Subacute necrotizing encephalopathy

Abstract

Subacute necrotizing encephalopathy (SNE) or Leigh's disease is associated with various defects in oxidative phosphorylation (OXPHOS). However, the relationships between these OXPHOS defects and nuclear DNA or mitochondrial DNA (mtDNA) mutations is still unclear. We evaluated three SNE pedigrees (two singleton cases and a pedigree) biochemically for OXPHOS abnormalities and genetically for four mtDNA point mutations. There was a complex I defect in all three pedigrees that was associated with a complex III defect in two individuals. An mtDNA mutation in the ATPase, subunit 6 gene (np 8993) was present in one SNE pedigree. This mutation was maternally inherited, heteroplasmic, produced marked clinical and biochemical heterogeneity between pedigree members, and varied along the maternal lineage at levels ranging from 0% to > 95% of the total mtDNAs. These mtDNA mutations were not present in the other two pedigrees. These observations emphasize the importance of screening for OXPHOS defects and mtDNA mutations in SNE cases.

Cytoplasmic transfer of the mtDNA nt 8993 T-->G (ATP6) point mutation associated with Leigh syndrome into mtDNA-less cells demonstrates cosegregation with a decrease in state III respiration and ADP/O ratio.

“…Members of two pedigrees harboring the MTATP6*NARP8993G mutation were investigated. Clinical details and molecular genetic analyses of these patients have been reported previously (8,10), and when referred to below, individuals are designated as in those reports.…”

“…Complex V is composed of 13 polypeptides, 2 ofwhich, MTATP6 and MTATP8, participate in Fo and are encoded by mtDNA (2). mtDNA missense mutations which affect the electron transport chain genes have frequently been associated with Leber hereditary optic neuropathy (LHON)(4), while those that have been reported for the H+-ATP synthase present with neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) (5,6) or Leigh syndrome (7)(8)(9)(10)(11)(12). Most ofthe NARP and Leigh syndrome cases are associated with a heteroplasmic (mixture of mutant and normal mtDNAs) T -* G transversion at nt 8993 (MTATP6*NARP8993G) which converts a highly conserved leucine to an arginine in MTATP6 (ATP6 Leu'56 -+ Arg) (5).…”

Mitochondrial Gene Therapy Improves Respiration, Biogenesis, and Transcription in G11778A Leber's Hereditary Optic Neuropathy and T8993G Leigh's Syndrome Cells

“…Human skin fibroblast cells were obtained from an infant who died of LS by 8 months and displayed poor respiration, neurodevelopmental delay, and sudden cardiac arrest (Holt et al, 1990;Shoffner et al, 1992). Quantitative analysis of SmaI-treated ATPase 6 PCR fragments from LS genomic DNA samples revealed > 95% of 8993T > G mutant mtDNA in this cell line, with a slight decrease up to *94% over 2 weeks upon addition of healthy mtDNA, compared with mtDNA present in normal healthy fibroblast cells (data not shown).…”

“…The 8993T > G mutation in the mtDNA-encoded ATP synthase 6 (ATPase 6) gene, when present in low abundance, results in NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) disease, and the individuals survive to adulthood. When present in very high abundance, LS results, leading to rapid lethality in infants (Holt et al, 1990;Shoffner et al, 1992;Tatuch et al, 1992).…”

Mitochondrial DNA Mutations and Mitochondrial Dysfunction in Epilepsy

“…Seizures may be an early clinical feature of Leigh's syndrome, a multisystemic disorder primarily of infancy in which central nervous system involvement predominates. Leigh's is associated with mtDNA mutations in a complex V (ATP synthase) gene at 8,993 bp (26), and in the nuclear encoded Surf-1 gene (27), as well as with biochemical deficiencies outside the respiratory chain, in particular, pyruvate dehydrogenase deficiency. Epilepsy also has been described in NARP (neuropathy, ataxia, and retinitis pigmentosa) associated with the same 8,993-bp mutation found in Leigh's syndrome (28), and in a fatal multisystem infantile disorder associated with depleted levels of mtDNA first described in 1991 (29), and probably linked to nuclear genes associated with mtDNA replication and maintenance (30).…”