Three Cases of Levodopa-Carbidopa Responsive Nocturnal Akinesis in Male Children of an Inbred Family in Rural Baluchistan, Pakistan

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.