Spinal Muscular Atrophy Power Point

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Spinal Muscular Atrophy Power Point

  1. 1. Spinal Muscular Atrophy<br />Type 1<br />Infantile<br />Werdnig-Hoffman disease<br />©<br />Terry L. Hill, PhD<br />
  2. 2. Aetiology<br />.....An autosomal recessive genetic disease<br />....SMN1 gene (survival motor neuron 1 protein) is missing, or mutated on chromosome 5<br />....Affects spinal cord nerve cells such that they atrophy, shrink and eventually die, resulting in increasing muscle weakness<br />....detectable through amniocentesis; adjuvant EMG and nerve conduction velocity test (NCV) may be also used<br />
  3. 3. Aetiology (cont’d)<br />....95%+ of patients have a homozygous disruption in the SMN1 gene on chromosome 5q, caused by mutation, deletion, or rearrangement (discovered in 1995)<br />....SMN2 gene generates only 10% of survival motor neuron (SMN) but appears manipulatable for therapeutic purposes [see www.curesma.org]<br />....other types: chronic infantile (Type II), chronic juvenile (Type III or Kugelberg-Werlander Disease), and adult onset (Type IV)<br />
  4. 4. Prevalence/Incidence<br />....after cystic Fibrosis, SMA disease is the most common autosomal-recessive inherited disorder<br />....SMA Type 1 affects ~ 1:10,000 live births<br />....Carrier frequency is ~ 1:45 in the world<br />....Two carriers have a 25% chance they will have an affected child, and a 50% chance of producing a child who would be a SMA carrier, and a 25% chance of producing a SMA non-carrier<br />
  5. 5. Prevalence/Incidence (cont’d)<br />....highest in European, Eastern Mediterranean, Japanese and African-American groups worldwide<br />...North America: genotype frequency...<br />1:37 Caucasian; 1:46 Ashkenazi Jew; 1:56 Asian; 1:91 African-American*; 1:125 Hispanic<br />*see hand-out journal abstract for proviso re: high frequency alleles<br />....males are most frequently affected<br />....Type II (onset is 6-18 months) is the largest group, accounting for one half of all SMA cases<br />
  6. 6. Disease Characteristics<br />....age of onset: 0-6 months, with most symptoms occurring by 3 months<br />....median survival is 7 months<br />....mortality rate of ~95% at 18 months<br />....severe, progressive muscle weakness and flaccid muscle tone (hypotonia)<br />
  7. 7. Disease Characteristics (cont’d)<br />....bulbar dysfunction includes poor suck ability, reduced swallowing, and increasing respiratory failure<br />....impaired fetal movements may be observable in 30% of cases<br />....60% are “floppy” babies at birth<br />....weakness is greater in proximal than distal muscles; may mimic myopathy<br />
  8. 8. (Cont’d)<br />....deep tendon reflexes are absent<br />....skeletal and limb deformities may be observed at birth<br />....fasciculations of the tongue are noticeable by 4-6 months<br />....prone to pulmonary infections, scoliosis,<br />joint contractures<br />
  9. 9. (Cont’d)<br />....poor head control<br />....retarded leg control and weight bearing<br />....can not sit up unsupported<br />....weakness of intercostal (ribs) muscles predicts small chest and enlarged abdomen<br />....patient “breathes through his/her stomach”<br />....cough is weak; lung fluid build-up is common in later stages<br />
  10. 10. (Cont’d)<br />....risk of aspirating while eating<br />....eventual weight loss may occur<br />....child exhibits average or often above-average intelligence<br />...crying is subdued<br />....seldom able to roll over by oneself<br />
  11. 11. Who should be tested?<br />....anyone with a family history of SMA and their spouses to determine carrier status of unaffected individuals<br />....pregnancies at risk due to a family history<br />....individuals clinically suspected of being affected<br />
  12. 12. Progression<br />....continual weakness of all obvious physical abilities<br />....increasing signs of distress (breathing, heart rate, congestion)<br />....pleuresy > pneumonia; cyanosis of limbs/body<br />....DNR orders may be issued<br />....death due to rapid respiratory failure/heart attack<br />
  13. 13. Parenting Issues<br />Anticipatory grief<br />....shock, numbness, disbelief<br />....anger, blame, guilt<br />....lashing out/quiet resignation<br />....sleeplessness, physical/psychological symptoms<br />....social role disruption or imbalance(as provider, parent to other siblings, husband/wife, neighbour, etc.)<br />
  14. 14. Parenting Issues (cont’d)<br />Coping<br />....alteration of life’s previous routines<br />....dealing with physicians, hospitals, home-care, agencies, special meals, bedroom adjustments<br />....concentrating at work; leave of absence or worse<br />....real or perceived stigma from others (interactions, avoidance) <br />
