T2DM is a chronic disorder with progressive neuromuscular alterations. L-arginine (ARG) is the most common semi-essential amino acid having several metabolic functions.

to investigate the impact of L-arginine in combating diabetic-induced neuromyopathy and its possible mechanisms.

ARG supplementation to diabetic rats improved altered behavior, significantly increased BW, insulin, TAC, irisin and Il-4, decreased levels of glucose, microRNA-29a, NF-κβ and LC3 expression, PAI-1, CK-MM and restored the normal histological appearance.

ARG supplementation potently alleviated diabetic-induced neuromuscular alterations.

We identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functional consequences of their FLVCR1 variants.

We ascertained 30 patients from 23 unrelated families with biallelic FLVCR1 variants and characterized a novel FLVCR1-related phenotype: severe developmental disorders with profound developmental delay, microcephaly (z-score −2.5 to −10.5), brain malformations, epilepsy, spasticity, and premature death. Brain malformations ranged from mild brain volume reduction to hydranencephaly. Severely affected patients share traits, including macrocytic anemia and skeletal malformations, with Flvcr1^−/− mice and DBA. FLVCR1 variants significantly reduce choline and ethanolamine transport and/or disrupt mRNA splicing.

These data demonstrate a broad FLVCR1-related phenotypic spectrum ranging from severe multiorgan developmental disorders resembling DBA to adult-onset neurodegeneration. Our study expands our understanding of Mendelian choline and ethanolamine disorders and illustrates the importance of anticipating a wide phenotypic spectrum for known disease genes and incorporating model organism data into genome analysis to maximize genetic testing yield.