Clinical characteristics: VPS35-related Parkinson disease (PARK-VPS35) is indistinguishable from Parkinson disease of unknown cause representing a simplex case (also referred to as "sporadic" Parkinson disease). PARK-VPS35 is characterized by typical parkinsonism (resting tremor, bradykinesia, rigidity, disturbance of postural reflexes) presenting on average a decade earlier than in individuals with simplex Parkinson disease of unknown cause. Median age of onset is approximately 50 years, with a range of onset spanning the third to eighth decade of life. PARK-VPS35 subtypes can include tremor dominant, akinetic rigid, gait difficulty, or mixed. Asymmetric presentation is typical. The disease course is usually milder than that of simplex Parkinson disease of unknown cause, with a decreased incidence of atypical signs. Dyskinesia and motor fluctuations may occur. Neuropsychiatric manifestations (depression and schizophrenia), learning difficulties, mild cognitive impairment, and dementia have been reported, albeit with lower occurrence than in simplex Parkinson disease of unknown cause. Additional findings include impaired sense of smell and autonomic manifestations including orthostasis and constipation.

Diagnosis/testing: The diagnosis of PARK-VPS35 is established in a proband with parkinsonism (bradykinesia with rigidity and/or resting tremor) and a heterozygous VPS35 pathogenic variant identified by molecular genetic testing.

Management: Treatment of manifestations: To date, treatment of PARK-VPS35 does not differ from that of simplex Parkinson disease of unknown cause. Drugs to treat motor manifestations include levodopa, in combination with a peripheral dopa decarboxylase inhibitor (carbidopa, benserazide), dopamine agonists, inhibitors of catechol-O-methyltransferase or monoamine oxidase-B, anticholinergics, and amantadine. Most individuals respond well to levodopa and other dopaminergic medications. Individuals benefit from physical, occupational, and speech therapies. Due to the lower risk of atypical signs, neuropsychiatric disturbances, and dementia, individuals with PARK-VPS35 seem to be good candidates for treatment with dopamine agonists. In addition, in those with dyskinesia and motor fluctuations, subthalamic deep brain stimulation and apomorphine intermittent injections or continuous therapy with an infusion pump should be considered. Peak-dose dyskinesia may be ameliorated with amantadine and dopaminergic treatment reduction (if tolerated). Low-dose clozapine, quetiapine, or pimavanserin and reduction of dopaminergic therapy can decrease delusions and hallucinations. Standard treatments for depression; consider droxidopa for orthostasis; symptomatic treatment for constipation.

Surveillance: Neurologic evaluations to assess tremor, bradykinesia, rigidity, gait, neuropsychiatric symptoms, cognition, and treatment efficacy every six to 12 months or as needed; neuropsychiatric and cognitive assessments as needed; assess for symptoms of orthostasis, measure blood pressure, and assess for constipation at each visit; echocardiogram as needed in those treated with ergot-derived dopamine agonists; assess family and social work needs at each visit.

Agents/circumstances to avoid: Drugs that may induce or exacerbate parkinsonism include but are not limited to neuroleptics, antidepressants, calcium channel blockers, valproate, lithium, and amiodarone. Ergot-derived dopaminergic drugs should be discontinued if fibrotic heart-valve changes are identified.

Genetic counseling: PARK-VPS35 is inherited in an autosomal dominant manner. About 90% of individuals diagnosed with PARK-VPS35 have positive family history of Parkinson disease. Each child of an individual with PARK-VPS35 has a 50% chance of inheriting the VPS35 pathogenic variant. Once the VPS35 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.