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Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene
Author(s) -
MartiSanchez Laura,
BaideMairena Heidy,
MarcéGrau Anna,
Pons Roser,
Skouma Anastasia,
LópezLaso Eduardo,
Sigatullina Maria,
Rizzo Cristiano,
Semeraro Michela,
Martinelli Diego,
Carrozzo Rosalba,
DionisiVici Carlo,
GonzálezGutiérrezSolana Luis,
CorreaVela Marta,
OrtigozaEscobar Juan Dario,
SánchezMontañez Ángel,
Vazquez Élida,
Delgado Ignacio,
AguileraAlbesa Sergio,
Yoldi María Eugenia,
Ribes Antonia,
Tort Frederic,
Pollini Luca,
Galosi Serena,
Leuzzi Vincenzo,
Tolve Manuela,
PérezGay Laura,
AldamizEchevarría Luis,
Del Toro Mireia,
Arranz Antonio,
Roelens Filip,
Urreizti Roser,
Artuch Rafael,
Macaya Alfons,
PérezDueñas Belén
Publication year - 2021
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12288
Subject(s) - dystonia , phenotype , exome sequencing , medicine , genotype , mutation , cohort , biology , endocrinology , genetics , gene , gastroenterology , psychiatry
Abstract 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.