Leber Hereditary Optic Neuropathy: Case Report and Literature Review (original) (raw)
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Brain, 1995
One hundred and seven patients from 79 families were defined as having Leber's hereditary optic neuropathy (LHON) by the presence of one of the mitochondrial DNA (mtDNA) mutations at positions 11778 (60 families), 3460 (seven families) or 14484 (12 families). Only half of the 11778 index patients had a history of similarly affected relatives; this proportion was higher with the 3460 (71%) and 14484 (100%) mutations. The ratios of affected male to female patients were 2.5:1 (11778), 2:1 (3460), and 5.7:1 (14484). Detailed clinical data were available for 79 patients from 55 families. Visual loss developed between the ages of 11 and 30 years in 69%, with a range of 6-62 years, and no significant differences between mutation groups or males and females. It was bilateral in all but two patients, to a median of counting fingers with a central scotoma, developing simultaneously in 22% and sequentially in 78%, with a median inter-eye delay of 8 weeks, and progressing in each eye over a period of 4-6 weeks. Nineteen patients had pain in an affected eye or on eye movements, and four experienced Uhthoff's phenomenon. Retinal microangiopathy was uncommon after 6 months from onset and was not detected in 36% of patients examined within 3 months of visual loss; the microangiopathy was particularly uncommon in the 14484 group. There was no difference in the overall visual outcome between the 11778 and 3460 groups with median final visual acuities of 1/60 and 3/60, respectively. Particularly severe visual loss occurred in one-third of women with the 11778 mutation, to vague perception of light or no perception of light in at least one eye. A multiple sclerosis-like illness was observed in 45% of females with the 11778 mutation. Prognosis was substantially better in the 14484 patients, with recovery to a final visual acuity of at least 6/24, in 71% of patients. Good visual outcome was strongly correlated with age at onset, all those with onset before 20 years having a final visual acuity better than 6/24 as opposed to only 2 out of 6 with later onset. Improvement in vision occurred as long as 4 years after onset. High alcohol and tobacco consumption, cranial or ocular trauma, young or old age at presentation, co-existing neurological disease, and recent childbirth with post-partum haemorrhage, all contributed to diagnostic difficulties in this series, usually in the absence of a family history. These problems were resolved by mtDNA analysis.
Leber's hereditary optic neuropathy: correlations between mitochondrial genotype and visual outcome
Journal of Medical Genetics, 1994
Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease associated with mitochondrial DNA (mtDNA) mutations. We describe the distribution of seven different mtDNA mutations and the clinical findings in 334 LHON patients belonging to 29 families. Mutations described only in LHON at nucleotide positions 11778, 3460, and 14484 were found in 15, two, and nine families respectively. In three families none of these mutations was found. Mutations described in LHON but also in controls at nucleotide positions 15257, 13708, 4917, and 4216 were found in one, 10, three and 12 families respectively. Combinations of mtDNA mutations were found in most families. The patient population mainly consisted of 79-2% to 89'5% males except for one family with only 10 of 17 patients being males (58-9%, p-0 036). In 11 families only the 11778 mutation was found; in this group (WX) the affected males had a mean age of onset of 29-2 years and a mean visual outcome of 0-113. In seven families the 14484, 13708, and 4216 mutations were found; in this group (MA) the affected males had a mean age of onset of 22-0 years and a mean visual outcome of 0-442. In two families no mutation was found at all; in this group (YX) the affected males had a mean age of onset of 18-9 years and a mean visual outcome of 0 167. The mean age of onset in the WX group is significantly higher than in the MA group (p< 0-01) and in the YX group (p001).
Collegium Antropologicum, 2006
Leber's hereditary optic neuroretinopathy (LHON) is manifested as a bilateral acute or subacute loss of central vision due to optic atrophy. It is linked to point mutations of mitochondrial DNA, which is inherited maternally. The most common mitochondrial DNA point mutations associated with LHON are G3460A, G11778A and T14484C. These mutations are linked with the defects of subunits of the complex I (NADH-dehydrogenase-ubiquinone reductase) in mitochondria. The G11778A mitochondrial DNA point mutation is manifested by a severe visual impairment. In this paper two Croatian families with the LHON G11778A mutation are presented. Three LHON patients from two families were younger males which had the visual acuity of 0.1 or below, the ophthalmoscopy revealed telangiectatic microangiopathy and papilloedema, while Goldmann kinetic perimetry showed a central scotoma. The mothers and female relatives were LHON mutants without symptoms, whereas their sons suffered from a severe visual impairment. Molecular diagnosis helps to explain the cause of LHON disease.
