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Genetics of Parkinson

Genetics of Parkinson. Carlos Singer MD Professor of Neurology Chief, Division of Parkinson and Movement Disorders University of Miami Leonard M. Miller School of Medicine May 20, 2010

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Genetics of Parkinson

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  1. Genetics of Parkinson Carlos Singer MD Professor of Neurology Chief, Division of Parkinson and Movement Disorders University of Miami Leonard M. Miller School of Medicine May 20, 2010 For more information, please call the National Parkinson Foundation at 800-327-4545 or visit www.parkinson.org.

  2. Genetics and Parkinson • Family history of PD is seen in 10-15% of patients with classic PD • A small percentage of these have a well defined mutation.

  3. Genetics and Parkinson • We have the technology to make this diagnosis in the majority of this small group of patients as their relatives. • We have no additional treatment even if the tests are “positive”

  4. Genetics and Parkinson • Why bother making the diagnosis of genetic Parkinson?

  5. Genetics and Parkinson • For the patient: Prognosis • For the unaffected relative who discover he or she is positive for the gene: Personal Planning: • Financial: life, disability, medical, long-term care • Family planning • Existential: change of profession, life style, “I wish I had …” • Anything else?

  6. Genetics and Parkinson • There are 13 different genetic mutations, some confirmed, some suspected. • We will talk about two of them. • Parkin mutation • LRRK2 mutation • We will talk about one additional mutation that is considered a “risk” gene • The “Gaucher’s disease” gene (GBA gene)

  7. PARK1/PARK44q21.3 –synuclein Autosomal dominant PARK2 6q25.2-27 Parkin Autosomal recessive PARK3 2p13 Unknown Autosomal dominant PARK5 4p14 UchL1 Autosomal dominant PARK6 1p35-p36 PINK1 Autosomal recessive PARK7 1p36 DJ-1 Autosomal recessive PARK8 12p11q13.1 LRRK2/Dardarin Autosomal dominant PARK9 1p36 ATP13A2 Autosomal recessive (Kufer-Rakeb Syndrome) PARK10 1p32 Unknown Late-onset susceptibility gene PARK11 2q36-37 Unknown Late-onset susceptibility gene PARK12X q21-q25 Unknown X-Linked PARK13 2p13.1 Omi/HtrA2 Autosomal dominant Dawson TM, Dawson VL. Mov Disord 2010;25 Gene related to Gaucher’s disease

  8. PARK 2: Parkin Mutation • No ethnic predisposition • Early age : < 40 years • If age of first symptoms is less than 30, there is a 25 % chance that person has the parkinmutation • After age 30 but before age 40 it is somewhere between 6 and 10%

  9. PARK 2: Parkin Mutation • The way the patient presents: • Young age of Onset • Similar tremor, rigidity and slowness • Some patients have an additional problem: dystonia • They respond well to L-dopa (Sinemet) • They have more of a tendency to develop similar problems with “wearing off” and involuntary movements (dyskinesias)

  10. PARK 2: Parkin Mutation • PARK 2 is autosomal recessive. • If both genes are affected, the individual will develop the disease at a young age, usually before age 40. • If only one gene is affected, there is the possibility – still unclear – that there is a PREDISPOSITION to develop the disease.

  11. Cautionary Note • Predisposition is not the same as predestination • Someone predisposed to a disease is at higher risk to develop the disease but MAY NOT develop it.

  12. PARK 2: Parkin Mutation • One DEFECTIVE GENE • No Early-Onset Parkinson • Late onset Parkinson? Not clear • Defective gene from mother • Defective gene from father • Early-Onset Parkinson

  13. PARK 2: Parkin Mutation • Issues more likely to be considered with relatives of PARK 2 patients by virtue of the young age of onset: • Family planning • Prenatal diagnosis • Pre-implantation genetic diagnosis

  14. Uncertainties and Speculations • If a patient has early onset PD but is parkin negative, the person may have a mutation in a so far undiscovered genetic address. • The patient may have gotten PD because of a combination of one or more of genetic “predispositions” (theoretical) • The patient may have gotten Parkinson because of a combination of one or more genetic predispositions and some unknown environmental exposure • The patient may have been exposed to one or more environmental exposures we do not yet understand.

  15. LRRK2 Mutation PARK 8 • LRRK2: Leucine Rich Repeat Kinase 2 • Protein encoded: dardarin • Chromosome 12 • Autosomal Dominant • Susceptible Populations • North African Berber Arabs, Ashkenazi Jews

  16. LRRK2 Mutation PARK 8 • The way the patient presents: • Indistinguishable from sporadic PD • Age of onset: 50’s-60’s • Levodopa responsive

  17. LRRK2 Mutation PARK 8 • PARK 8 is autosomal dominant • All you need is for one gene to be affected • As the patient becomes older the chances to come down with symptoms of Parkinson increase • at 50 there is a 25 % chance of having the symptoms • at 80 the chances increase up to 80%

  18. Gaucher’s disease • is not Parkinson’s Disease • is an ENZYME deficiency • a substance is accumulated in excess • affects liver, bone, blood in some people and the nervous system in others BUT IT IS NOT PARKINSONS’ DISEASE.

  19. Gaucher’s Disease • It is a lysosomal storage disorder • Caused by accumulation of material that is not being normally recycled with the accumulation causing problems in a variety of organs: liver, spleen, bone, brain.

  20. The Gaucher’s Disease Gene • One DEFECTIVE GENE • No Gaucher’s Disease • Defective gene from mother • Defective gene from father • Gaucher’s Disease

  21. The Parkin Gene • One DEFECTIVE GENE • No Early-Onset Parkinson • Late onset Parkinson? Maybe • Defective gene from mother • Defective gene from father • Early-Onset Parkinson

  22. Gene for Gaucher’s Disease = GBA In Parkinson disease GBA mutation in one of the two genes • Ashkenazi Jewish Parkinson patients 10.7%-31.3% have one GBA mutation • Non-Ashkenazi Jewish Parkinson patients 2.3%- 9.4% have one GBA mutation Velayati et al. Curr Neurol Neurosci Rep 2010; 10:190-198

  23. Predisposition is not the same as predestination • Someone predisposed to a disease is at higher risk to develop the disease but MAY NOT develop it.

  24. Having ONE defective GBA gene is a risk factor for developing Parkinson’s disease. • Hypertension is a risk factor for stroke.

  25. Should a patient then be tested for the GBA gene, especially if he or she is Ashkenazi Jewish, even if there are no other affected relatives? • It will make no difference in terms of treatment. It will make no difference to relatives since having the mutation does not mean that they will develop Parkinson.

  26. gauchers at NINDS • Gauchers News • European Gaucher Alliance • GeneReview/UW/NIH entry on Gaucher disease • National Gaucher Foundation • Children's Gaucher Research Fund • Hide & Seek Foundation For Lysosomal Disease Research

  27. Conclusions • The clearly genetic forms of Parkinson represent a small group of Parkinson patients • Most sporadic cases of Parkinson or even cases of people with family history of Parkinson have an unknown cause • The performance of genetic testing has at present no immediate significance to the affected person. • Depending on the case, it may have significance to the relatives of the affected person.

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