Genetic Basis Of Parkinson Disease

PARKINSON DISEASE
Literature Review by:
Galuh DN Astuti, MD
RahajengTunjungputri, MD
Magister of Biomedical Science/ Genetic Counseling
Faculty of MedicineDiponegoro University, 2010

Parkinsonism
Parkinson disease
Parkinsonism in other neurodegenerative disorders
- Pick disease
- Progressive supranuclear palsy
- Multiple System atrophies
- Alzheimer disease
- Huntington disease (rigid variant)
Secondary Parkinsonism
drug-induced, infection, toxin, tumors

Parkinson Disease ?
a chronic progressive neurodegenerativemovement disorder characterized by aprofound & selective loss of nigrostriataldopaminergic neurons with accumulation of Lewy bodies (protein aggregate)
2nd most common neurodegenerative disorder after Alzheimer disease
Prevalence : 0.5 - 1 %(65 - 69 y.o)
1 - 3 %(> 80 y.o)
men > women
all races and ethnic groups are affected

Clinical manifestation :TRAP
Tremor at rest
Rigidity
Akinesia (or bradykinesia)
Posturalinstability
Autonomic dysfunction
Neuropsychiatric disorder

ETIOLOGY
Unknown
Interaction between environmental and genetic factor

Risk factors
Increasing age
Family history
Male gender
Caucasian
Personality
Environmental risk factors

Basal Ganglia
a large group of nuclei at the base of the cerebral cortex that controls movement, coordination & affects voluntary movement
Including :
- caudate nucleus
- putamen
- globus pallidus
- subthalamic nucleus
- substantia nigra

Parkinson Disease?
breakdown the connection between neurons in substantia nigra and putamen portion of striatum  loss of dopaminergic neurons  decrease in neurotransmission  dysfunction of globus pallidus interna and subthalamic  difficulty of motor control
Symptom  60-80 % cell impaired

DIAGNOSIS
History taking
Physical Examination
No laboratory tests or imaging studies to confirm the diagnos
Antiparkinsonian medication?
Imaging test:
- MRI
- CT scan
- PET
- SPECT
Dopamine transporter imaging

Treatment
Indication:
when the patient is sufficiently botheredby symptoms to desire treatment
when the diseaseis producing disability
Non Pharmalogical
support and education
exercise : stretching, strengthening, cardiovascular fitness & balance training
Pharmacotherapy
- Levodopa
- Anticholinergics
- Amantadine
- MAO-B inhibitors
- Dopamine agonists
- COMT inhibitor

Levodopa
dopa decarboxylase
Levodopa dopamine
Complication :
- Wearing off
- Dose failures
- ON-OFF
- Dyskinesias & dystonia

Levodopa + Carbidopa
Dopamine production in the brain
Side effects
Carbidopa : inhibits dopa decarboxylase outside the BBB

Surgical treatment
Pallidal surgery
Thalamic surgery
Subthalamic surgery
Transplantation surgery

Genetic basis of PD
Most PD cases are sporadic
5–10% of PD patients carry a mutation causing monogenic form of the disorder
These genes also play a role in the sporadic form of the disease
Different genes influence:
Inheritance pattern
Phenotype
Age of onset

Role of genes in PD

Monogenic forms of PD
Xiromerisiou G, Dardiotis E, Tsimourtou V, Kountra PM, Paterakis KN, Kapsalaki EZ, Fountas KN, Hadjigeorgiou GM. Genetic basis of Parkinson disease. Neurosurg Focus. 2010 Jan;28(1):E7.

PARK1, PARK4

PARK2
Parkin was the first gene identified for AR form of PD
Very common cause of parkinsonism
Localize at synapse, function as ubiquitinligase at ubiquitination protein degradation pathway
Severe and selective degeneration in substantianigra pars compacta without Lewy bodies
Mutations: missense, nonsense, rearrangement
Onset before 40 years, slow progression, dystonia occurring early and frequently
Unusual feature: focal dystonia, early postural instability, autonomic failure

PARK8 (LRRK2)
PARK8 encodes multidomain protein, leucine-rich repeat kinase 2 (LRRK2);
mutations cause autosomal dominant PD
α-synuclein-type neuropathology
Mutations account for 3-7% of familial PD cases, 0.5-3% of sporadic cases
c.6055G > A; p.G2019S is the most frequent of several amino acid substitutions in PARK8 gene
Prevalence vary with ethnicity of PD patients:
North American and Northern European white population (1-2%)
Portuguese (6%)
Ashkenazi Jewish (18.3%)
North African Arab populations (39%)
Rare in Korean population

Common intersecting pathway in PD
Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R183-94. Review.

Genetic susceptibility in sporadic PD
90% of PD: complex interaction of genetics and environment
Environmental risk factors: association between pesticide use, use of well water, rural living, and agricultural employment (conflicting results)
Specific polymorphic variants have been validated as genetic susceptibility factors
The Rep1, a mixed nucleotide repeat in the promoter region of SNCA, has been confirmed as a risk factor.
Two variants in the LRRK2 gene, G2385R and R1628P, confer susceptibility to PD in Asian populations.
Polymorphisms in genes identified in familial PD may exert a disease-modulating effect that, interacting with other genetic or environmental susceptibility factors, may drive the accumulated risk over a critical threshold to cause neurodegeneration.

Genetic modifiers
Krüger R. LRRK2 in Parkinson's disease - drawing the curtain of penetrance: a commentary.
BMC Med. 2008 Nov 5;6:33.

Conclusion
The value of screening for mutations in asymptomatic family members of LRRK2-mutation carriers are still questionable because until now no neuroprotective therapy has been implemented and symptomatic treatment is performed regardless of the presence or absence of mutations in known genes (Kruger, 2008)
Specific polymorphic variants have been validated as genetic susceptibility factors and protective factors (Xiromerisiou G et al, 2010)
Knowledge of genetic basis of PD will discover key facts of the pathogenesis and lead to new targeted therapeutic strategies in the future (Xiromerisiou G et al, 2010)

References
Krüger R. LRRK2 in Parkinson's disease - drawing the curtain of penetrance: a commentary. BMC Med. 2008 Nov 5;6:33.
Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R183-94. Review.
Xiromerisiou G, Dardiotis E, Tsimourtou V, Kountra PM, Paterakis KN, Kapsalaki EZ, Fountas KN, Hadjigeorgiou GM. Genetic basis of Parkinson disease. Neurosurg Focus. 2010 Jan;28(1):E7.

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Genetic Basis Of Parkinson Disease

by Rahajeng Tunjungputri on Apr 03, 2010

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