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Genetic Basis Of Parkinson Disease

Literature review

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Genetic Basis Of Parkinson Disease

  1. 1. PARKINSON DISEASE<br />Literature Review by:<br />Galuh DN Astuti, MD<br />RahajengTunjungputri, MD<br />Magister of Biomedical Science/ Genetic Counseling<br />Faculty of MedicineDiponegoro University, 2010<br />
  2. 2. Parkinsonism<br />Parkinson disease<br />Parkinsonism in other neurodegenerative disorders<br /> - Pick disease<br /> - Progressive supranuclear palsy<br /> - Multiple System atrophies <br /> - Alzheimer disease<br /> - Huntington disease (rigid variant)<br />Secondary Parkinsonism<br /> drug-induced, infection, toxin, tumors<br />
  3. 3. Parkinson Disease ?<br />a chronic progressive neurodegenerativemovement disorder characterized by aprofound & selective loss of nigrostriataldopaminergic neurons with accumulation of Lewy bodies (protein aggregate)<br />2nd most common neurodegenerative disorder after Alzheimer disease <br />Prevalence : 0.5 - 1 %(65 - 69 y.o)<br />1 - 3 %(> 80 y.o)<br />men > women<br />all races and ethnic groups are affected<br />
  4. 4. Clinical manifestation :TRAP<br />Tremor at rest<br />Rigidity<br />Akinesia (or bradykinesia)<br />Posturalinstability<br />Autonomic dysfunction<br />Neuropsychiatric disorder<br />
  5. 5. ETIOLOGY<br />Unknown<br />Interaction between environmental and genetic factor<br />
  6. 6. Risk factors<br />Increasing age<br />Family history<br />Male gender<br />Caucasian<br />Personality<br />Environmental risk factors<br />
  7. 7. Basal Ganglia<br />a large group of nuclei at the base of the cerebral cortex that controls movement, coordination & affects voluntary movement <br />Including :<br /> - caudate nucleus<br /> - putamen<br /> - globus pallidus<br /> - subthalamic nucleus<br /> - substantia nigra<br />
  8. 8.
  9. 9. Parkinson Disease?<br />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<br />Symptom  60-80 % cell impaired<br />
  10. 10.
  11. 11. DIAGNOSIS<br />History taking<br />Physical Examination <br />No laboratory tests or imaging studies to confirm the diagnos<br />Antiparkinsonian medication?<br />Imaging test:<br /> - MRI<br /> - CT scan <br /> - PET <br /> - SPECT<br />Dopamine transporter imaging<br />
  12. 12. Treatment <br />Indication:<br /><ul><li> when the patient is sufficiently botheredby symptoms to desire treatment
  13. 13. when the diseaseis producing disability</li></ul>Non Pharmalogical<br />support and education<br />exercise : stretching, strengthening, cardiovascular fitness & balance training<br />Pharmacotherapy <br /> - Levodopa <br /> - Anticholinergics<br /> - Amantadine<br /> - MAO-B inhibitors<br /> - Dopamine agonists<br /> - COMT inhibitor<br />
  14. 14. Levodopa <br />dopa decarboxylase<br />Levodopa dopamine<br />Complication :<br /> - Wearing off<br /> - Dose failures<br /> - ON-OFF<br /> - Dyskinesias & dystonia<br />
  15. 15. Levodopa + Carbidopa<br />Dopamine production in the brain<br /> Side effects<br /> Carbidopa : inhibits dopa decarboxylase outside the BBB<br />
  16. 16. Surgical treatment<br />Pallidal surgery<br />Thalamic surgery<br />Subthalamic surgery <br />Transplantation surgery <br />
  17. 17. Genetic basis of PD<br />Most PD cases are sporadic<br />5–10% of PD patients carry a mutation causing monogenic form of the disorder<br />These genes also play a role in the sporadic form of the disease<br />Different genes influence: <br />Inheritance pattern<br />Phenotype<br />Age of onset<br />
  18. 18. Role of genes in PD<br />
  19. 19. Monogenic forms of PD<br />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.<br />
  20. 20. PARK1, PARK4<br />
  21. 21. PARK2 <br />Parkin was the first gene identified for AR form of PD<br />Very common cause of parkinsonism<br />Localize at synapse, function as ubiquitinligase at ubiquitination protein degradation pathway<br />Severe and selective degeneration in substantianigra pars compacta without Lewy bodies<br />Mutations: missense, nonsense, rearrangement<br />Onset before 40 years, slow progression, dystonia occurring early and frequently<br />Unusual feature: focal dystonia, early postural instability, autonomic failure<br />
  22. 22. PARK8 (LRRK2)<br />PARK8 encodes multidomain protein, leucine-rich repeat kinase 2 (LRRK2); <br />mutations cause autosomal dominant PD <br />α-synuclein-type neuropathology<br />Mutations account for 3-7% of familial PD cases, 0.5-3% of sporadic cases<br />c.6055G > A; p.G2019S is the most frequent of several amino acid substitutions in PARK8 gene<br />Prevalence vary with ethnicity of PD patients: <br />North American and Northern European white population (1-2%) <br />Portuguese (6%)<br />Ashkenazi Jewish (18.3%) <br />North African Arab populations (39%)<br />Rare in Korean population<br />
  23. 23. Common intersecting pathway in PD<br />Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R183-94. Review.<br />
  24. 24. Genetic susceptibility in sporadic PD<br />90% of PD: complex interaction of genetics and environment<br />Environmental risk factors: association between pesticide use, use of well water, rural living, and agricultural employment (conflicting results)<br />Specific polymorphic variants have been validated as genetic susceptibility factors<br />The Rep1, a mixed nucleotide repeat in the promoter region of SNCA, has been confirmed as a risk factor.<br />Two variants in the LRRK2 gene, G2385R and R1628P, confer susceptibility to PD in Asian populations. <br />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.<br />
  25. 25. Genetic modifiers<br />Krüger R. LRRK2 in Parkinson's disease - drawing the curtain of penetrance: a commentary.<br />BMC Med. 2008 Nov 5;6:33.<br />
  26. 26. Conclusion<br />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)<br />Specific polymorphic variants have been validated as genetic susceptibility factors and protective factors (Xiromerisiou G et al, 2010)<br />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)<br />
  27. 27. References<br />Krüger R. LRRK2 in Parkinson's disease - drawing the curtain of penetrance: a commentary. BMC Med. 2008 Nov 5;6:33.<br />Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R183-94. Review.<br />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.<br />

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