Case Report: Two siblings with a novel homozygous SLC18A2 variant causing parkinsonism-dystonia-2: a case series from Saudi Arabia.

PMID 42245405 | PMCID PMC13233055 | DOI 10.3389/fgene.2026.1812336 · Frontiers in genetics · 2026 · View on PubMed ↗

BACKGROUND: Monoamine neurotransmitter disorders are rare, early-onset neurological conditions that frequently mimic cerebral palsy or epileptic encephalopathies, resulting in diagnostic delay. Parkinsonism-dystonia-2 (PKDYS2), caused by biallelic variants in SLC18A2, encodes vesicular monoamine transporter 2 (VMAT2), which is essential for dopamine and serotonin vesicular storage and release. The disorder is characterized by global developmental delay, parkinsonism, dystonia, and autonomic dysfunction. METHODS: This retrospective case report describes two siblings from a consanguineous family diagnosed with PKDYS2. Clinical, neuroimaging, and genetic data were collected from medical records, with longitudinal follow-up to assess disease progression and treatment response. Whole-exome sequencing (WES) was performed, and variants were analyzed using standard bioinformatics pipelines. A homozygous splice-site variant in SLC18A2 (c.1122 + 2T>C) was identified, classified as likely pathogenic according to ACMG/ClinGen criteria, and confirmed by Sanger sequencing with parental segregation. RESULTS: Both siblings presented in early infancy with hypotonia, developmental delay, dystonia, and oculogyric crises, with normal neuroimaging. WES identified a homozygous SLC18A2 splice-site variant (c.1122 + 2T>C) in both patients. Pramipexole resulted in partial improvement in one patient but was poorly tolerated in the other. Alternative therapies, including clonidine and trihexyphenidyl, provided limited symptomatic benefit. Both patients demonstrated severe and persistent neurodevelopmental impairment at follow-up. CONCLUSION: This case report identifies a previously unreported SLC18A2 splice-site variant (c.1122 + 2T>C) in two siblings with a severe neurodevelopmental phenotype characterized by hypotonia, dystonia, autonomic dysfunction, and parkinsonian features. These findings highlight the key role of genetic testing in establishing the diagnosis, avoiding ineffective treatments, and guiding management. Early genetic evaluation should be considered in children with early-onset movement disorders.