1 / 40

early-onset forms of Parkinson’s disease

early-onset forms of Parkinson’s disease. Dr. Pupak Derakhshandeh (PhD) Assis. Prof. Med. Sci. of Tehran Univ . Parkinson's Disease . one of the most common human neurodegenerative diseases progressive degenerative disorder affecting one of the regions of the brain controlling movement.

darrin
Download Presentation

early-onset forms of Parkinson’s disease

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. early-onset forms ofParkinson’s disease Dr. Pupak Derakhshandeh (PhD)Assis. Prof. Med. Sci. of Tehran Univ.

  2. Parkinson's Disease

  3. one of the most common human neurodegenerative diseases • progressive • degenerative disorder • affecting one of the regions of the brain controlling movement

  4. The most common symptoms • Tremor • muscular stiffness • and slowness of movement

  5. there are different types of parkinsonism • the most common condition today is the one first recognized in 1817 by James Parkinson • At present there is no cure • but treatments do exist and are available

  6. Dopamine • symptoms are due to a deficiency of the brain chemical: • Dopamine • the nerve cells containing dopamine: die

  7. Dopamine - A Neurotransmitter • One of the neurotransmitters playing a major role in addiction is dopamine • As a chemical messenger, dopamine is similar to adrenaline • Dopamine affects brain processes that control movement, emotional response, and ability to experience pleasure and pain • Regulation of dopamine: plays a crucial role in our mental and physical health • Neurons containing the neurotransmitter dopamine are clustered in the midbrain in an area called the substantia nigra • In Parkinson's disease, the dopamine- transmitting neurons in this area die. • To help relieve their symptoms, we give these people L-DOPA, a drug that can be converted in the brain to dopamine

  8. substantia nigra • Neurons containing the neurotransmitter dopamine are clustered in the midbrain in an area called the substantia nigra

  9. incidence • The incidence of Parkinsonism increases with age • and is uncommon in people younger than forty • Parkinson's disease affects both men and women • across all ethnic groups and is a serious health problem in all the world

  10. Slowness of movement • This is the most disabling symptom • The slowness makes it difficult to get out of a chair or turn in bed • Fine movements such as buttoning clothing, handwriting, and using a fork or knife may become difficult • Later, the person appears to be in slow motion and if not treated may become virtually frozen like a statue • Because of the enormous energy it takes to overcome slowness, the person with Parkinson's disease often complains of being "weak" although there is no true muscular weakness

  11. Tremor • Tremor or shaking occurs in about two-thirds of people with Parkinsonism • the most visible and obvious sign of the disease • Parkinson tremor usually affects the hands and feet • it sometimes involves the lips, tongue, and jaw

  12. Muscle stiffness • Stiffness combined with slowness • may cause aching muscles and joints, especially in the shoulders • This is sometimes misinterpreted as "arthritis" or "bursitis”

  13. Masked face • showing little or no emotion through facial expression • Blinking and spontaneous eye movements are less frequent • This can be misinterpreted as lack of interest or depression

  14. Walking difficulties • The gait may be slow with short steps • It is common to have difficulties with balance

  15. Speech problems • About one half of all individuals with Parkinson's disease develop difficulty with their speech • Communication can be complicated further by a fast mumbling speech with uncontrollable repetitions of the first syllable

  16. Swallowing difficulties • difficulty eating because their ability to swallow has become impaired • Food may collect in the mouth or the back of the throat resulting in choking or coughing

  17. Parkinson’s disease in the family synuclein gene

  18. No alterations in -synuclein gene dosage observed in sporadic Parkinson's (Movement disorders disease : official journal of the Movement Disorder Society. 2006 Mar 21)

  19. Synuclein (SNCA) • point mutations seen in familial Parkinson's disease (PD) • are rarely found in sporadic disease • usually develop symptoms around age 45 (AD) • synuclein mRNA expression : play a role in the etiology of the disease • a SNP in alpha-synuclein (SNCA), showed the strongest association with PD (Hum Mul Gent 2006 Apr 1;15(7):1151-8. Epub 2006 Feb 24)

