Leber's hereditary optic neuropathy with late disease onset: clinical and molecular characteristics of 20 patients.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease that typically causes bilateral blindness in young men. Here we describe the clinical and molecular characteristics of 20 patients with disease onset after the age of 50 years (late onset-LHON). METHODS: From a cohort of 251 affected and 277 unaffected LHON carriers, we identified 20 patients with onset of visual loss after the age of 50 years. Using structured questionnaires, data including basic demographic details, age of onset, progression of visual loss and severity as well as exposure to possible environmental triggers including alcohol, smoking and illicit drugs were retrospectively collected. Groups were compared using the Mann-Whitney-U-Test for two independent groups of sampled data. RESULTS: The proportion of late onset-LHON in our cohort was 8% (20 patients, 15 males, 5 females). The mtDNA mutations m.11778G > A and m.3460G > A were found in 16 and 4 patients, respectively. Among 89 asymptomatic carriers above the age of 50 years (28 males, 61 females), the mtDNA mutations m.11778G > A, m.3460G > A and m.14484 T > C were found in 60, 12 and 17 carriers, respectively. Late onset-LHON patients had significantly higher mean cumulative tobacco and alcohol consumption compared with unaffected carriers. However, there was no significant difference between late onset- and typical LHON patients with regard to daily tobacco and weekly alcohol consumption before disease onset. CONCLUSION: As already shown for typical LHON, alcohol consumption and smoking are important trigger factors also for the late manifestation. LHON should be considered in the differential diagnosis of subacute blindness even in older patients.

Patients with Leber hereditary optic neuropathy fail to compensate impaired oxidative phosphorylation.

Ninety-five percent of Leber hereditary optic neuropathy (LHON) patients carry a mutation in one out of three mtDNA-encoded ND subunits of complex I. Penetrance is reduced and more male than female carriers are affected. To assess if a consistent biochemical phenotype is associated with LHON expression, complex I- and complex II-dependent adenosine triphosphate synthesis rates (CI-ATP, CII-ATP) were determined in digitonin-permeabilized peripheral blood mononuclear cells (PBMCs) of thirteen healthy controls and for each primary mutation of a minimum of three unrelated patients and of three unrelated carriers with normal vision and were normalized per mitochondrion (citrate synthase activity) or per cell (protein content). We found that in mitochondria, CI-ATP and CII-ATP were impaired irrespective of the primary LHON mutation and clinical expression. An increase in mitochondrial density per cell compensated for the dysfunctional mitochondria in LHON carriers but was insufficient to result in a normal biochemical phenotype in early-onset LHON patients.

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.

Quality of life in patients with leber hereditary optic neuropathy.

PURPOSE: Leber hereditary optic neuropathy (LHON) is an inherited mitochondrial optic neuropathy characterized by bilateral, severe loss of central vision. In this study, the first formal assessment was conducted of visual disability in affected and unaffected individuals from molecularly confirmed LHON pedigrees. METHODS: Four hundred two LHON carriers--196 affected and 206 unaffected--from 125 genealogically distinct pedigrees were prospectively interviewed using the well-validated visual function index (VF-14) questionnaire: m.3460G>A (n = 71), m.11778G>A (n = 270), and m.14484T>C (n = 61). RESULTS: The mean age of onset of visual loss was 27.9 years (SD, 14.9) and mean disease duration was 15.5 years (SD, 15.4), with 74.5% of the affected subjects being men. The mean VF-14 score was 25.1 (SD, 20.8) in the affected patients, compared with 97.3 (SD, 7.1) in the unaffected carriers. Within the affected group, VF-14 score did not worsen with increasing disease duration and individuals with the m.14484T>C mutation had higher VF-14 scores compared with those in the m.3460G>A and m.11778G>A groups. Reading small print and reading a newspaper or book were the two VF-14 items that presented the greatest difficulty. CONCLUSIONS: LHON has a severe negative impact on quality of life and has the worst VF-14 score when compared with other previously studied ophthalmic disorders. However, affected LHON carriers can be reassured that their level of visual impairment is unlikely to progress with time. The VF-14 questionnaire will be a useful tool for assessing the natural history of LHON and measuring outcome in future treatment trials.

Postnatal onset cortical dysplasia associated with infarction of white matter.

On MRI at 35 weeks of a boy born at 25 weeks, focal disorganization of the cortex was observed near a frontal venous infarct developed in the first week. Disruption of the final steps of cell migration, injury to the subplate and/or disruption of corticospinal axons are possible mechanisms behind it. Preterms with white matter lesions at or below 25 weeks postconceptional age should be scrutinized for cortical dysplasia.

Sonographic maturation of third-trimester cerebellar foliation after birth.

The development of cerebellar folia of third-trimester preterms has not been described with ultrasound before. We set out to determine normal development of the pons and cerebellar folia for future measurements of hypoplasia and atrophy. Study sonograms were made in preterms admitted to the neonatal intensive care unit with postmenstrual age (PMA) from 25 wk until term. On a weekly basis, transcranial measurements were made in the axial and coronal planes at the asterion with high-frequency transducers (8.5 and 13 MHz). The axial images showed the pons and fourth ventricle. The coronal images showed cerebellar folia and white matter. In the same coronal plane, the depth of cerebellar fissures at the rostral cerebellar convexity could be observed. A total of 172 cranial sonograms were performed on 98 neonates. The development of folia could be measured with ultrasound through the asterion. We showed that pons area, mean of three fissure depths, hemisphere area, and number of folia in the horizontal fissure correlated significantly with PMA. Hemisphere area described the same trend of growth as the transverse cerebellar diameter used in fetal sonography.