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Am J Med Genet A. 2018 Dec;176(12):2554-2560. doi: 10.1002/ajmg.a.60677. Epub 2018 Nov 26.

Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.

Author information

1
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
2
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
3
Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center, New York, New York.
4
The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
5
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
6
Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.
7
Department of Neurology, Northwell Health, Zucker School of Medicine at Hofstra/Northwell, New York.
8
Division of Neuroradiology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
9
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas.
10
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas.

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.

KEYWORDS:

alopecia; neurodevelopmental disorder; ornithine decarboxylase 1 (ODC1); polyamines; putrescine

PMID:
30475435
DOI:
10.1002/ajmg.a.60677

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