Autosomal recessive Leber hereditary optic neuropathy, a new neuro-ophthalmo-genetic paradigm.
Guy LenaersCléis BeaulieuMajida CharifSylvie GerberJosseline KaplanJean-Michel RozetPublished in: Brain : a journal of neurology (2023)
Leber Hereditary Optic Neuropathy (LHON) is a primary inherited neurodegenerative disorder of the optic nerve. It has been ascribed to variants in the mitochondrial genome, mainly the m.3460G > A, m.11778G > A and m.14484T > C mutations in ND1, ND4 and ND6 respectively. Nonetheless, inconclusive molecular diagnosis is not uncommon. Recently, biallelic mutations in the NDUFS2, DNAJC30, MCAT and NDUFA12 nuclear genes have been identified in unresolved LHON cases, identifying an autosomal recessive LHON (arLHON, OMIM:619382). The clinical presentation of arLHON copies that of typical mtLHON, with an acute phase of sudden and severe vision loss, telangiectatic and tortuous vessels around the optic nerve, and swelling of the retinal nerve fiber layer (RNFL). This is followed by a chronic phase of RNFL loss, but eventually, affected individuals recovered partial or full visual acuity. Idebenone treatment significantly improved vision recovery in DNAJC30-associated patients. As mtLHON, arLHON predominantly affected male as compared to female carriers. The discovery of arLHON cases breaks with the dogma of exclusive maternal inheritance. It defines a new neuro-ophthalmo-genetic paradigm which should be considered in individuals manifesting a LHON phenotype, but inconclusive molecular diagnosis. NDUFS2, DNAJC30, MCAT and NDUFA12 should be investigated in these individuals, knowing that other arLHON genes might exist.
Keyphrases
- optic nerve
- genome wide
- optical coherence tomography
- copy number
- intellectual disability
- end stage renal disease
- mitochondrial dna
- ejection fraction
- dna methylation
- chronic kidney disease
- newly diagnosed
- prognostic factors
- genome wide identification
- muscular dystrophy
- early onset
- high throughput
- autism spectrum disorder
- peripheral nerve
- high resolution
- gene expression
- genome wide analysis
- african american
- mass spectrometry
- gestational age