  15. 15. (Cont’d)<br />....transference (displacing feelings, fears, conflicts from the past) onto one’s partner<br />....blaming God<br />....irrational thoughts, including suicide<br />....changing transportation demands<br />....finding community supports<br />
  16. 16. (Cont’d)<br />Post-loss grieving<br />....experiencing all aspects of the grieving process, but made worse because it was your child (not the natural order of things)<br />....funeral/burial issues<br />....possible growing apart due to different rates or ‘stages’ of grieving, or possible closer bonding<br />....divorce rates remain high among SMA parents<br />
  17. 17. (Cont’d)<br />....dealing with surviving sibling issues (school-work, friends, stigma, self-blame/self-doubt)<br />....regaining former roles; ‘new’ roles in getting on with life<br />....what to do with his/her bedroom? clothes? toys?<br />...how to handle birthdays, anniversary dates, memories,Christmas/Hunnaka/Ramadan<br />
  18. 18. ....customized orthopaedic chair<br />....lots of toys, reaching games, water therapy<br />....soft but firm crib mattress, with side pillows to support side sleeping<br />....access to physiotherapists, respirologist, occupational therapists, dietary or nutritional therapists, social services staff (CCAC, Home-Care, PSW, VON, etc.<br />....pharmacology therapy is not available<br />Supports<br />
  19. 19. (Cont’d)<br />....gene-specific therapy is not yet available<br />....genetic counselling<br />....Nasogastric Tube (NG-Tube)<br />....Gastrostomy Tube (G-Tube)<br />....chest physiotherpay (CPT); postural drainage<br />...Cough Assist Machine (positive to sudden negative airway pressure, to simulate a cough)<br />
  20. 20. (Cont’d)<br />....pulse oximeter (placed on finger to measure possible respiratory distress)<br />....BiPAP (Bilevel Positive Airway Pressure); note...a CPAP (Continuous Positive Airway Pressure) should NEVER be used on SMA patients<br />....Negative Pressure Ventilator, e.g., a Port-a-Lung<br />
  21. 21. Care-giver Skills<br />....patience, patience, patience<br />....empathy, warmth, friendliness, positive outlook, leadership, knowledge, in control<br />....encourage mobility range of motion, muscle flexibility, prevent contractures (with no pain or exhaustion)<br />....know wheel-chair and seat designs, body jacket, all assistive devices<br />....<br />
  22. 22. Treatments/Research<br />***pre-clinical drug development of a molecule of the tetracycline family; Paratek Pharmaceuticals, Boston and FSMA 5-year contract; Fall, 2009<br />***clinical trials soon (US) re: quinazoline use; Vertex Pharmaceuticals, deCode Genetics, and FSMA; June, 2009<br />***stem cell trials for SMA Type 1 soon; California Stem Cell (CSC); also Johns Hopkins University<br />
  23. 23. (Cont’d)<br />***Valporic acid clinical trials with 42 SMA subjects published [see online Journal PLoS ONE; Project Cure SMA Group]<br />2007-2008<br />***Dr. RashmiKothary, Ottawa Health Research Institute, “Establishment and Characterization of Primary Motor Neuron Cultures from an SMN Hypomorphic Series of Mice”<br />***Dr. Jocelyn Cote, University of Ottawa, “A Role for ArginineMethylation in the Regulation of SMA activites<br />
  24. 24. (Cont’d)<br />** *Dr. Alex E. McKenzie, MD, PhD, Children’s Hospital of Eastern Ontario. The assessment of the efficacy of a new drug found in SMA cellular asssays<br />***Dr. Jean-Yves Masson, PhD, Laval University. DNA damage signaling and repair in Spinal Muscular Atrophy<br />
  25. 25. (Cont’d)<br />2008-2009<br />***Dr. Guy D’Anjou, MD, Centre de rechereche, Hopital Sainte-Justine, Montreal, and Dr. Louise Simard, PhD, University of Manitoba. “Multi-center Phase II Trial of Valporic Acid and Carnitine in Patients with Spinal Muscular Atrophy; also, with Dr. Christina Brahe, PhD, IstitutodiGeneticaMedica, Rome, Italy. :SMN Biomarker: Towards a validated international standard operating procedure”<br />2009-2010<br />***Dr. Jocelyn Cote, PhD, University of Ottawa. “Quantitative Proteomic Study of the Motor Neuron SMN Complex”<br />
  26. 26. Acknowledgements<br />I wish to thank the FSMA (US) and the FSMA (Canada) for much of the sourcing of the contained material, and most heartedly refer you to their respective websites:<br />www.fsma.org<br />www.curesma.ca<br />Canadian video:<br />www.youtube.com/watch?v=U0Rr1uJrV14<br />(this is an Ontario family)<br />
  27. 27. FSMC Contacts<br />FSMAC<br /> President:<br />Bettylou Ross, bettylou@curesma.ca<br /> Winnipeg, Manitoba (headquarters)<br />

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