MAPK8IP3-related neurodevelopmental disorder: Case report and therapeutic rationale for a truncating variant

New author and patient outcomes added.

This report explores a therapeutic hypothesis for addressing the potential effects of a loss-of-function variant in the MAPK8IP3gene. We describe a pediatric male with developmental delay associated with an early truncation variant in MAPK8IP3. This genetic alteration is suspected to reduce levels of functional JIP3 protein (encoded by the MAPK8IP3gene), potentially contributing to developmental manifestations, including hypotonia, gait imbalance, frequent falls, and motor incoordination. We hypothesize that increasing MAPK8IP3expression may mitigate the patient’s symptoms by enhancing the production of functional JIP3 protein, a critical regulator of axonal transport. This hypothesis assumes haploinsufficiency or JIP3 loss-of-function as a potential pathological mechanism; however, other mechanisms have not been excluded in humans. mediKanren, an artificial intelligence reasoner, identified vitamin A (retinoic acid) as a potential therapeutic intervention for this disorder. Evidence suggests that retinoic acid upregulates JSAP1, the JIP3 ortholog in mice, supporting its potential to enhance JIP3 expression.This report outlines the rationale for this therapeutic hypothesis, which is informed by genetic findings, prior literature, and recent mechanistic insights. Further studies are needed to validate underlying disease mechanisms and to evaluate the candidate therapy for safety and efficacy.