OP46 – 2969: Novel phenotypes of childhood encephalomyopathies with mitochondrial DNA depletion or deletions.

Objective To study the clinical manifestations and occurrence of mtDNA depletion and deletions in paediatric patients with neuromuscular diseases, in order to estimate the role of mtDNA rearrangements in pathogenesis of these diseases and to identify novel clinical phenotypes associated with mtDNA depletion or deletions. Methods Muscle DNA samples from patients presenting with undefined encephalomyopathies or myopathies were analysed for mtDNA content by quantitative real-time PCR and for deletions by long-range PCR. Direct sequencing of mtDNA maintenance genes and whole-exome sequencing were used to study the genetic aetiologies of diseases. Clinical and laboratory findings were collected. Results Muscle samples were obtained from 104 paediatric patients with neuromuscular diseases. MtDNA depletion was found in three patients with severe early-onset encephalomyopathy or myopathy Two of these patients presented with novel types of mitochondrial DNA depletion syndromes associated with increased serum creatine kinase and multiorgan disease without mutations in any of the known mtDNA maintenance genes; muscle electron micrograph of one patient revealed disordered myofibrillar structure, pathological endoplasmic reticulum membranes and accumulation of glycogen and extracellular collagen fibres. The third patient with mtDNA depletion and severe myopathy was diagnosed with merosine-deficient muscular dystrophy caused by a homozygous mutation in the LAMA2 gene. Two patients with an early-onset Kearns-Sayre/Pearson-like phenotype harboured a large-scale mtDNA deletion, minor multiple deletions and high mtDNA content (4.9 and 6.9-fold increase relative to the median of age-matched controls). Conclusion We describe two novel early-onset phenotypes associated with mtDNA depletion, one of them presenting with pathologic endoplasmic reticulum membranes. Furthermore, mtDNA depletion can be a secondary finding in hereditary muscular dystrophy. We suggest that a large-scale mtDNA deletion, minor multiple deletions and high mtDNA content associated with Kearns-Sayre/Pearson syndromes may be secondary changes caused by mutations in an unknown nuclear gene. [ABSTRACT FROM AUTHOR]