Parkinson's Disease, Early Onset via the PINK1 Gene

Early onset Parkinson's disease (EOPD) is a neurodegenerative disorder resulting from the progressive loss of dopaminergic neurons with onset before 40 years of age. The core motor features of Parkinson's disease include bradykinesia, rigidity, tremor and postural instability (Beitz 2014). 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 EOPD is slow; patients display a stooped posture, shuffling gait, lower limb dystonia and have an increased likelihood of falling. Non-motor features of PD include mood disorders, such as depression or anxiety, and sleep disturbance. Dementia may be seen late in PD disease progression manifesting as personality changes and/or memory loss.

The key neuropathology of PD is the loss of dopaminergic neurons in the substantia nigra. Because Parkinson's 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 PD diagnosis.

EOPD caused by variants in the PINK1 gene is inherited in an autosomal recessive manner. Pathogenic missense, splice site, and frameshift variants in PINK1 have been reported in EOPD cases (Tan et al. 2006; Kumazawa et al. 2008). Heterozygous PINK1 variants have been reported in patients with idiopathic PD with an age of onset of ~50 years (Abou-Sleiman et al. 2006; Kumazawa et al. 2008). The pathogenicity of heterozygous PINK1 variants remains unclear, however it is suggested that they may predispose individuals to a later onset PD phenotype.

PINK1 encodes a serine/threonine protein kinase that localizes to both the cytosol and mitochondria. PINK1 has been shown to have roles in regulating mitochondrial function, storage, mobility, and clearance (Sim et al. 2012). PINK1 contains an N-terminal mitochondrial targeting sequence (MTS). In healthy mitochondria with high membrane potential, the MTS of PINK1 is cleaved in the mitochondria and PINK1 localization shifts to the cytosol. Cytosolic PINK1 has been shown to have neuroprotective properties and promotes dendrite outgrowth. During mitochondrial stress, the mitochondria becomes depolarized and PINK1 is stabilized on the outer mitochondrial membrane. PINK1 accumulation leads to recruitment of Parkin and mitochondrial clearance by the proteasome (Vives-Bauza et al. 2010). Pathogenic variants in PINK1 are enriched in the kinase domain, indicating that kinase activity is essential for protein function (Matenia and Mandelkow 2014). The phosphorylation targets of PINK1 are largely unknown. It is hypothesized that loss of PINK1 kinase activity leads to the accumulation of dysfunctional mitochondria and death of dopaminergic neurons. It is this loss of dopaminergic neurons that underlies the PD phenotype.

PINK1 sequencing in PD patients, who were previously screened for variants in PARK2, identified homozygous pathogenic PINK1 variants in ~1.28% (5/391) of unrelated individuals (Kumazawa et al. 2008). Heterozygous, possibly pathogenic PINK1 variants were identified in ~1.28% (5 of 391) of unrelated individuals.

This test provides full coverage of all coding exons of the PINK1 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).