Infantile Parkinsonism-Dystonia 1 or Dopamine Transporter Deficiency Syndrome via the SLC6A3 Gene

Infantile Parkinsonism-dystonia 1 or dopamine transporter deficiency syndrome is characterized by early infantile-onset progressive parkinsonism-dystonia. Age onset of the disease is 0.5 to 7 months. The major symptoms include generalized bradykinesia, generalized rigidity, cogwheeling rigidity, hypomimia, resting distal tremor, axial hypotonia, eye movement disorders, pyramidal tract features, cognitive development delay and severe gross motor delay. Other features include gastrointestinal complications and sleeping difficulties. Patients can die of secondary respiratory complications and cardiac failure (Kurian et al. 2009. PubMed ID: 19478460; Kurian et al. 2011. PubMed ID: 21112253). It has also been reported that some patients present with progressive parkinsonism dystonia with juvenile onset, or even later-onset (Ng et al. 2014. PubMed ID: 24613933). Of note, biochemical analysis in cerebrospinal fluid from all affected patients revealed increased ratios of homovanillic acid to 5-hydroxyindoleacetic acid, which are degradation products of dopamine and serotonin respectively (Kurian et al. 2011. PubMed ID: 21112253).

Infantile Parkinson-dystonia 1 or dopamine transporter deficiency syndrome is inherited in an autosomal recessive manner and is caused by pathogenic variants in the SLC6A3 gene, which encodes the dopamine transporter (Kurian et al. 2009. PubMed ID: 19478460). Pathogenic variants in SLC6A3 include missense, nonsense, splicing, small frameseshift deletions/insertions, small indels, as well as large deletions (Kurian et al. 2009. PubMed ID: 19478460; Kurian et al. 2011. PubMed ID: 21112253; Ng et al. 2014. PubMed ID: 24613933, Puffenberger et al. 2012. PubMed ID: 22279524; Human Gene Mutation Database).

Clinical sensitivity of SLC6A3 in a large cohort of patients with infantile Parkinsonism-dystonia 1 or dopamine transporter deficiency syndrome is unavailable in the literature, because most of the studies are case reports or family studies. Pathogenic variants in SLC6A3 are the most common cause of infantile Parkinsonism with dystonia. Analytical sensitivity should be high as nearly all reported pathogenic variants are detectable by sequencing.

This test provides full coverage of all coding exons of the SLC6A3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).