Genetic Counseling and Prenatal Diagnosis for the Mitochondrial DNA Mutations at Nucleotide 8993

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 After reviewing 44 published and 12 unpublished pedigrees, we considered the possibility of prenatal diagnosis for two common mtDNA mutations at nucleotide 8993.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.

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)

“…The MT-ATP6 gene encodes a subunit of the 550 kKDa multi-subunit Complex V (ATP synthase or F 1 F o ATPase), which is one of the key enzymes involved in the aerobic generation of energy, synthesizing ATP from ADP using the proton gradient generated across the mitochondrial inner membrane (Kucharczyk et al 2009). Unlike many pathogenic mtDNA variants, the m.8993T>G and m.8993T>C variants display a strong genotype-phenotype correlation, with a lack of tissue or age-dependent variation in mutant load (White et al 1999a) which enables accurate prediction of the probability of severe outcome and empirical recurrence risks (White et al 1999b). Overall, LS develops whenever the m.8993T>G mutant load exceeds 90%, while the milder NARP (neurogenic muscle weakness, ataxia and retinitis pigmentosa) phenotype occurs with moderate levels of approximately 70-90% mutant loads (Thorburn and Rahman 2014).…”

“…Other properties of m.8993T>G variant include de novo occurrences with rapid segregation toward homoplasmy, often within a single generation, observed in approximately 20% of families (White et al 1999a). Likely explanations for these sporadic cases include spontaneous variants arising during oogenesis (Degoul et al 1997); or presence of a mitochondrial genetic "bottleneck", in which only a small subpopulation of mtDNA molecules are preferentially amplified to "repopulate" the oocyte (Blok et al 1997;White et al 1999b).…”

Selective elimination of mutant mitochondrial genomes as therapeutic strategy for the treatment of NARP and MILS syndromes

“…5 Two diseases, neuropathy, ataxia and retinitis pigmentosa (NARP 6 ) and maternally-inherited Leigh syndrome (MILS 7 ) are associated with this mutation. The syndromes associated with T8993G mutation are heteroplasmic conditions, that is, both wild type and mutant mtDNA are present in cells of affected individuals.…”

Preimplantation genetic diagnosis for mitochondrial DNA disorders: ethical guidance for clinical practice

“…10 -12 For these mutations, in general, symptoms seem to occur above B50% mutant load and the frequency and severity increases with increasing mutant load. 10 Patients with severe NARP syndrome generally have mutant loads above 70 -80%, although some exceptions have been reported as well. 10 Patients with severe Leigh syndrome generally have mutant loads above 80%.…”