Case Report: A Novel Mutation in the Mitochondrial MT-ND5 Gene Is Associated With Leber Hereditary Optic Neuropathy (LHON).

Martin Engvall,Helene Bruhn,Anna Wedell,Valerio Carelli,Aki Kawasaki,Frank Träisk,Nicole Lesko,Anna Wredenberg,Rolf Wibom,Florian A Schober

doi:10.3389/fneur.2021.652590

Abstract

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease causing severe bilateral visual loss, typically in young adults. The disorder is commonly caused by one of three primary point mutations in mitochondrial DNA, but a number of other rare mutations causing or associated with the clinical syndrome of LHON have been reported. The mutations in LHON are almost exclusively located in genes encoding subunits of complex I in the mitochondrial respiratory chain. Here we report two patients, a mother and her son, with the typical LHON phenotype. Genetic investigations for the three common mutations were negative, instead we found a new and previously unreported mutation in mitochondrial DNA. This homoplasmic mutation, m.13345G>A, is located in the MT-ND5 gene, encoding a core subunit in complex I in the mitochondrial respiratory chain. Investigation of the patients mitochondrial respiratory chain in muscle found a mild defect in the combined activity of complex I+III. In the literature six other mutations in the MT-ND5 gene have been associated with LHON and by this report a new putative mutation in the MT-ND5 can be added.

Highlights

Leber hereditary optic neuropathy (LHON) usually manifests as a sequential subacute optic neuropathy
LHON is a rare cause of optic neuropathy, with a prevalence of about 1 in 30,000 to 1 in 50,000 people in the population [4,5,6]
If there is no family history of LHON, there is an inherent risk that the clinician will falsely suspect the patient with LHON to have optic neuritis since both disorders often manifest at age 15–35 years

Summary

INTRODUCTION

Leber hereditary optic neuropathy (LHON) usually manifests as a sequential subacute optic neuropathy. Over the following weeks or months vision continues to deteriorate as a result of the progressive loss of retinal ganglion cells and atrophy of the optic nerves [3]. Testing for the three primary LHON mutations was negative, but whole genome sequencing (WGS) analysis of DNA from muscle targeting both nuclear genes causing mitochondrial and other metabolic diseases and mtDNA identified the same unique homoplasmic mutation in both subjects, m.13345G>A, p.(Ala337Thr) in MTND5. Even though the family history was negative, the sequential visual loss and absence of response to treatment for optic neuritis suggested mitochondrial origin, but since the three most common mutations associated with LHON were negative we pursued more extensive molecular analysis, see below. OCT (Topcon R , Dublin, CA) showed severe thinning of the pRNFL; 50 microm in the RE and 48 microm in the LE consistent with bilateral optic atrophy

DISCUSSION

Findings

ETHICS STATEMENT