Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis.
DNA Polymerase gamma
/ genetics
Female
Heterozygote
High-Throughput Nucleotide Sequencing
Humans
Methylenetetrahydrofolate Reductase (NADPH2)
/ genetics
Middle Aged
Mitochondrial Diseases
/ diagnosis
Mutation
Paraparesis, Spastic
/ diagnosis
Sequence Analysis, DNA
Spastic Paraplegia, Hereditary
/ diagnosis
Twins, Monozygotic
Journal
Journal of human genetics
ISSN: 1435-232X
Titre abrégé: J Hum Genet
Pays: England
ID NLM: 9808008
Informations de publication
Date de publication:
Jan 2020
Jan 2020
Historique:
received:
15
06
2019
accepted:
04
10
2019
revised:
03
09
2019
pubmed:
28
10
2019
medline:
14
7
2020
entrez:
25
10
2019
Statut:
ppublish
Résumé
Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.
Identifiants
pubmed: 31645654
doi: 10.1038/s10038-019-0689-y
pii: 10.1038/s10038-019-0689-y
doi:
Substances chimiques
MTHFR protein, human
EC 1.5.1.20
Methylenetetrahydrofolate Reductase (NADPH2)
EC 1.5.1.20
DNA Polymerase gamma
EC 2.7.7.7
POLG protein, human
EC 2.7.7.7
Types de publication
Case Reports
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
91-98Subventions
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : SNSF 31003A_138521
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