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

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.