Genetic and phenotypic variability of optic neuropathies

Abstract

Hereditary optic neuropathies comprise a group of clinically and genetically heterogeneous disorders. Two subgroups can be formed: isolated hereditary optic atrophies and optic neuropathy as part of complex disorders. In group 1 of hereditary optic neuropathies, optic nerve dysfunction is typically the only manifestation of the disease. This group comprises autosomal dominant, autosomal recessive and X-linked recessive optic atrophy and the maternally inherited Leber's hereditary optic neuropathy. Among the autosomal-dominant forms of optic atrophy, Kjer's disease is most frequently observed. In the second group of complex disorders, various neurologic and other systemic abnormalities are regularly observed. Most frequent in this group are mtDNA mutations, inherited peripheral neuropathies, Charcot-Marie-Tooth disorders (CMT2A2, CMTX5), hereditary sensory neuropathy type 3 (HSAN3), Friedreich's ataxia, leukodystrophies, sphingolipidoses, ceroid-lipofuscinoses and neurodegeneration with brain iron accumulation. We review current knowledge about the underlying genetic predispositions, the most urgent open questions and how this may affect our management of this heterogeneous group of disorders in the future.

Leberʼsche hereditäre Optikusneuropathie

“…Mit zunehmender Effizienz der molekulargenetischen Diagnostik wird nun erkannt, dass Mitochondriopathien einer Vielzahl von bislang unklaren neurologischen und augenärztlichen Symptomen zugrunde liegen. Ophthalmologische Manifestationen umfassen dabei Motilitätsstörungen, Retinopathien und Optikusneuropathien, häufig gepaart mit neurosensorischen Auffälligkeiten oder Myopathien, die sich klinisch und genetisch überlappen können und als Teile eines Manifestationsspektrums zu sehen sind [11]. Die LHON führt meist zu einer isolierten Optikusbeteiligung.…”

Panel-based genetic diagnostic testing for inherited eye diseases is highly accurate and reproducible, and more sensitive for variant detection, than exome sequencing

“…Genetic diagnostic testing for these disorders is challenging due to their genetic heterogeneity. For example, mutations in over 200 genes can cause IRDs, and multiple genes are known to underlie inherited forms of glaucoma and optic atrophy (complete gene list available at: https://sph.uth.edu/retnet/ ) 14 - 16 . It is increasingly desirable to obtain genetic diagnoses for patients with these disorders, as this information can influence patient care by both informing genetic risk assessment and identifying patients who would benefit from novel gene-based therapies 17 - 21 .…”

Mutation Screening of Mitochondrial DNA as Well as OPA1 and OPA3 in a Chinese Cohort With Suspected Hereditary Optic Atrophy

“…1 These kinds of disorders have several modes of inheritance, but autosomal dominant optic atrophy (DOA, OMIM165500) and Leber's hereditary optic atrophy (LHON, OMIM535000) are the two most common forms. 1 Autosomal DOA, with prevalence between 1:12000 and 1:50000, is a disorder characterized by early onset bilateral visual loss, defects in color vision, paracentral or central scotomata, and typical temporal optic nerve pallor. [2][3][4] The condition of DOA is genetically heterogeneous and five chromosome loci: OPA1, OPA3, OPA4, OPA5, and OPA8, have been mapped for it.…”