JIMD Reports, Volume 23

Komulainen, Tuomas, Hautakangas, Milla-Riikka, Hinttala, Reetta, Pakanen, Salla, Vähäsarja, Vesa, Lehenkari, Petri, Olsen, Päivi, Vieira, Päivi, Saarenpää-Heikkilä, Outi, Palmio, Johanna, Tuominen, Hannu, Kinnunen, Pietari, Majamaa, Kari, Rantala, Heikki, Uusimaa, Johanna, Tuomas Komulainen, Milla-Riikka Hautakangas, Reetta Hinttala, Salla Pakanen, Vesa Vähäsarja, Petri Lehenkari, Päivi Olsen, Päivi Vieira, Outi Saarenpää-Heikkilä, Johanna Palmio, Hannu Tuominen, Pietari Kinnunen, Kari Majamaa, Heikki Rantala, Johanna Uusimaa

To study the clinical manifestations and occurrence of mtDNA depletion and deletions in paediatric patients with neuromuscular diseases and to identify novel clinical phenotypes associated with mtDNA depletion or deletions. 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 the diseases. Clinical and laboratory findings were collected. 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 (CK) and multiorgan disease without mutations in any of the known mtDNA maintenance genes; one patient had pathologic endoplasmic reticulum (ER) membranes in muscle. The third patient with mtDNA depletion 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. Novel encephalomyopathic mtDNA depletion syndrome with structural alterations in muscle ER was identified. mtDNA depletion may also refer to secondary mitochondrial changes related to 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.