Invitae Hereditary Parkinson's Disease and Parkinsonism Panel

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, after Alzheimer’s disease. The average age of onset is 60 years, but individuals with hereditary forms of PD often present much earlier, in their 40s or younger. Average disease duration is approximately 10 years; however, disease duration varies depending on the causative gene, clinical subtype, and age of onset.

PD is characterized by a wide spectrum of progressive motor features including bradykinesia (reduced motor activity), resting tremor, skeletal muscle rigidity, and, later in the course of the disorder, postural instability. The primary motor features of PD typically result from the progressive loss of dopaminergic neurons in the substantia nigra pars compacta region of the brainstem, along with the presence of Lewy body inclusions in surviving neurons. Motor impairment is often accompanied by non-motor features, including cognitive and psychiatric symptoms, autonomic disturbances, sleep disorders, and sensory dysfunction. These features may be due to degeneration of other types of neurons (serotoninergic, noradrenergic, or cholinergic) in various regions of the brain. Hereditary parkinsonism may also occur as part of a more complex syndrome, and in some of these syndromes parkinsonism may not be the primary feature, or it may present atypically. For example, there are various dystonia-parkinsonism conditions (associated with variants in the GCH1, PRKRA, SLC6A3, SPR, and TH genes) which typically present in childhood or adolescence with features of both dystonia and parkinsonism.

^*Preliminary-evidence gene

Parkinsonism is a variable clinical feature; some individuals with parkinsonism may also have features such as dystonia, other movement disorders, or dementia. The clinical sensitivity of this test may vary depending on the clinical presentation of the affected individual.

Parkinsonism associated with variants in the CHCHD2, DCTN1, GCH1, LRRK2, MAPT, SNCA, SPR, and VPS53 genes are associated with autosomal dominant inheritance, while the ATP13A2, DNAJC6, FBXO7, PRKN, PARK7, PINK1, PRKRA, SLC6A3, and TH genes are associated with autosomal recessive forms of parkinsonism.

As many forms of hereditary parkinsonism are adult-onset conditions with variable expressivity and age of onset, penetrance is typically age-dependent and is thus difficult to calculate. Symptom expressivity also varies, even within families, for many subtypes of parkinsonism.

Some genes associated with recessive forms of parkinsonism are thought to have close to 100% penetrance, including ATP13A2 (Kufor Rakeb syndrome), DCTN1 (Perry syndrome), and PARK7 (juvenile-onset PD).

Overall, PD has a prevalence of 0.3% in the general population, 1-2% in individuals over age 60, and 3-4% in individuals over the age of 80.

The majority of PD is likely caused by a combination of genetic and environmental risk factors. However, an estimated 5-10% of PD has a monogenic cause.

The clinical spectrum of hereditary forms of parkinsonism is broad. Genetic testing can confirm the suspected clinical diagnosis or rule out disorders with a similar clinical presentation. A confirmed genetic diagnosis may help predict disease prognosis and progression, facilitate early detection and treatment of symptoms, inform family planning and carrier screening, or promote enrollment in clinical trials.

Diagnostic testing is important as the list of treatable forms of parkinsonism continues to grow. In the case of dopa-responsive PD and dystonia-parkinsonism, administration of levodopa can produce excellent and sustained responses.

For management guidelines please visit:

• American Academy of Neurology