Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene.
Abnormalities, Multiple
/ genetics
Amino Acid Metabolism, Inborn Errors
/ genetics
Brain
/ diagnostic imaging
Child, Preschool
Dystonia
/ diagnosis
Enoyl-CoA Hydratase
/ deficiency
Female
Heterozygote
High-Throughput Nucleotide Sequencing
Humans
Infant
Internationality
Leigh Disease
/ diagnosis
Magnetic Resonance Imaging
Male
Metabolic Networks and Pathways
/ genetics
Mutation
Phenotype
Survival Rate
Thiolester Hydrolases
/ deficiency
Valine
/ metabolism
ECHS1
HIBCH
Leigh syndrome
basal ganglia cavitation
methacrylate metabolites
paroxysmal dystonia
valine catabolism
Journal
Journal of inherited metabolic disease
ISSN: 1573-2665
Titre abrégé: J Inherit Metab Dis
Pays: United States
ID NLM: 7910918
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
revised:
03
07
2020
received:
03
04
2020
accepted:
14
07
2020
pubmed:
18
7
2020
medline:
25
12
2021
entrez:
18
7
2020
Statut:
ppublish
Résumé
The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.
Substances chimiques
Thiolester Hydrolases
EC 3.1.2.-
ECHS1 protein, human
EC 4.2.1.17
Enoyl-CoA Hydratase
EC 4.2.1.17
Valine
HG18B9YRS7
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
401-414Informations de copyright
© 2020 SSIEM.
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