Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I.
Adolescent
Adult
Age of Onset
Biopsy
Brain
/ diagnostic imaging
Cells, Cultured
Child
DNA, Mitochondrial
Electron Transport Complex I
/ deficiency
Female
Fibroblasts
/ metabolism
Humans
Infant
Infant, Newborn
Leigh Disease
/ genetics
MELAS Syndrome
/ genetics
Magnetic Resonance Imaging
Mitochondrial Diseases
/ genetics
Muscle, Skeletal
/ metabolism
Mutation
Complex I
Leigh syndrome
MEGS
MELAS syndrome
MT-ND genes
Mitochondria
mtDNA
Journal
BMC pediatrics
ISSN: 1471-2431
Titre abrégé: BMC Pediatr
Pays: England
ID NLM: 100967804
Informations de publication
Date de publication:
29 01 2020
29 01 2020
Historique:
received:
27
08
2019
accepted:
07
01
2020
entrez:
31
1
2020
pubmed:
31
1
2020
medline:
28
8
2020
Statut:
epublish
Résumé
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. 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. 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- 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-
Sections du résumé
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-
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-
Identifiants
pubmed: 31996177
doi: 10.1186/s12887-020-1912-x
pii: 10.1186/s12887-020-1912-x
pmc: PMC6988306
doi:
Substances chimiques
DNA, Mitochondrial
0
Electron Transport Complex I
EC 7.1.1.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
41Subventions
Organisme : Ministerstvo Zdravotnictví Ceské Republiky
ID : AZV 17-30965A
Pays : International
Organisme : Ministerstvo Zdravotnictví Ceské Republiky
ID : RVO VFN 64165
Pays : International
Organisme : Univerzita Karlova v Praze
ID : Q26/LF1
Pays : International
Organisme : Univerzita Karlova v Praze
ID : UNCE 204064
Pays : International
Organisme : Univerzita Karlova v Praze
ID : SVV260367
Pays : International
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