Parkinson's Disease, Juvenile via the PRKN/PARK2 Gene

Parkinson disease, juvenile is a neurodegenerative disorder with onset before 40 years of age. The core motor features of Parkinson disease include bradykinesia, rigidity, tremor and postural instability (Beitz. 2014. PubMed ID: 24389262). Patients commonly present with a unilateral resting tremor, often described as a pill rolling motion, or bradykinesia, a slowness in the execution of movement. Disease progression of juvenile Parkinson disease caused by variants in the PRKN/PARK2 gene is slow. As the disease progresses, patients display a stooped posture, shuffling gait, lower limb dystonia and have an increased likelihood of falling. Non-motor features of Parkinson disease include mood disorders, such as depression or anxiety, and sleep disturbance. Dementia may be seen late in Parkinson disease progression manifesting as personality changes and/or memory loss.

The key neuropathology of Parkinson disease is the loss of dopaminergic neurons in the substantia nigra (Beitz. 2014. PubMed ID: 24389262). The Lewy bodies, aggregates of alpha-synuclein, in dopaminergic neurons are not seen in PRKN/PARK2 cases (Doherty and Hardy. 2013. PubMed ID: 23653422). Because Parkinson disease results in decreased dopamine levels, patients often respond to treatment with levodopa, a chemical that can cross the blood-brain barrier and be converted into dopamine. Response of motor symptoms to levodopa is also used as evidence to support a Parkinson diagnosis.

Parkinson disease, juvenile is inherited in an autosomal recessive manner and is caused by pathogenic variants in the PRKN gene. Missense, nonsense, splice site, frameshift variants and small frameshift deletions/duplications in PRKN have been reported in the patients with Parkinson disease (Abbas et al. 1999. PubMed ID: 10072423; Angeli et al. 2013. PubMed ID: 23818421; Hedrich et al. 2004. PubMed ID: 15390068). In addition, numerous large deletions and duplications of PRKN were found to result in Parkinson disease, juvenile (Lücking et al. 2000. PubMed ID: 10824074; Bravo et al. 2018. PubMed ID: 30328284). Complex rearrangements in PRKN have also been documented (Wang et al. 2013. PubMed ID: 23616242; Morais et al. 2016. PubMed ID: 27182553).

Many studies have identified Parkinson disease, juvenile patients with single, heterozygous PRKN pathogenic variants. Notably, the age of disease onset is ~10 yrs later in patients with heterozygous PRKN variants compared to those with homozygous or compound heterozygous variants (Hedrich et al. 2004. PubMed ID: 15390068). At this time it remains unclear whether heterozygous PRKN variants are causative of Parkinson disease juvenile or if they simply represent genetic risk factors.

The PRKN gene encodes the E3 ubiquitin ligase Parkin. Ubiquitination is a post-translational modification that alters the stability of proteins. Models of how pathogenic variants in PRKN result in Parkinson disease rely on intersections between the ubiquitin-proteasome and autophagy pathways. Loss of Parkin has been proposed to protect aberrant proteins from degradation by the proteasome, and accumulation of these proteins is believed to inhibit autophagy (Lonskaya et al. 2013. PubMed ID: 24386307). PRKN and another Parkinson gene, PINK1, have also been shown to be required for proper mitochondrial clearance (Bertolin et al. 2013. PubMed ID: 24149440). Impaired autophagy and mitophagy are believed to lead to cell death and loss of dopaminergic neurons in the substantia nigra. Dopamine is crucial for controlling movement, and loss of dopamine leads to increased aberrant motor activities. It is unclear whether loss of dopamine also underlies other symptoms of Parkinson disease, as these symptoms are not improved by levodopa treatment.

In one study, homozygous or compound heterozygous point pathogenic variants in PRKN were identified in 10% (5 of 50) of Parkinson disease, juvenile patients (Hedrich et al. 2002. PubMed ID: 11971093).

This test provides full coverage of all coding exons of the PRKN 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).