LRRK2- Related Parkinson Disease

Excerpt

Clinical characteristics: LRRK2-related Parkinson disease (PARK-LRRK2) is characterized by initial motor features of bradykinesia and asymmetric tremor at rest or rigidity. Dystonia and gait abnormalities that may include freezing and postural instability may also be present. Onset is generally after age 50 years, although early onset (in the 20s) and late onset (in the 90s) have been described. PARK-LRRK2 is indistinguishable from Parkinson disease of unknown cause representing a simplex case (also referred to as "sporadic" Parkinson disease) on an individual basis. However, on average individuals with PARK-LRRK2 have slightly slower motor progression and better survival. Overall, nonmotor symptoms in PARK-LRRK2, especially REM sleep behavior disorder and cognitive decline, may occur at reduced frequency and the latter may progress more slowly compared to Parkinson disease of unknown cause. Melanoma is more common in individuals with Parkinson disease, including those with PARK-LRRK2.

Diagnosis/testing: The diagnosis of PARK-LRRK2 is established in a proband with Parkinson disease and a heterozygous LRRK2 pathogenic variant identified by molecular genetic testing.

Management: Treatment of manifestations: Symptomatic treatment of the motor features of parkinsonism is the same as for other known causes of Parkinson disease: pharmacologic replacement of dopamine, most commonly accomplished with the precursor of dopamine, levodopa, combined with carbidopa. Dopamine receptor agonists may also be used, as well as monoamine oxidase type B inhibitors, amantadine, adenosine receptor A2A antagonists, and/or anticholinergics. Dyskinesias may occur with therapy at similar or increased rates compared with Parkinson disease of unknown cause. Exercise is usually recommended. Physical, occupational, and voice therapy may be beneficial. Treatment of nonmotor manifestations – such as cognitive changes, constipation, depression, anxiety, urinary issues, sleep disorders, and orthostatic hypotension – should be addressed based on an individual basis; standard treatment of melanoma per dermatologist and oncologist.

Surveillance: At least annual evaluation (typically every three months) for both motor and nonmotor symptoms. Motor evaluation focuses on gait and frequency of falls, slowness of movement and dexterity, tremor, and rigidity. Evaluation for nonmotor signs and symptoms includes assessment of constipation, cognitive changes, mood disorder, impulse control disorders, other psychiatric disorders, urinary frequency, sexual dysfunction, sleep disturbance, and orthostatic hypotension. At least annual dermatologic evaluation for melanoma.

Agents/circumstances to avoid: Dopamine-blocking therapies may exacerbate parkinsonism.

Pregnancy management: While data is limited, most support treatment with levodopa and dopa decarboxylase inhibitors during pregnancy.

Genetic counseling: PARK-LRRK2 is inherited in an autosomal dominant manner with reduced penetrance. To date, all individuals with PARK-LRRK2 whose parents have undergone molecular genetic testing have the disorder as the result of an LRRK2 pathogenic variant inherited from a parent. However, because the penetrance of PARK-LRRK2 is reduced, a high percentage of probands report unaffected parents. Each child of an individual with a heterozygous LRRK2 pathogenic variant has a 50% chance of inheriting the LRRK2 pathogenic variant. Once the causative LRRK2 pathogenic variant(s) has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.