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.

After more than 9 years of follow-up, we describe three affected male siblings from a consanguineous family (PKSOK) in rural Baluchistan, Pakistan, who presented with levodopa–carbidopa responsive nocturnal akinesia associated with tyrosine hydroxylase deficiency. The affected individuals also show delayed motor milestones, mild intellectual disability, speech and psychomotor delay, without epilepsy, spasticity, cerebellar ataxia, or daytime motor weakness. The marked improvement in nocturnal motor symptoms following levodopa–carbidopa (100 mg/25 mg) treatment raised the possibility of an underlying disorder of dopamine biosynthesis. Exome sequencing of the two affected siblings (IV:16 and IV:18) revealed twenty rare (frequency < 0.001) homozygous coding variants shared between them. However, segregation analysis with the disease phenotype ruled out the potential involvement of all these twenty variants. Therefore, we extended the analysis beyond the coding region variants to non-coding variants, which revealed a homozygous variant, c.-70G>A, in the regulatory region of TH (tyrosine hydroxylase). The c.-70G>A variant has been previously reported in three studies; however, our study represents the first report in the South Asian population. Our study also expands the phenotypic spectrum of disorders associated with variants in TH and highlights the importance of considering variants in regulatory regions of TH in patients with atypical but levodopa-responsive neurological phenotypes.