Identification of novel mitochondrial mutations in Leber's hereditary optic neuropathy
Molecular vision, 2010
To screen mitochondrial DNA (mtDNA) variations in Leber hereditary optic neuropathy (LHON). Ten LHON patients were selected from neuro-ophthalmology clinics of All India Institute of Medical Sciences (AIIMS), New Delhi, India. Clinical evaluation included slit-lamp biomicroscopy, fundus examination, and neuroimaging. DNA was isolated from whole blood samples. The entire coding region of the mitochondrial genome was amplified by PCR in ten patients and 20 controls. The full mtDNA genome except D-loop was sequenced. All sequences were analyzed against mitochondrial reference sequence NC_012920. MtDNA sequencing revealed a total of 30 nucleotide variations in the ten LHON patients and 29 in the 20 controls. Of 30 changes, 30.00% (9/30) were nonsynonymous, and the remaining 70.00% (21/30) were synonymous. In controls, a total of five changes were nonsynonymous. Out of the total 14 nonsynonymous changes observed in cases and controls, four (p.A52T in nicotinamide adenine dinucleotide [NA...
The American Journal of Human Genetics, 2007
Leber hereditary optic neuropathy (LHON) is due primarily to one of three common point mutations of mitochondrial DNA (mtDNA), but the incomplete penetrance implicates additional genetic or environmental factors in the pathophysiology of the disorder. Both the 11778GrA and 14484TrC LHON mutations are preferentially found on a specific mtDNA genetic background, but 3460GrA is not. However, there is no clear evidence that any background influences clinical penetrance in any of these mutations. By studying 3,613 subjects from 159 LHON-affected pedigrees, we show that the risk of visual failure is greater when the 11778GrA or 14484TrC mutations are present in specific subgroups of haplogroup J (J2 for 11778GrA and J1 for 14484TrC) and when the 3460GrA mutation is present in haplogroup K. By contrast, the risk of visual failure is significantly less when 11778GrA occurs in haplogroup H. Substitutions on MTCYB provide an explanation for these findings, which demonstrate that common genetic variants have a marked effect on the expression of an ostensibly monogenic mtDNA disorder. From the Mitochondrial Research Group (G.H.; C.M.; A.P.; J.E.; P.G.; P.Y.
Medicina
Leber hereditary optic neuropathy (LHON) is one of the most common inherited mitochondrial optic neuropathies, caused by mitochondrial DNA (mtDNA) mutations. Three most common mutations, namely m.11778G>A, m.14484T>G and m.3460G>A, account for the majority of LHON cases. These mutations lead to mitochondrial respiratory chain complex I damage. Typically, LHON presents at the 15–35 years of age with male predominance. LHON is associated with severe, subacute, painless bilateral vision loss and account for one of the most common causes of legal blindness in young individuals. Spontaneous visual acuity recovery is rare and has been reported in patients harbouring m.14484T>C mutation. Up to date LHON treatment is limited. Idebenone has been approved by European Medicines Agency (EMA) to treat LHON. However better understanding of disease mechanisms and ongoing treatment trials are promising and brings hope for patients. In this article we report on a patient diagnosed with L...
Investigative Opthalmology & Visual Science, 2017
PURPOSE. Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease that typically causes bilateral blindness in young men. It is characterized by as yet undisclosed genetic and environmental factors affecting the incomplete penetrance. METHODS. We identified 27 LHON subjects who possess heteroplasmic primary LHON mutations. Mitochondrial DNA (mtDNA) copy number was evaluated. RESULTS. The presence of centrocecal scotoma, an edematous, hyperemic optic nerve head, and vascular tortuosity, as well as telangiectasia was recognized in affected subjects. We found higher cellular mtDNA content in peripheral blood cells of unaffected heteroplasmic mutation carriers with respect to the affected. CONCLUSIONS. The increase of cellular mtDNA content prevents complete loss of vision despite the presence of a heteroplasmic state of LHON primary mutation, suggesting that it is a key factor responsible for penetrance of LHON.
Journal of clinical neurology (Seoul, Korea), 2012
Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder with optic nerve atrophy. Although there are no other associated neurological abnormalities in most cases of LHON, cases of "LHON plus" have been reported. The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. These results suggest that the combination of G11778A and T3394C mutations leads to an atypical LHON phenotype.