Intellectual disability (ID), which affects around 2% to 3% of the population, accounts for 0.63% of the overall prevalence of neurodevelopmental disorders (NDD). ID is characterized by limitations in a person’s intellectual and adaptive functioning, and is caused by pathogenic variants in more than 1000 genes. Here, we report a rare missense variant (c.350T>C; p.(Leu117Ser)) in HACE1 segregating with NDD syndrome with clinical features including ID, epilepsy, spasticity, global developmental delay, and psychomotor impairment in two siblings of a consanguineous Pakistani kindred. HACE1 encodes a HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), which is involved in protein ubiquitination, localization, and cell division. HACE1 is also predicted to interact with several proteins that have been previously implicated in the ID phenotype in humans. The p.(Leu117Ser) variant replaces an evolutionarily conserved residue of HACE1 and is predicted to be deleterious by various in silico algorithms. Previously, eleven protein truncating variants of HACE1 have been reported in individuals with NDD. However, to our knowledge, p.(Leu117Ser) is the second missense variant in HACE1 found in an individual with NDD.

The consumption of fructose-containing sweeteners and high-fat foods has increased over recent decades (Du et al., 2025; Hassel et al., 2015; 2015; Jensen et al., 2018; 2018; Krause & Wegner, 2020;...

After following up of more than 9 years, we report three affected male siblings from a consanguineous family (PKSOK) in rural Baluchistan, Pakistan, presenting with a novel, levodopa/carbidopa-responsive Nocturnal Akinesia Syndrome (NAS). Clinical features include nocturnal hypotonia, developmental delay, mild intellectual disability, speech impairment, and psychomotor delay without classical metabolic crises or spasticity. Exome sequencing identified a predicted pathogenic homozygous missense variant [c.313G>A; p.(Gly105Ser)] in the Isovaleryl-CoA dehydrogenase (IVD) gene, traditionally associated with Isovaleric Acidemia (IVA). However, the clinical phenotype of affected individuals of family PKSOK deviates from classical IVA, exhibiting unique levodopa-responsive motor symptoms rather than metabolic decompensation. Protein-protein interaction analyses predicted IVD interactions with dopamine receptors DRD1 and DRD4, suggesting a functional link between metabolic enzymes and dopaminergic neurotransmission and circadian rhythm. The potential involvement of GABAergic pathways may further explain the motor phenotype and therapeutic responsiveness. This study expands the phenotypic spectrum of IVD variants, highlighting new mechanisms underlying movement disorders and offering important implications for diagnosis and targeted treatment in similar rare neurometabolic syndromes.