Infantile Parkinsonism-Dystonia Panel

Infantile Parkinsonism-dystonia is set of a rare inherited progressive neurological disorders. Major features include infantile onset Parkinsonism and dystonia. Patients present with pyramidal tract signs, rigidity, tremor, bradykinesia, hypotonia, cognitive development delay and severe gross motor delay. Other features include irritable, feeding difficulties, abnormal eye movement, gastrointestinal complications and sleeping difficulties. Patients can also suffer from secondary respiratory complications or cardiac failure (Kurian et al. 2009. PubMed ID: 19478460; Kurian et al. 2011. PubMed ID: 21112253). Biochemical analysis of neurotransmitter breakdown products in cerebrospinal fluid can be used to differentiate the diagnosis (Kurian et al. 2011. PubMed ID: 21112253; Rilstone et al. 2013. PubMed ID: 23363473).

This panel focuses on genes for infantile Parkinson-dystonia (SLC6A3 and SLC18A2), as well as genes for other genetic disorders with phenotypic overlap with infantile Parkinsonism (DDC, DNM1L, PLA2G6, TH). Pathogenic variants in genes in this panel are all inherited in an autosomal recessive manner, with the exception that DNM1L pathogenic variants can also be inherited in an autosomal dominant manner. Most of the pathogenic variants are missense.

The major gene in this panel, SLC6A3, encodes the dopamine transporter which regulates the active reuptake of dopamine from the synapse. Pathogenic variants in SLC6A3 are causative for infantile Parkinson-dystonia 1 (Kurian et al. 2009. PubMed ID: 19478460; Kurian et al. 2011. PubMed ID: 21112253; Ng et al. 2014. PubMed ID: 24613933).

SLC18A2 encodes vesicular monoamine transporter 2 which translocates dopamine and serotonin into synaptic vesicles of neurons. Pathogenic variants in SLC18A2 are causative for infantile Parkinson-Dystonia 2 (Rilstone et al. 2013. PubMed ID: 23363473).

DDC encodes DOPA decarboxylase which catalyzes the conversion of DOPA to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine. Pathogenic variants in DDC are causative for aromatic L-amino acid decarboxylase (AADC) deficiency (Brun et al. 2010. PubMed ID: 20505134).

DNM1L encodes dynamin-like protein 1 which mediates mitochondrial and peroxisomal fission. Certain pathogenic variants in DNM1L are causative for severe infantile Parkinsonism or lethal encephalopathy (Díez et al. 2017. PubMed ID: 28436574; Chang et al. 2010. PubMed ID: 20696759).

PLA2G6 encodes a calcium-independent phospholipases A2 group VI which catalyzes hydrolysis of the sn-2 acyl-ester bonds in phospholipids. Pathogenic variants in PLA2G6 are causative for infantile neuroaxonal dystrophy, and PLA2G6-related dystonia-parkinsonism (Salih et al. 2013. PubMed ID: 24130795; Romani et al. 2015. PubMed ID: 25164370).

TH encodes the tyrosine hydroxylase enzyme, a rate-limiting enzyme in the biosynthesis of catecholamines, including dopamine. Pathogenic variants in the TH gene are causative for Segawa syndrome (Yosunkaya et al. 2010. PubMed ID: 20399390).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

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

Other genes in this panel can help with differential diagnosis.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).