Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.
Am J Med Genet A
; 176(12): 2554-2560, 2018 12.
Article
de En
| MEDLINE
| ID: mdl-30475435
ABSTRACT
Polyamines serve a number of vital functions in humans, including regulation of cellular proliferation, intracellular signaling, and modulation of ion channels. Ornithine decarboxylase 1 (ODC1) is the rate-limiting enzyme in endogenous polyamine synthesis. In this report, we present four patients with a distinct neurometabolic disorder associated with de novo heterozygous, gain-of-function variants in the ODC1 gene. This disorder presents with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, and characteristic facial dysmorphisms. Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum. Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels. Therapies aimed at reducing putrescine levels, including ODC1 inhibitors, dietary interventions, and antibiotics to reduce polyamine production by gastrointestinal flora could be considered as disease-modifying therapies. As the ODC1 gene has been implicated in neoplasia, cancer surveillance may be important in this disorder.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Transporteurs d'acides dicarboxyliques
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Protéines de transport de la membrane mitochondriale
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Alopécie
/
Dysmorphophobies
/
Mégalencéphalie
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Troubles du développement neurologique
/
Mutation gain de fonction
Type d'étude:
Diagnostic_studies
/
Risk_factors_studies
Limites:
Adolescent
/
Child
/
Female
/
Humans
/
Male
Langue:
En
Journal:
Am J Med Genet A
Sujet du journal:
GENETICA MEDICA
Année:
2018
Type de document:
Article