Genetics of Parkinson disease

Domingo, Aloysius; Klein, Christine

doi:10.1016/b978-0-444-63233-3.00014-2

Cited by 119 publications

(123 citation statements)

References 135 publications

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“…The etiology of idiopathic PD is multifactorial, likely arising from a combination of polygenic inheritance, environmental exposures, and gene–environment interactions. Although monogenic, inherited forms of PD are rare and constitute around 5% to 10% of all cases, 20% of patients with PD report having 1 affected first‐ or second‐degree relative . The initial discovery of α‐synuclein gene mutations and multiplications as a cause of PD more than 20 years ago have been followed by intensive research and the identification of numerous genes linked to PD pathogenesis .…”

Section: Genetic‐based Targeted Therapies Currently Being Tested In Pmentioning

confidence: 99%

“…Although monogenic, inherited forms of PD are rare and constitute around 5% to 10% of all cases, 20% of patients with PD report having 1 affected first‐ or second‐degree relative . The initial discovery of α‐synuclein gene mutations and multiplications as a cause of PD more than 20 years ago have been followed by intensive research and the identification of numerous genes linked to PD pathogenesis . This review summarizes how these initial genetic findings enabled targeting therapies for α‐synuclein ( SNCA ), glucocerebrosidase ( GBA ), and leucine‐rich repeat kinase ( LRRK2 ), as these are the most advanced in clinical development (Table ).…”

Section: Genetic‐based Targeted Therapies Currently Being Tested In Pmentioning

confidence: 99%

“…In neurons, α‐synuclein normally participates in the regulation of neurotransmitter release from the presynaptic terminals . Mutations and multiplications in SNCA cause familial PD . Recently, genomewide association studies have consistently identified common genetic variants close to the SNCA locus that increase the risk for idiopathic PD .…”

Section: Therapeutic Approaches Targeting α‐Synucleinmentioning

confidence: 99%

“…Mutations in the gene‐encoding leucine‐rich repeat kinase 2 ( LRRK2 ) were initially identified in a series of families with autosomal dominant parkinsonism. Some LRRK2 mutations are relatively common; for instance, the G2019S variant is present worldwide and has a high prevalence in North Africa where it accounts for more than 30% of PD cases . Of note, LRRK2 mutations have an age‐dependent incomplete penetrance (ie, some individuals live until old age without any clinical signs of PD) and noncoding polymorphisms close to the LRRK2 locus can also act as risk factors for sporadic disease.…”

Section: Therapeutic Approaches Targeting the Lrrk2 Pathwaymentioning

confidence: 99%

“…5 Mutations and multiplications in SNCA cause familial PD. 3 Recently, genomewide association studies have consistently identified common genetic variants close to the SNCA locus that increase the risk for idiopathic PD. 6,7 A large body of evidence suggests that the accumulation of a-synuclein plays a key role in PD.…”

Section: Therapeutic Approaches Targeting A-synucleinmentioning

confidence: 99%

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Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic

Sardi¹,

2018

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The greatest unmet medical need in Parkinson's disease (PD) is treatments that slow the relentless progression of symptoms. The discovery of genetic variants causing and/or increasing the risk for PD has provided the field with a new arsenal of potential therapies ready to be tested in clinical trials. We highlight 3 of the genetic discoveries (α‐synuclein, glucocerebrosidase, and leucine‐rich repeat kinase) that have prompted new therapeutic approaches now entering the clinical stages. We are at an exciting juncture in the journey to developing disease‐modifying treatments based on knowledge of PD genetics and pathology. This review focuses on therapeutic paradigms that are under clinical development and highlights a wide range of key outstanding questions in PD. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Section: Genetic‐based Targeted Therapies Currently Being Tested In Pmentioning

confidence: 99%

Section: Genetic‐based Targeted Therapies Currently Being Tested In Pmentioning

confidence: 99%

Section: Therapeutic Approaches Targeting α‐Synucleinmentioning

confidence: 99%

Section: Therapeutic Approaches Targeting the Lrrk2 Pathwaymentioning

confidence: 99%

Section: Therapeutic Approaches Targeting A-synucleinmentioning

confidence: 99%

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Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic

Sardi¹,

2018

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Association of Subthalamic Deep Brain Stimulation With Motor, Functional, and Pharmacologic Outcomes in Patients With Monogenic Parkinson Disease

et al. 2019

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Key Points Question Does the outcome of subthalamic deep brain stimulation vary among common monogenic forms of Parkinson disease? Findings In this systematic review and meta-analysis involving 518 patients from 17 published studies, treatment with subthalamic deep brain stimulation for patients with Parkinson disease with LRRK2 , GBA , or PRKN gene mutation yielded similar motor outcomes but different changes in dopaminergic doses, activities of daily living, motor complications, and cognitive functions. Meaning Genetic screening for LRRK2, GBA, and PRKN mutations in patients with Parkinson disease who are candidates for subthalamic deep brain stimulation may serve to inform outcomes.

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Discordance in monozygotic Parkinson's disease twins – continuum or dichotomy?

Balck

Borsche

Kasten

et al. 2019

Ann Clin Transl Neurol

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Differences in concordance rates between monozygotic and dizygotic twin pairs with Parkinson's disease (PD) have been used to estimate genetic influences in PD pathogenesis. We hypothesized that “discordance” may not in all cases adequately reflect the multifaceted disease manifestation of PD that involves a continuum from prodromal to definite PD. Deep clinical phenotyping, combining motor, nonmotor, and imaging modalities in five monozygotic, seemingly discordant twin pairs revealed motor and/or nonmotor features and/or nigral hyperechogenicity in all of the five putatively unaffected twins. In conclusion, our data suggest that concordance rates in monozygotic twins may be higher than previously appreciated.

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Genetics of Parkinson disease

Cited by 119 publications

References 135 publications

Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic

Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic

Association of Subthalamic Deep Brain Stimulation With Motor, Functional, and Pharmacologic Outcomes in Patients With Monogenic Parkinson Disease

Discordance in monozygotic Parkinson's disease twins – continuum or dichotomy?

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