Increased Mortality and Comorbidity Associated With Leber's Hereditary Optic Neuropathy: A Nationwide Cohort Study.

Purpose: Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease in which optic neuropathy is considered a key feature. Several other manifestations of LHON have been reported; however, only little is known of their incidence and the life expectancy in LHON patients. Methods: This study, based on Danish nationwide health registries, included 141 patients diagnosed with LHON and 297 unaffected family members in the maternal line. The incidence of comorbidities and mortality for patients with LHON and unaffected family members was compared with that in the general population. Results: Having LHON was associated with an almost 2-fold risk of mortality with a rate ratio (RR) of 1.95 (95% confidence interval [CI]: 1.47-2.59; P < 0.001). The incidence of several diseases was increased for LHON patients, but not for family members. The incidence of stroke was 5.73 per 1000 patient-years for LHON patients compared to 2.33 for the general population, and the RR was 2.38 (95% CI: 1.58-3.58; P < 0.001). The incidence of demyelinating disorders was 2.24 compared to 0.21 for the general population; RR was 12.89 (95% CI: 6.70-24.77; P < 0.001). A 4-fold risk of dementia was seen for LHON patients (RR: 4.26, 95% CI: 1.91-9.48; P < 0.001), incidence 1.45 for LHON and 0.37 for the general population. Moreover, LHON patients had an increased risk of epilepsy, atherosclerosis, nerve symptoms, neuropathy, and alcohol-related disorders. Conclusions: The manifestation of LHON was associated with increased mortality and increased incidence of several disorders including stroke, demyelinating disorder, dementia, and epilepsy.

Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases.

OBJECTIVES: We sought to determine the clinical spectrum, survival, and long-term functional outcome of a cohort of pediatric patients with mitochondrial diseases and to identify prognostic factors. METHODS: Medical charts were reviewed for 73 children diagnosed between 1985 and 2005. The functional status of living patients was assessed prospectively by using the standardized Functional Independence Measure scales. RESULTS: Patients fell into 7 phenotypic categories: neonatal-onset lactic acidosis (10%), Leigh syndrome (18%), nonspecific encephalopathy (32%), mitochondrial (encephalo)myopathy (19%), intermittent neurologic (5%), visceral (11%), and Leber hereditary optic neuropathy (5%). Age at first symptoms ranged from prenatal to 16 years (median: 7 months). Neurologic symptoms were the most common (90%). Visceral involvement was observed in 29% of the patients. A biochemical or molecular diagnosis was identified for 81% of the patients as follows: deficiency of complex IV (27%), of pyruvate dehydrogenase or complex I (25% each), of multiple complexes (13%), and of pyruvate carboxylase (5%) or complexes II+III (5%). A mitochondrial DNA mutation was found in 20% of patients. At present, 46% of patients have died (median age: 13 months), 80% of whom were <3 years of age. Multivariate analysis showed that age at first symptoms was a major independent predictor of mortality: patients with first symptoms before 6 months had a highly increased risk of mortality. Cardiac or visceral involvement and neurologic crises were not independent prognostic factors. Living patients showed a wide range of independence levels that correlated positively with age at first symptoms. Among patients aged >5 years (n = 32), 62% had Functional Independence Measure quotients of >0.75. CONCLUSIONS: Mitochondrial diseases in children span a wide range of symptoms and severities. Age at first symptoms is the strongest predictor mortality. Despite a high mortality rate in the cohort, 62% of patients aged >5 years have only mild impairment or normal functional outcome.