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PMID: 10417290 Published · ppublish English Journal Article

Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993.

American journal of human genetics ·Vol. 65 ·No. 2 ·1999-08-00 ·Pages 474-82

White SL, Collins VR, Wolfe R, Cleary MA, Shanske S, DiMauro S, Dahl HH, Thorburn DR

Abstract

Mitochondrial genetics is complicated by heteroplasmy, or mutant load, which may be from 1%-99%, and thus may produce a gene dosage-type effect. Limited data are available for genotype/phenotype correlations in disorders caused by mtDNA mutations; therefore, prenatal diagnosis for mtDNA mutations has been hindered by an inability to predict accurately the clinical severity expected from a mutant load measured in fetal tissue. After reviewing 44 published and 12 unpublished pedigrees, we considered the possibility of prenatal diagnosis for two common mtDNA mutations at nucleotide 8993. We related the severity of symptoms to the mutant load and predicted the clinical outcome of a given mutant load. We also used the available data to generate empirical recurrence risks for genetic counseling, which may be used in conjunction with prenatal diagnosis.

MeSH Terms
Adenosine Triphosphatases/genetics Child DNA, Mitochondrial/genetics Female Gene Dosage Genetic Counseling Genotype Humans Logistic Models Male Molecular Sequence Data Mothers Mutation Pedigree Phenotype Prenatal Diagnosis Prognosis Risk Assessment
Chemicals
DNA, Mitochondrial Adenosine Triphosphatases
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
White S L
The Murdoch Institute, Royal Children's Hospital, Melbourne, Australia.
Collins V R
Wolfe R
Cleary M A
Shanske S
DiMauro S
Dahl H H
Thorburn D R
References (39)
39 references, click to expand
  1. Isolated case of mental retardation and ataxia due to a de novo mitochondrial T8993G mutation.
    Am J Hum Genet. 1996 Mar;58(3):636-8 PMID: 8644724
  2. Leigh syndrome: clinical features and biochemical and DNA abnormalities.
    Ann Neurol. 1996 Mar;39(3):343-51 PMID: 8602753
  3. Mitochondrial genetics '98 is the bottleneck cracked?
    Am J Hum Genet. 1998 Apr;62(4):752-7 PMID: 9529369
  4. Comparative biochemical studies in fibroblasts from patients with different forms of Leigh syndrome.
    J Inherit Metab Dis. 1996;19(1):43-50 PMID: 8830176
  5. Clinical, biochemical, and molecular analysis of a maternally inherited case of Leigh syndrome (MILS) associated with the mtDNA T8993G point mutation.
    J Inherit Metab Dis. 1995;18(6):682-8 PMID: 8750605
  6. Leigh syndrome associated with mitochondrial DNA 8993 T-->G mutation and ragged-red fibers.
    Pediatr Neurol. 1996 Jul;15(1):72-5 PMID: 8858707
  7. A near homoplasmic T8993G mtDNA mutation in a patient with atypic Leigh syndrome not present in the mother's tissues.
    J Inherit Metab Dis. 1997 Mar;20(1):49-53 PMID: 9061567
  8. Leigh syndrome resulting from de novo mutation at position 8993 of mitochondrial DNA.
    J Inherit Metab Dis. 1997 Mar;20(1):102-3 PMID: 9061574
  9. Skewed segregation of the mtDNA nt 8993 (T-->G) mutation in human oocytes.
    Am J Hum Genet. 1997 Jun;60(6):1495-501 PMID: 9199572
  10. Mitochondrial disease associated with the T8993G mutation of the mitochondrial ATPase 6 gene: a clinical, biochemical, and molecular study in six families.
    J Neurol Neurosurg Psychiatry. 1997 Jul;63(1):16-22 PMID: 9221962
  11. Heterogeneous clinical presentation of the mtDNA NARP/T8993G mutation.
    Neurology. 1997 Jul;49(1):270-3 PMID: 9222207
  12. Segregation of the G8993 mutant mitochondrial DNA through generations and embryonic tissues in a family at risk of Leigh syndrome.
    J Pediatr. 1997 Sep;131(3):447-9 PMID: 9329425
  13. Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes.
    Brain. 1997 Oct;120 ( Pt 10):1713-21 PMID: 9365365
  14. Mitochondrial DNA polymorphism in a maternal lineage of Holstein cows.
    Proc Natl Acad Sci U S A. 1982 Aug;79(15):4686-90 PMID: 6289312
  15. Origin, cellular expression, and cybrid transmission of mitochondrial CAP-R, PYR-IND, and OLI-R mutant phenotypes.
    Somatic Cell Genet. 1983 Jan;9(1):1-24 PMID: 6836447
