Identification of a Novel SLC18A2 Splicing Variant in a Case of Infantile Parkinsonism–Dystonia Type 2
TL;DR
The first genetically confirmed Iranian patient, an 18‐month‐old boy presenting with profound developmental delay, axial hypotonia, limb hypertonia, dystonia, oculogyric crises, ptosis, and autonomic dysfunction is reported, expanding the mutational spectrum of SLC18A2‐related disease and highlighting the importance of early genetic diagnosis.
Abstract
Parkinsonism–dystonia Type 2 (PKDYS2) is a rare autosomal recessive disorder caused by SLC18A2 variants affecting the vesicular monoamine transporter 2 (VMAT2). We report the first genetically confirmed Iranian patient, an 18‐month‐old boy presenting with profound developmental delay, axial hypotonia, limb hypertonia, dystonia, oculogyric crises, ptosis, and autonomic dysfunction. Brain MRI, metabolic studies, and neurophysiological evaluations were normal. Whole‐exome sequencing identified a novel homozygous canonical splice‐site variant in SLC18A2 (NM_003054.6:c.1071‐2A > G), confirmed by Sanger sequencing and absent from population databases. SpliceAI predicted loss of the native splice acceptor site (DS_AL = 0.74), supporting a deleterious effect on RNA splicing. According to ACMG criteria, the variant was classified as likely pathogenic. Levodopa–benserazide failed to provide sustained benefit and caused irritability and insomnia, whereas pramipexole produced modest improvement in bradykinesia, ptosis, and sweating with persistence of dystonia and oculogyric crises. Comparison with reported international cases shows a consistent phenotype and limited therapeutic response. This case expands the mutational spectrum of SLC18A2‐related disease and highlights the importance of early genetic diagnosis.