Delineating -associated disease: From isolated neuropathy to early onset neurodegeneration.

Objective: To delineate the phenotypic and genotypic spectrum in carriers of mitochondrial mutations in a large international cohort.

Methods: We analyzed in detail the clinical, genetical, and neuroimaging data from 132 mutation carriers from national registries and local databases from Europe, USA, Japan, and China.

Results: We identified 113 clinically affected and 19 asymptomatic individuals with a known pathogenic mutation. The most frequent mutations were m.8993 T > G (53/132, 40%), m.8993 T > C (30/132, 23%), m.9176 T > C (30/132, 23%), and m.9185 T > C (12/132, 9%). The degree of heteroplasmy was high both in affected (mean 95%, range 20%-100%) and unaffected individuals (mean 73%, range 20%-100%). Age at onset ranged from prenatal to the age of 75 years, but almost half of the patients (49/103, 48%) became symptomatic before their first birthday. In 28 deceased patients, the median age of death was 14 months. The most frequent symptoms were ataxia (81%), cognitive dysfunction (49%), neuropathy (48%), seizures (37%), and retinopathy (14%). A diagnosis of Leigh syndrome was made in 55% of patients, whereas the classic syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP) was rare (8%).

Conclusions: In this currently largest series of patients with mitochondrial mutations, the phenotypic spectrum ranged from asymptomatic to early onset multisystemic neurodegeneration. The degree of mutation heteroplasmy did not reliably predict disease severity. Leigh syndrome was found in more than half of the patients, whereas classic NARP syndrome was rare. Oligosymptomatic presentations were rather frequent in adult-onset patients, indicating the need to include mutations in the differential diagnosis of both ataxias and neuropathies.