Parkinson disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder of the central nervous system. The cardinal motor features are bradykinesia, resting tremor, muscle rigidity, and, particularly in later stages, postural instability. The first clinical manifestations are typically unilateral and may include postural or action tremor and limb dystonia. Common non-motor manifestations comprise insomnia, depression, anxiety, REM sleep behaviour disorder, fatigue, constipation, and hyposmia. Onset is most commonly around age 68 years, with juvenile-onset (<21 years), early-onset (21-50 years), and late-onset (≥50 years) categories recognised. With disease progression, bilateral involvement, balance disturbances with falls, levodopa-induced dyskinesias, and motor fluctuations develop. Inter- and intra-familial variability is well documented, and dementia and/or psychosis occur in 30-40% of affected individuals.

Recent studies indicate that up to 15% of PD patients carry pathogenic variants in PD-associated genes.

Pathogenic germline variants in more than 15 genes have been implicated in monogenic Parkinson’s disease. The most frequently identified contributors include GBA1 (~7.7%), LRRK2 (~2.4%), and PRKN (~2.1%) in the North American PD GENEration cohort, with PINK1 and SNCA accounting for additional, rarer fractions. Inheritance across the monogenic spectrum encompasses autosomal dominant (LRRK2, RAB32, SNCA, VPS35), autosomal recessive (ATP13A2, DNAJC6, FBXO7, PARK7, PINK1, PLA2G6, PRKN, SYNJ1, VPS13C), and X-linked (RAB39B) forms; GBA1 variants act as major risk-conferring alleles. Typical PD is associated with brain alpha-synuclein deposition and Lewy body formation at autopsy, although clinically similar phenotypes can occur without Lewy bodies, particularly in LRRK2– and PRKN-related PD.

Monogenic Parkinson’s disease is inherited in an autosomal dominant, autosomal recessive, or X-linked manner, depending on the underlying gene. For autosomal dominant forms, each child of an affected individual has a 50% risk of inheriting the familial pathogenic variant; for autosomal recessive forms, the recurrence risk for siblings of an affected proband is 25%. De novo events are very rare; almost all individuals with autosomal dominant PD have inherited the pathogenic variant from a parent, who may or may not be clinically affected.

The clinical diagnosis rests on the cardinal motor features and is operationalised by the clinical diagnostic criteria for Parkinson’s disease (2015). Meeting these criteria establishes the clinical diagnosis of PD. Additional supportive criterion sets include the . In instances of diagnostic uncertainty, dopamine transporter single-photon emission computed tomography (DAT-SPECT) or fluorodopa positron emission tomography (PET) can support a diagnosis of dopaminergic deficit and is most commonly used to distinguish PD from essential tremor.

Main differential diagnoses include:

• Parkinson-plus syndromes (multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies): degenerative parkinsonism with additional features (autonomic failure, supranuclear gaze palsy, cortical signs, visual hallucinations) and typically poor levodopa response; MAPT, GRN, C9orf72 and others
• (SCA2, SCA3): cerebellar atrophy and cerebellar eye signs in an individual with otherwise typical PD signs; a levodopa-responsive parkinsonian syndrome very similar to PD has been reported; ATXN2, ATXN3
• Dopa-responsive dystonia (GTP cyclohydrolase 1 deficiency): childhood- or adolescent-onset dystonia and parkinsonism with dramatic, sustained response to low-dose levodopa; normal DAT-SPECT; GCH1

• Establishing the molecular diagnosis through identification of the underlying pathogenic variant(s).
• Informing clinical management of the affected individual; molecular confirmation is a prerequisite for targeted medical care, with management decisions made by the treating physicians in consultation with the affected individual.
• Enabling predictive and carrier testing of at-risk relatives once the familial pathogenic variant has been identified.

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• Cook L, Verbrugge J, Schwantes-An TH, Schulze J, Foroud T, Hall A, et al. Parkinson’s disease variant detection and disclosure: PD GENEration, a North American study. Brain. 2024;147(8):2668-2679. PMID: .
• Trevisan L, Gaudio A, Monfrini E, Avanzino L, Di Fonzo A, Mandich P. Genetics in Parkinson’s disease: state-of-the-art and future perspectives. Br Med Bull. 2024;149(1):60-71. PMID: .