  20. Alpha-synuclein • Alpha-synuclein is part of the synuclein family including beta- and gamma-synuclein Synucleins are very common in the brain • SNCA located on chrmosome 4 • expresses the140-amino acid protein alpha-synuclein (OMIM*163890) • (http://health.upenn.edu/cndr/research1/tausyn/tausyn.htm)

  21. Parkinson’s disease in famillier except for its: • early onset • and very fulminant course • a larger than expected number of people with Parkinson’s disease • Gene: PARK4

  22. Dosage effect on clinical phenotype • even in the absence of mutations detectable by sequence analysis • simple multiplications of SNCA can cause autosomal dominant forms of PD • a dosage effect on clinical phenotype, with duplication of the gene resulting in a phenotype similar to PD • but triplication resulting in early-onset parkinsonism with dementia

  23. neither mutations in the coding region of SNCA • nor over expression of the gene due to multiplication • appear to be common causes of PD • It remains possible: • other genetic factors may influence -synuclein mRNA expression • play a role in the etiology of the disease

  24. an association between the polymorphic sequence repeat in the promoter region of SNCA and PD risk (Mellick GD, Maraganore DM, Silburn PA. Australian data and meta-analysis lend support for alpha-synuclein (NACP-Rep1) as a risk factor for Parkinson's disease. Neurosci Lett 2005; 375: 112-116. )

  25. Lewy bodies • similar to the beta-amyloid plaques found in Alzheimer's patients)   • The Lewy bodies lead to loss of neurons • then dopamine (a neurotransmitter) • and finally loss of motor control

  26. First, a-synuclein is the primary component of Lewy bodies in all PD patients • two different a-synuclein missense mutations (A30P and A53T) are associated with: • rare, autosomal dominant • early-onset PD and have been shown to form fibrils

  27. PD-linked mutations (A30P and A53T) • correlated to the onset of disease phenotype • in vitro a-synuclein oligomerization: • suggesting that the process of a-synuclein fibrillization may initiate neurodegeneration

  28. mitochondrial dysfunction

  29. The role of mitochondrial dysfunction in Parkinson's disease • functions of DJ1, PINK1 and OMI/HTRA2 • which are all associated with the mitochondria • in cellular protection against oxidative damage (Nature Reviews Neuroscience 7, 207-219 (March 2006) |

  30. The DJ-1 gene • encodes a ubiquitous, highly conserved protein • DJ-1 mutations are associated with PARK7 • a monogenic form of human PARKINSONISM • The function of the DJ-1 protein: • in the oxidative stress response • loss of DJ-1 function leads to neurodegeneration • & PARKINSON's disease (Science 10 January 2003:Vol. 299. no. 5604, pp. 256 – 259)

  31. PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET; PARK6

  32. PARK6 • Localization of a novel locus for autosomal recessive early-onset parkinsonism: • on human chromosome 1p35-p36

  33. unrelated families with autosomal recessive PD from various regions in Asia that showed linkage to the PARK6 locus • Families: consanguineous • Age at onset ranged from 18 to 56 years, although most had onset in the third or fourth decades

  34. mutations affecting the PINK1 kinase domain in PARK6 families • onset in patients with PINK1 mutations was earlier and increased reflexes were found more frequently than in patients without PINK1 or parkin mutations (Hatano et al., 2004; Healy et al., 2004; Rogaeva et al., 2004; Rohe et al., 2004; Valente et al., 2004a; Valente et al., 2004b; Bonifati et al., 2005; Klein et al., 2005)

  35. pedigrees of families with PINK1 mutations (AR)

  36. PINK1 mutations • All missense (C125G, E240K, L369P, G386A and G409V) mutations replace highly conserved residues

  37. Relative frequencies of patients with PINK1 or parkin mutations and without PINK1 and parkin mutations according to the age at onset

  38. PINK1 mutations • that heterozygous mutations in genes: • autosomal recessive forms with an early onset can also cause later onset Parkinson's disease !

  39. Molecular Findings in Familial Parkinson Disease • Mutations in Park2 gene account for 38% of the families with recessive parkinsonism in Spain • Heterozygous carriers of a single Park2 mutation either were asymptomatic or developed clinical symptoms in late adulthood • (Arch Neurol. 2002;59:966-970)

More Related