Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I

Abstract

Background: Maternally inherited complex I deficiencies due to mutations in MT-ND genes represent a heterogeneous group of multisystem mitochondrial disorders (MD) with a unfavourable prognosis. The aim of the study was to characterize the impact of the mutations in MT-ND genes, including the novel m.13091 T > C variant, on the course of the disease, and to analyse the activities of respiratory chain complexes, the amount of protein subunits, and the mitochondrial energy-generating system (MEGS) in available muscle biopsies and cultivated fibroblasts. Methods: The respiratory chain complex activities were measured by spectrophotometry, MEGS were analysed using radiolabelled substrates, and protein amount by SDS-PAGE or BN-PAGE in muscle or fibroblasts. Results: In our cohort of 106 unrelated families carrying different mtDNA mutations, we found heteroplasmic mutations in the genes MT-ND1, MT-ND3, and MT-ND5, including the novel variant m.13091 T > C, in 13 patients with MD from 12 families. First symptoms developed between early childhood and adolescence and progressed to multisystem disease with a phenotype of Leigh or MELAS syndromes. MRI revealed bilateral symmetrical involvement of deep grey matter typical of Leigh syndrome in 6 children, cortical/white matter stroke-like lesions suggesting MELAS syndrome in 3 patients, and a combination of cortico-subcortical lesions and grey matter involvement in 4 patients. MEGS indicated mitochondrial disturbances in all available muscle samples, as well as a significantly decreased oxidation of [1-14 C] pyruvate in fibroblasts. Spectrophotometric analyses revealed a low activity of complex I and/or complex I + III in all muscle samples except one, but the activities in fibroblasts were mostly normal. No correlation was found between complex I activities and mtDNA mutation load, but higher levels of heteroplasmy were generally found in more severely affected patients. Conclusions: Maternally inherited complex I deficiencies were found in 11% of families with mitochondrial diseases in our region. Six patients manifested with Leigh, three with MELAS. The remaining four patients presented with an overlap between these two syndromes. MEGS, especially the oxidation of [1-14 C] pyruvate in fibroblasts might serve as a sensitive indicator of functional impairment due to MT-ND mutations. Early onset of the disease and higher level of mtDNA heteroplasmy were associated with a worse prognosis.

The Phenotypic Spectrum of 47 Czech Patients with Single, Large-Scale Mitochondrial DNA Deletions

“…Activity of respiratory chain complexes were measured by spectrophotometry in 25 muscle samples (methodology described in Danhelovska et al [ 16 ]). Activities within reference range was found only in 4/25 samples.…”

Clinicopathological findings of a mitochondrial encephalopathy, lactic acidosis, and stroke‐like episodes/Leigh syndrome overlap patient with a novel m.3482A>G mutation in MT‐ND1

“…Striatum lesions were found in two patients: one showed bilateral lesions 12 and the other had only left‐sided lesions 19 . Symmetrical midbrain lesions were reported in two patients 13,20 . However, combined striatum and brainstem lesions were only seen in the current patient.…”

“…However, combined striatum and brainstem lesions were only seen in the current patient. These patients, except for our patient, were diagnosed with MELAS or LHON/MELAS; however, their LS‐like radiological lesions were not pathological confirmed 12,13,19,20 …”

“…For a better understanding, we reviewed the radiological findings of 21 patients with MELAS or LS associated with MT‐ND1 mutation, including the current patient (Table 1). 12–25 According to Table 1, 11 patients presented with MELAS or LHON/MELAS, and 10 patients with LS or Leigh‐like phenotype. Only one patient with early‐onset LS having stroke‐like MRI findings was previously reported; however, postmortem analysis was performed 20 …”

Impact of cardiovascular involvement on the clinical course of paediatric mitochondrial disorders

“…The molecular basis of this phenomenon is difficult to assess, possibly related to its dual genetic control (nuclear and mtDNA) and to the fact that it is the largest complex in the mitochondrial respiratory chain. The clinical spectrum of complex I deficiency is heterogeneous but the majority of affected individuals show an early-onset, rapidly progressive disease, occurring with severe lactic acidosis, Leigh syndrome, leukoencephalopathy, hepatopathy and/or cardiomyopathy [ 25 – 27 ].…”