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

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-offunction 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. K E Y W O R D S alopecia, neurodevelopmental disorder, ornithine decarboxylase 1 (ODC1), polyamines, putrescine

Polyamine Homeostasis in Snyder-Robinson Syndrome

“…These studies do, however, form a basis and provide knowledge for leading biochemical changes to study in affected tissues as well as for development of therapeutic strategies, particularly those aimed at replenishing intracellular spermine. Recently, a novel neurodevelopmental disorder was described resulting from gene variants that increase ODC activity [37,38]. Although, unlike SRS, these patients have elevated levels of ODC and putrescine, several clinical manifestations are similar, including hypotonia and developmental delays.…”

Clinical Validation of Targeted and Untargeted Metabolomics Testing for Genetic Disorders: A 3 Year Comparative Study

“…In contrast, GUM analysis in the same cohort successfully identified a case where a diagnostically-relevant metabolite was linked to the phenotype and genotype. N-acetylputrescine, an intermediate in the spermine synthetic pathway, was detected in a patient with a variant in ODC1 24 . Although this translates to a diagnostic yield of 0.7%, lower than observations from previous studies (estimated at 1-5% in patients with neuro-developmental symptoms), it does showcase the utility of GUM for validation of omics discoveries [25][26][27][28][29][30] .…”

The human phenotype of ornithine decarboxylase superactivity: A new syndrome

“…In the December 2019 issue of the American Journal of Medical Genetics part A, Bupp, Schultz, Uhl, Rajasekaran, and Bachmann () report the first patient with ODC superactivity. Subsequently, Rodan et al () described four additional patients with…”

“…A transgenic mouse model of superactivity of spermidine/spermine N1‐acetyltranferase (encoded by SAT1 or SAT2 ) has also been shown to have a hairless phenotype with increased putrescine levels in whole skin samples (Pietilä, Parkkinen, Alhonen, & Jänne, ), whereas a patient with a duplication of SAT1 and increased enzyme activity had sparse, thin hair with a two‐fold elevation of putrescine in fibroblasts (Gimelli et al, ). The pathophysiology of the nonintegumentary manifestations of ODC superactivity are hard to pinpoint, although Rodan et al () mention the possibility of disrupted GABA metabolism in the brain, given the fact that GABA can be synthesized from N‐acetylputrescine in glial cells (Yoon et al, ). Given the widespread role of polyamines in physiology, however, it is not difficult to understand the multisystemic nature of this novel disease.…”

“…Bupp et al () described elevation of putrescine in red blood cells, while Rodan et al () reported elevation of N‐acetylputrescine in plasma from one patient. The latter is reminiscent of what has been reported in Snyder‐Robinson syndrome, where the accumulated substrate undergoes N‐acetylation, and the elevated N‐acetylated product (N8‐acetylspermidine) can be identified via plasma metabolomics (Abela et al, ).…”