Characterization of a Leber’s hereditary optic neuropathy (LHON) family harboring two primary LHON mutations m.11778G greater than A and m.14484T greater than C of the mitochondrial DNA.

Authors

Catarino CB1, Ahting U2, Gusic M3, Iuso A3, Repp B3, Peters K4, Biskup S4, von Livonius B5, Prokisch H3, Klopstock T6.
  1. Department of Neurology, Friedrich-Baur Institute, Ludwig-Maximilians-Universität München, Munich, Germany.
  2. Institute of Human Genetics, Technische Universität München, Munich, Germany.
  3. Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
  4. CeGaT GmbH, Tübingen, Germany.
  5. Department of Ophthalmology, Ludwig-Maximilians-Universität München, Munich, Germany.
  6. Department of Neurology, Friedrich-Baur Institute, Ludwig-Maximilians-Universität München, Munich, Germany; DZNE-German Center for Neurodegenerative Diseases,Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Electronic address: Thomas.Klopstock@med.LMU.de.

Abstract

Leber’s hereditary optic neuropathy (LHON) is an inherited mitochondrial disease that usually leads to acute or subacute bilateral central vision loss. In 95% of cases, LHON is caused by one of three primary mutations of the mitochondrial DNA (mtDNA), m.11778G>A in the MT-ND4 gene, m.14484T>C in the MT-ND6 gene, or m.3460G>A in the MT-ND1 gene. Here we characterize clinically, genetically, and biochemically a LHON family with multiple patients harboring two of these primary LHON mutations, m.11778G>A homoplasmic and m.14484T>C heteroplasmic. The unusually low male-to-female ratio of affected family members is also seen among the other patients previously reported with two primary LHON mutations m.11778G>A and m.14484T>C. While the index patient had very late onset of symptoms at 75years and severe visual loss, her two daughters had both onset in childhood (6 and 9years), with moderate to mild visual loss. A higher degree of heteroplasmy of the m.14484T>C mutation was found to correlate with an earlier age at onset in this family. Ours is the first LHON family harboring two primary LHON mutations where functional studies were performed in several affected family members. A more pronounced bioenergetic defect was found to correlate with an earlier age at onset. The patient with the earliest age at onset had a more significant complex I dysfunction than all controls, including the LHON patient with only the m.11778G>A mutation, suggesting a synergistic effect of the two primary LHON mutations in this patient.