LRRK2 Parkinson Disease

Excerpt

Clinical characteristics: LRRK2 Parkinson disease (PD) is characterized by features consistent with idiopathic PD: initial motor features of slowly progressive asymmetric tremor at rest and/or bradykinesia, cogwheel muscle rigidity, postural instability, and gait abnormalities that may include festination and freezing. Certain nonmotor symptoms in LRRK2-PD, especially REM sleep behavior disorder and cognitive decline, may occur at similar or slightly reduced frequency compared to typical idiopathic* PD. Onset is generally after age 50, although early-onset (in the 20s) and late-onset (in the 90s) disease has been described.

* Idiopathic PD refers to the presence of signs and symptoms of PD for which the etiology is currently unknown and in which there is no known family history of PD.

Diagnosis/testing: The diagnosis of LRRK2-PD relies on clinical findings and the identification of a heterozygous pathogenic variant in LRRK2.

Management: Treatment of manifestations: Symptomatic treatment of parkinsonism is the same as for idiopathic Parkinson disease: pharmacologic replacement of dopamine, most commonly accomplished with the precursor of dopamine, L-dopa, combined with carbi-dopa. Dopamine agonists may also be used, as well as monoamine oxidase-B (MAO-B) inhibitors, amantadine, and/or anticholinergics. Physical, occupational, and voice therapy may be beneficial. Exercise is often recommended. Treatment of nonmotor manifestations – e.g., depression, anxiety, sleep disorders, urinary issues, orthostatic hypotension – should be addressed based on individual manifestations.

Surveillance: Annual evaluation for both motor and nonmotor symptoms. Motor evaluation focuses on gait and falls, slowness of movement and dexterity, tremor, and rigidity. Evaluation for nonmotor signs and symptoms includes assessment of constipation, mood disorder, impulse control disorders, other psychiatric disorders, cognitive changes, sleep disturbance, orthostatic hypotension, and urinary frequency. In addition, at least yearly evaluation for melanoma.

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

Genetic counseling: LRRK2-PD is inherited in an autosomal dominant manner. However, given the reduced penetrance associated with LRRK2-PD, a high percentage of affected individuals report unaffected parents. De novo mutation may occur; its frequency is unknown. Each child of an individual with LRRK2 Parkinson disease has a 50% chance of inheriting the pathogenic variant. However, the risk of developing disease is lower than 50% because of age-related reduced penetrance. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.