  16. Familial Leigh's syndrome: association with a defect in oxidative metabolism probably restricted to brain.
    J Neurol. 1987 May;234(4):215-9 PMID: 3612192
  17. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy.
    Am J Hum Genet. 1990 Mar;46(3):428-33 PMID: 2137962
  18. Prenatal diagnosis of mitochondrial DNA8993 T----G disease.
    Am J Hum Genet. 1992 Mar;50(3):629-33 PMID: 1539598
  19. Heteroplasmic mtDNA mutation (T----G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high.
    Am J Hum Genet. 1992 Apr;50(4):852-8 PMID: 1550128
  20. Subacute necrotizing encephalopathy: oxidative phosphorylation defects and the ATPase 6 point mutation.
    Neurology. 1992 Nov;42(11):2168-74 PMID: 1436530
  21. Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF).
    Am J Hum Genet. 1992 Dec;51(6):1187-200 PMID: 1334369
  22. Retinitis pigmentosa, ataxia, and mental retardation associated with mitochondrial DNA mutation in an Italian family.
    Br J Ophthalmol. 1993 Feb;77(2):84-8 PMID: 8435424
  23. Maternally inherited Leigh syndrome.
    J Pediatr. 1993 Mar;122(3):419-22 PMID: 8095070
  24. The mitochondrial DNA mutation at 8993 associated with NARP slows the rate of ATP synthesis in isolated lymphoblast mitochondria.
    Biochem Biophys Res Commun. 1993 Apr 15;192(1):124-8 PMID: 8476414
  25. A T-to-G mutation at nucleotide pair 8993 in mitochondrial DNA in a patient with Leigh's syndrome.
    J Child Neurol. 1993 Apr;8(2):129-33 PMID: 8505474
  26. Noninvasive diagnosis of the MELAS syndrome from blood DNA.
    Ann Neurol. 1993 Jul;34(1):116 PMID: 8517674
  27. A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome.
    Ann Neurol. 1993 Sep;34(3):410-2 PMID: 8395787
  28. Variable retinal and neurologic manifestations in patients harboring the mitochondrial DNA 8993 mutation.
    Arch Ophthalmol. 1993 Nov;111(11):1525-30 PMID: 8240109
  29. The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome.
    Ann Neurol. 1993 Dec;34(6):827-34 PMID: 8250532
  30. A T-->C mutation at nt 8993 of mitochondrial DNA in a child with Leigh syndrome.
    Neurology. 1994 May;44(5):972-4 PMID: 8190310
  31. Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G).
    Am J Med Genet. 1994 Apr 15;50(3):265-71 PMID: 8042671
  32. Different restriction fragment pattern of mtDNA indicative of generalized 8993 point mutations in a boy with lactic acidosis.
    J Inherit Metab Dis. 1994;17(2):249-50 PMID: 7967485
  33. Brain and muscle energy metabolism studied in vivo by 31P-magnetic resonance spectroscopy in NARP syndrome.
    J Neurol Neurosurg Psychiatry. 1994 Dec;57(12):1492-6 PMID: 7798979
  34. Mitochondrial DNA 8993 (NARP) mutation presenting with a heterogeneous phenotype including 'cerebral palsy'.
    Arch Dis Child. 1994 Nov;71(5):419-22 PMID: 7529982
  35. Heteroplasmic mitochondrial tRNA(Lys) mutation and its complementation in MERRF patient-derived mitochondrial transformants.
    Muscle Nerve Suppl. 1995;3:S95-101 PMID: 7603536
  36. Correlation between the clinical symptoms and the proportion of mitochondrial DNA carrying the 8993 point mutation in the NARP syndrome.
    Pediatr Res. 1995 May;37(5):634-9 PMID: 7603783
  37. Altered properties of mitochondrial ATP-synthase in patients with a T-->G mutation in the ATPase 6 (subunit a) gene at position 8993 of mtDNA.
    Biochim Biophys Acta. 1995 Jun 9;1271(2-3):349-57 PMID: 7605802
  38. De novo mutation in the mitochondrial ATP synthase subunit 6 gene (T8993G) with rapid segregation resulting in Leigh syndrome in the offspring.
    Hum Genet. 1995 Sep;96(3):290-4 PMID: 7649544
  39. Maternally inherited cardiomyopathy and hearing loss associated with a novel mutation in the mitochondrial tRNA(Lys) gene (G8363A).
    Am J Hum Genet. 1996 May;58(5):933-9 PMID: 8651277
Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/302488
Published
1999-08-00
Pages
474-82
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1377946
Subset
IM
Databases
OMIM
516060, 551500
External Links
PubMed source DOI: 10.1086/302488 PMC Full Text View journal details
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