Spinal Muscular Atrophy

Type 1Infantile

Werdnig-Hoffman disease©

Terry L. Hill, PhD

Aetiology.....An autosomal recessive genetic disease....SMN1 gene (survival motor neuron 1 protein) is

missing, or mutated on chromosome 5....Affects spinal cord nerve cells such that they

atrophy, shrink and eventually die, resulting in increasing muscle weakness

....detectable through amniocentesis; adjuvant EMG and nerve conduction velocity test (NCV) may be also used

Aetiology (cont’d)....95%+ of patients have a homozygous disruption in the SMN1 gene on chromosome 5q, caused by mutation, deletion, or rearrangement (discovered in 1995)....SMN2 gene generates only 10% of survival motor neuron (SMN) but appears manipulatable for therapeutic purposes [see www.curesma.org]....other types: chronic infantile (Type II), chronic juvenile (Type III or Kugelberg-Werlander Disease), and adult onset (Type IV)

Prevalence/Incidence....after cystic Fibrosis, SMA disease is the most common autosomal-recessive inherited disorder....SMA Type 1 affects ~ 1:10,000 live births....Carrier frequency is ~ 1:45 in the world....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

Prevalence/Incidence (cont’d)....highest in European, Eastern Mediterranean, Japanese and African-American groups worldwide...North America: genotype frequency...1:37 Caucasian; 1:46 Ashkenazi Jew; 1:56 Asian; 1:91 African-American*; 1:125 Hispanic*see hand-out journal abstract for proviso re: high frequency alleles....males are most frequently affected....Type II (onset is 6-18 months) is the largest group, accounting for one half of all SMA cases

Disease Characteristics....age of onset: 0-6 months, with most symptoms occurring by 3 months....median survival is 7 months....mortality rate of ~95% at 18 months....severe, progressive muscle weakness and flaccid muscle tone (hypotonia)

Disease Characteristics (cont’d)....bulbar dysfunction includes poor suck ability, reduced swallowing, and increasing respiratory failure....impaired fetal movements may be observable in 30% of cases....60% are “floppy” babies at birth....weakness is greater in proximal than distal muscles; may mimic myopathy

(Cont’d)....deep tendon reflexes are absent....skeletal and limb deformities may be observed at birth....fasciculations of the tongue are noticeable by 4-6 months....prone to pulmonary infections, scoliosis,joint contractures

(Cont’d)....poor head control....retarded leg control and weight bearing....can not sit up unsupported....weakness of intercostal (ribs) muscles predicts small chest and enlarged abdomen....patient “breathes through his/her stomach”....cough is weak; lung fluid build-up is common in later stages

(Cont’d)....risk of aspirating while eating....eventual weight loss may occur....child exhibits average or often above-average intelligence...crying is subdued....seldom able to roll over by oneself

Who should be tested?....anyone with a family history of SMA and their spouses to determine carrier status of unaffected individuals....pregnancies at risk due to a family history....individuals clinically suspected of being affected

Progression....continual weakness of all obvious physical abilities....increasing signs of distress (breathing, heart rate, congestion)....pleuresy > pneumonia; cyanosis of limbs/body....DNR orders may be issued....death due to rapid respiratory failure/heart attack

Parenting IssuesAnticipatory grief....shock, numbness, disbelief....anger, blame, guilt....lashing out/quiet resignation....sleeplessness, physical/psychological symptoms....social role disruption or imbalance(as provider, parent to other siblings, husband/wife, neighbour, etc.)

Parenting Issues (cont’d)Coping....alteration of life’s previous routines....dealing with physicians, hospitals, home-care, agencies, special meals, bedroom adjustments....concentrating at work; leave of absence or worse....real or perceived stigma from others (interactions, avoidance)

(Cont’d)....transference (displacing feelings, fears, conflicts from the past) onto one’s partner....blaming God....irrational thoughts, including suicide....changing transportation demands....finding community supports

(Cont’d)Post-loss grieving....experiencing all aspects of the grieving process, but made worse because it was your child (not the natural order of things)....funeral/burial issues....possible growing apart due to different rates or ‘stages’ of grieving, or possible closer bonding....divorce rates remain high among SMA parents

(Cont’d)....dealing with surviving sibling issues (school-work, friends, stigma, self-blame/self-doubt)....regaining former roles; ‘new’ roles in getting on with life....what to do with his/her bedroom? clothes? toys?...how to handle birthdays, anniversary dates, memories,Christmas/Hunnaka/Ramadan

....customized orthopaedic chair

....lots of toys, reaching games, water therapy

....soft but firm crib mattress, with side pillows to support side sleeping....access to physiotherapists, respirologist, occupational therapists, dietary or nutritional therapists, social services staff (CCAC, Home-Care, PSW, VON, etc.....pharmacology therapy is not available

Supports

(Cont’d)....gene-specific therapy is not yet available....genetic counselling....Nasogastric Tube (NG-Tube)....Gastrostomy Tube (G-Tube)....chest physiotherpay (CPT); postural drainage...Cough Assist Machine (positive to sudden negative airway pressure, to simulate a cough)

(Cont’d)....pulse oximeter (placed on finger to measure possible respiratory distress)....BiPAP (Bilevel Positive Airway Pressure); note...a CPAP (Continuous Positive Airway Pressure) should NEVER be used on SMA patients....Negative Pressure Ventilator, e.g., a Port-a-Lung

Care-giver Skills....patience, patience, patience....empathy, warmth, friendliness, positive outlook, leadership, knowledge, in control....encourage mobility range of motion, muscle flexibility, prevent contractures (with no pain or exhaustion)....know wheel-chair and seat designs, body jacket, all assistive devices....

Treatments/Research***pre-clinical drug development of a molecule of

the tetracycline family; Paratek Pharmaceuticals, Boston and FSMA 5-year contract; Fall, 2009

***clinical trials soon (US) re: quinazoline use; Vertex Pharmaceuticals, deCode Genetics, and FSMA; June, 2009

***stem cell trials for SMA Type 1 soon; California Stem Cell (CSC); also Johns Hopkins University

(Cont’d)***Valporic acid clinical trials with 42 SMA subjects published [see online Journal PLoS ONE; Project Cure SMA Group]2007-2008***Dr. Rashmi Kothary, Ottawa Health Research Institute, “Establishment and Characterization of Primary Motor Neuron Cultures from an SMN Hypomorphic Series of Mice”***Dr. Jocelyn Cote, University of Ottawa, “A Role for Arginine Methylation in the Regulation of SMA activites

(Cont’d)** *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***Dr. Jean-Yves Masson, PhD, Laval University. DNA damage signaling and repair in Spinal Muscular Atrophy

(Cont’d)2008-2009***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, Istituto di Genetica Medica, Rome, Italy. :SMN Biomarker: Towards a validated international standard operating procedure”2009-2010***Dr. Jocelyn Cote, PhD, University of Ottawa. “Quantitative Proteomic Study of the Motor Neuron SMN Complex”

AcknowledgementsI 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:

www.fsma.orgwww.curesma.ca

Canadian video:www.youtube.com/watch?v=U0Rr1uJrV14

(this is an Ontario family)

FSMC ContactsFSMAC

President:Bettylou Ross, bettylou@curesma.ca Winnipeg, Manitoba (headquarters)