In this case report and literature review, we report a likely-pathogenic variant in SLC6A3 causing a severe phenotype of dopamine transporter deficiency syndrome.

Dopamine transporter deficiency syndrome (infantile parkinsonism-dystonia-1, PKDYS1) is a rare movement disorder characterized by a severe parkinsonism-dystonia phenotype. Onset of PKDYS1 is usually in infancy, though presentation can be variable, and progression is rapid with age. Affected individuals have progressively worsening hand tremors, hyperkinesia, hypokinetic movements, and dystonia. PKDYS1 is caused by homozygous or compound heterozygous pathogenic variants in SLC6A3, which encodes the dopamine transporter (DAT1).

Case report and literature review.

A 15 month old girl, the product of a consanguineous marriage, presented with the progressive loss of developmental milestones and increasing irritability starting at 3-4 months of age. MRI was normal. She developed choking episodes, loss of sleep structure, spasticity, dystonia, and seizures. Whole exome sequencing demonstrated a previously unreported biallelic homozygous variant in exon 13 of the SLC6A3 gene: c.1639dupC:p.His547ProfsX56. This variant causes a frameshift mutation. Sanger sequencing confirmed that the mother and father were both carriers of the same variant. Both parents and the patient’s two siblings are phenotypically unaffected. Common therapeutic treatments for parkinsonism, such as L-dopa, anticholinergic and carbidopa-levodopa, did not improve the patient's symptoms.  

We present a novel likely-pathogenic variant in the SLC6A3 gene.  The patient’s presentation was severe and unresponsive to common therapeutic options.  Furthermore, the presence of seizures in this patient expands the phenotypic spectrum of the disorder. As such, this previously unreported variant is associated with a severe PKDYS1 phenotype that includes seizures.