Blog
About

0
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found

      Childhood-onset Leber hereditary optic neuropathy

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup.

          Related collections

          Most cited references 17

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          Gene–environment interactions in Leber hereditary optic neuropathy

          Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations of mitochondrial DNA (mtDNA). Environmental factors are thought to precipitate the visual failure and explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm this to be the case. LHON has no treatment, so identifying environmental triggers is the key to disease prevention, whilst potentially revealing new mechanisms amenable to therapeutic manipulation. To address this issue, we conducted a large, multicentre epidemiological study of 196 affected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary pathogenic mtDNA mutations: m.3460G>A, m.11778G>A and m.14484T>C. A comprehensive history of exposure to smoking, alcohol and other putative environmental insults was collected using a structured questionnaire. We identified a strong and consistent association between visual loss and smoking, independent of gender and alcohol intake, leading to a clinical penetrance of 93% in men who smoked. There was a trend towards increased visual failure with alcohol, but only with a heavy intake. Based on these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate their alcohol intake.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation.

            In a study of the phenotypic characteristics of pedigrees of Leber's hereditary optic neuropathy positive for the mitochondrial DNA mutation at position 11778, 28 of 49 pedigrees were represented by singleton cases. Seven families, including six singleton pedigrees, had maternal family members with a mixture of mutant and normal mitochondrial DNA (heteroplasmy). Seventy-two affected individuals from 43 families showed a male predominance of 81.9% (59/72) and ages of onset of visual loss ranging from 8 to 60 years. The time interval between affected eyes averaged 1.8 months; the duration of progression of visual loss in each eye averaged 3.7 months. Visual acuity was 20/200 or worse in 107 of 109 (98.2%) eyes. Telangiectatic microangiopathy, disk pseudoedema, or vascular tortuosity, ophthalmoscopic features believed to be classic of Leber's hereditary optic neuropathy, were noted in 30 of 52 patients. Visual-evoked responses were typically absent or abnormal. Electrocardiograms, fluorescein angiograms, cerebrospinal fluid analyses, brain computed tomography, and magnetic resonance imaging were usually normal. There were no consistent neurologic or systemic illnesses associated with these Leber's pedigrees. In many cases, the diagnosis would not have been suspected because of the absence of a compatible family history, typical clinical profile, or ophthalmoscopic appearance. Genetic analysis showed the mitochondrial DNA mutation at position 11778, which established the diagnosis of Leber's hereditary optic neuropathy and has allowed for a broader view of the clinical features of this disease.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Treatment strategies for inherited optic neuropathies: past, present and future

              Bilateral visual loss secondary to inherited optic neuropathies is an important cause of registrable blindness among children and young adults. The two prototypal disorders seen in clinical practice are Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). About 90% of LHON cases are due to one of three mitochondrial DNA (mtDNA) point mutations: m.3460G>A, m.11778G>A, and m.14484T>C, which affect critical complex I subunits of the mitochondrial respiratory chain. The majority of patients with DOA harbour pathogenic mutations within OPA1, a nuclear gene that codes for a multifunctional inner mitochondrial membrane protein. Despite their contrasting genetic basis, LHON and DOA share overlapping pathological and clinical features that serve to highlight the striking tissue-specific vulnerability of the retinal ganglion cell (RGC) layer to disturbed mitochondrial function. In addition to severe visual loss secondary to progressive optic nerve degeneration, a subgroup of patients will also develop a more aggressive syndromic phenotype marked by significant neurological deficits. The management of LHON and DOA remains largely supportive, but major advances in our understanding of the mechanisms underpinning RGC loss in these two disorders are paving the way for novel forms of treatment aimed at halting or reversing visual deterioration at different stages of the disease process. In addition to neuroprotective strategies for rescuing RGCs from irreversible cell death, innovative in vitro fertilisation techniques are providing the tantalising prospect of preventing the germline transmission of pathogenic mtDNA mutations, eradicating in so doing the risk of disease in future generations.
                Bookmark

                Author and article information

                Journal
                British Journal of Ophthalmology
                Br J Ophthalmol
                BMJ
                0007-1161
                1468-2079
                October 25 2017
                November 2017
                November 2017
                March 17 2017
                : 101
                : 11
                : 1505-1509
                Article
                10.1136/bjophthalmol-2016-310072
                28314831
                © 2017

                Comments

                Comment on this article