Parkinson Disease and Parkinsonism Panel

Parkinsonism refers to all clinical conditions characterized by tremor, muscle rigidity, bradykinesia and postural instability. Parkinson disease is the primary and most common form of Parkinsonism.

Parkinson disease affects more than 1% of 55-year-olds and more than 3% of those older than age 75 years. Males are more likely to be affected than females. The most common onset for Parkinson disease is around age 60. However, the juvenile form can have onset before 20 years of age. Early onset form is ≤ 50 years of age, while late-onset is after 50 years of age. Within Parkinson disease, only a small fraction of patients (5-10%) are monogenic (Mendelian) inherited (Abeliovich and Gitler. 2016. PubMed ID: 27830778).

The major symptoms of Parkinson's disease include bradykinesia, rigidity, tremor and postural instability. Patients commonly present with a unilateral resting tremor, often described as a pill rolling motion, or bradykinesia, which is a slowness in the execution of movement. 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 (Beitz. 2014. PubMed ID: 24389262; Abeliovich and Gitler. 2016. PubMed ID: 27830778). The key neuropathology of Parkinson disease is the loss of dopaminergic neurons in the substantia nigra in the midbrain (Beitz. 2014. PubMed ID: 24389262). The hallmark of Parkinson disease in neuropathology is the presence of intraneuronal proteinaceous inclusions, termed Lewy bodies or Lewy neurites (Abeliovich and Gitler. 2016. PubMed ID: 27830778). The presence of Lewy bodies, aggregates of alpha-synuclein, in dopaminergic neurons is variable (Doherty and Hardy. 2013. PubMed ID: 23653422). 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.

The genetic etiology of the Parkinson disease and Parkinson related disorders is extremely heterogeneous, ranging from monogenic causes with little or no influence from modifiers or environmental factors to genetically complex forms involving multiple genes, modifier genes and environmental factors (Clarimón and Kulisevsky. 2013. PubMed ID: 24532987; Hernandez et al. 2016. PubMed ID: 27090875; Klein and Schlossmacher. 2007. PubMed ID: 17761553; Abeliovich and Gitler. 2016. PubMed ID: 27830778). Parkinson disease or Parkinsonism related disorders are inherited via autosomal dominant, autosomal recessive, X-linked or complex inheritance. Parkinson diseases or Parkinson related disorders can be sporadic or inherited in families.

The panel covers well-characterized genes causative for Parkinson disease (for example, PRKN, PARK7, PINK1, LRRK2, SNCA, VPS35, DNAJC6 and PLA2G6), as well as many other genes for Parkinsonism related disorders which show overlap phenotype with Parkinson disease (APP, PSEN1, etc.). Certain genes such as GBA1/GBA and MAPT are susceptibility genes for Parkinson Disease. Recent studies show that the Parkinson disease phenotype is influenced by the severity of the pathogenic variants in the GBA1 gene (Thaler et al 2018. PubMed ID:29784561; Taguchi et al. 2017. PubMed ID: 28847804).

See individual gene test descriptions for information on molecular biology of gene products and mutation spectra.

Up to 40% of Parkinson disease patients with age at onset of less than 30 years and 17% of those with age at onset of less than 50 years harbor a pathogenic variant in one of the known monogenic genes linked to Parkinson disease. Within these genes, pathogenic variants in PRKN and LRRK2 are the leading causes of Parkinson disease (Clarimón and Kulisevsky. 2013. PubMed ID: 24532987).

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

This panel typically provides 99.5% 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).

All genetic tests have limitations. In particular, this sequencing test does not detect large deletions/duplications or complex rearrangement between the functional GBA1 gene and its pseudogene.

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).