Document Type

Article

Publication Date

11-2024

Identifier

DOI: 10.1016/j.pediatrneurol.2024.07.010

Abstract

BACKGROUND: GTPases of the Rab family are important orchestrators of membrane trafficking, and their dysregulation has been linked to a variety of neuropathologies. In 2017, we established a causal link between RAB11A variants and developmental and epileptic encephalopathy. In this study, we expand the phenotype of RAB11A-associated neurodevelopmental disorder and explore genotype-phenotype correlations.

METHODS: We assessed 16 patients with pathogenic or likely pathogenic RAB11A variants, generally de novo, heterozygous missense variants. One individual had a homozygous nonsense variant, although concomitant with a pathogenic LAMA2 variant, which made their respective contributions to the phenotype difficult to discriminate.

RESULTS: We reinforce the finding that certain RAB11A missense variants lead to intellectual disability and developmental delays. Other clinical features might include gait disturbances, hypotonia, magnetic resonance imaging abnormalities, visual anomalies, dysmorphisms, early adrenarche, and obesity. Epilepsy seems to be less common and linked to variants outside the binding sites. Individuals with variants in the binding sites seem to have a more multisystemic, nonepileptic phenotype.

CONCLUSIONS: Similar to other Rab-related disorders, RAB11A-associated neurodevelopmental disorder can also impact gait, tonus, brain anatomy and physiology, vision, adrenarche, and body weight and structure. Epilepsy seems to affect the minority of patients with variants outside the binding sites.

Journal Title

Pediatric neurology

Volume

160

First Page

45

Last Page

53

MeSH Keywords

Humans; rab GTP-Binding Proteins; Male; Child; Female; Neurodevelopmental Disorders; Child, Preschool; Genetic Association Studies; Adolescent; Cohort Studies; Mutation, Missense; Phenotype; Intellectual Disability; Epilepsy; Infant; Developmental Disabilities

Keywords

Epileptic encephalopathy; GTPase; Neurodevelopmental disorder; RAB11

Comments

This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.

Publisher's Link: https://www.pedneur.com/article/S0887-8994(24)00261-3/fulltext

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