrier permeability with thymidine phosphorylase deficiency. Ann Neurol 56(6):881–886PubMedCrossRefGoogle Scholar
  30. 30.
    Hirano M, Silvestri G, Blake DM et al (1994) Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology 44(4):721–727PubMedCrossRefGoogle Scholar
  31. 31.
    Amiot A, Tchikviladze M, Joly F et al (2009) Frequency of mitochondrial defects in patients with chronic intestinal pseudo-obstruction. Gastroenterology 137(1):101–109PubMedCrossRefGoogle Scholar
  32. 32.
    Chinnery PF, Turnbull DM (1997) Clinical features, investigation, and management of patients with defects of mitochondrial DNA. J Neurol Neurosurg Psychiatry 63(5):559–563PubMedCrossRefGoogle Scholar
  33. 33.
    Kapur RP, Fligner C, Maghsoodi B et al (2011) Gastrointestinal neuromuscular pathology in alpers disease. Am J Surg Pathol 35(5):714–722PubMedCrossRefGoogle Scholar
  34. 34.
    Marti’ R, Verschuuren JJGM, Buchman A et al (2005) Late-oset MNGIE due to partial loss of thymidine phosphorylase activity. Ann Neurol 58(4):649–652CrossRefGoogle Scholar
  35. 35.
    Echaniz-Laguna A, Chassagne M, de Sèze J et al (2010) POLG1 variations presenting as multiple sclerosis. Arch Neurol 67(9):1140–1143PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Sha Tang
    • 1
    • 2
  • Elliot L. Dimberg
    • 3
  • Margherita Milone
    • 4
  • Lee-Jun C. Wong
    • 1
    • 2
  1. 1.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  2. 2.Medical Genetics LaboratoriesBaylor College of MedicineHoustonUSA
  3. 3.Department of NeurologyMayo ClinicJacksonvilleUSA
  4. 4.Department of NeurologyMayo ClinicRochesterUSA

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