A Chinese Family With Adult-Onset Leigh-Like Syndrome Caused by the Heteroplasmic m.10191T>C Mutation in the Mitochondrial MTND3 Gene

Abstract

Leigh syndrome (LS) is a mitochondrial disease of infancy and early childhood, that is rarely seen in adults. The high degree of genetic and clinical heterogeneity makes LS a very complex syndrome. The clinical manifestations include neurological symptoms and various non-neurological symptoms, with different mutations differing in presentations and therapies. The m.10191T>C mutation in the mitochondrial DNA gene encoding in the respiratory chain complex I (CI) subunit of MTND3 results in the substitution of a highly conserved amino acid (p.Ser45Pro) within the ND3 protein, leading to CI dysfunction and causing a broad clinical spectrum of disorders that includes LS. Patients with the m.10191T>C mutation are rare in general, even more so in adults. In the present study, we report a family of patients with very rare adult-onset Leigh-like syndrome with the m.10191T>C mutation. The 24-year-old proband presented with seizures 6 years ago and developed refractory status epilepticus on admission. She had acute encephalopathy accompanied by lactic acidosis, symmetrical putamen and scattered cortical lesions. The video electroencephalogram suggested focal-onset seizures. She harbored the heteroplasmic m.10191T>C mutation in her blood and fibroblasts. Her aunt was diagnosed with mitochondrial disease at the age of 42, and had the heteroplasmic m.10191T>C mutation in her fibroblasts. Her aunt's son (cousin) died of respiratory failure at the age of 8, and we suspected he was also a case of LS. Furthermore, we reviewed the previously reported patients with the m.10191T>C mutation and summarized their characteristics. Recognizing the characteristics of these patients will help us improve the clinical understanding of LS or Leigh-like syndrome.

Association Between Epilepsy and Leigh Syndrome With MT-ND3 Mutation, Particularly the m.10191T>C Point Mutation

“…In this study, the six patients with the m.10191T>C mutation were associated with epilepsy, suggesting that this mutation is important in Leigh syndrome with MT-ND3 mutation. Additionally, the results of this study suggested that even the same MT-ND3 mutation may may be strongly associated with epilepsy and these findings are consistent with those of this study (7). The value of this study lies in the fact that its findings are consistent with those of the previous studies and that it undertakes a more focused analysis of the characteristics of epilepsy in Leigh syndrome with the m.10191T>C mutations.…”

“…Among the various presentations of mtDNAassociated Leigh syndrome, several studies have reported a specific gene related to epilepsy. Some studies have found that m.10191T>C, a major nucleotide change in MT-ND3 gene, is strongly related to epilepsy (7,21). In this study, the six patients with the m.10191T>C mutation were associated with epilepsy, suggesting that this mutation is important in Leigh syndrome with MT-ND3 mutation.…”

“…In addition, the possibility of other factors and of heteroplasmy acting upon the onset of symptoms can also be considered. Also, although not measured in this study, heteroplasmy in brain may be different than in the blood leukocytes measured and might show a closer relationship to the neurologic presentations (7).…”

“…Genotypephenotype studies of each of these mutations are currently underway. Among them, several studies have found that Leigh syndrome with MT-ND3 mutation (hereafter referred as Leigh syndrome with MT-ND3 mutation) is strongly associated with epilepsy (6)(7)(8). This knowledge may assist neurologists with the development of treatment plans and prognosis predictions for the patients with Leigh syndrome with the MT-ND3 mutation.…”

Pathogenic Bi-allelic Mutations in NDUFAF8 Cause Leigh Syndrome with an Isolated Complex I Deficiency

“…Onset is typically in infancy or early childhood, though adult-onset Leigh syndrome is reported. 2,3 Although it is phenotypically well defined, its vast genetic heterogeneity, with >75 disease-associated genes having been reported to date, makes identification of the genetic defect challenging. 4 Causative pathogenic variants have been identified in both the nuclear genome and the mitochondrial genome (mtDNA), and these variants affect various aspects of mitochondrial function including structural subunits and assembly factors of respiratory chain complexes (e.g., NDUFS2 [MIM: 602985] 5 and SURF1 [MIM: 185620] 6 ), Krebs cycle components (e.g., PDHA1 [MIM: 300502] 7 ), mitochondrial protein translation (e.g., MTFMT [MIM 611766] 8 ), and valine metabolism (e.g., ECHS1 [MIM 602292] 9 ).…”