Tuesday, September 14, 2010

FPWR Conference Notes

I know this will likely bore some, but for all who are interested, here are my personal notes from the FPWR Conference this past weekend. They are very incomplete, and I just wrote down whatever things struck me. Some are things we already know, some things are new ideas, but it's all there. Please ask questions about anything that doesn't make sense. I probably won't know the answer anyway. lol

Session 1: Hypotonia & PWS
Ron Cohn, M.D., Associate Professor of Pediatrics, Neurology and Genetic Medicine at Johns Hopkins Medical Center

Difference in tone vs. strength
-tone: information that muscles get about how they should relax or contract; example: if someone came up from behind you and grabbed your arm, the reactivity/speed with which it would contract is tone
-strength: holding up arm for 5 min. Does take tone, but holding it up takes strength

Good tone test: hold hands together and ask a patient to get up from the ground

600 different disorders can cause hypotonia

Degree of early hypotonia not seemingly correlated with later prognosis

Central vs. Peripheral Hypotonia
-profound weakness + hypotonia = lower motor neuron (peripheral)
            -babies have weak cry
            -no antigravity movements
            -visually quite alert
-less weakness and decreased alertness = central
            -axial/truncal weakness  - when you lift the baby up, he/she would slip
through your hands

Causes of central: chromosomal, structural brain abnormalities, inborn errors of metabolism, many syndromic disorders

Causes of peripheral: connective tissue & skeletal muscle disorders, [couldn’t catch the rest of this]

Is PWS central, peripheral, or both?
-decreased muscle mass in PWS study à may relate to this, although shouldn’t make a difference if the hypotonia in PWS was just central
-muscle/leg strength lower than in “normal” obese persons
-abnormal muscle biopsy in PWS à variation in muscle fiber size; type II muscle atrophy; immature muscle fibers
            -important for cell survival in skeletal muscle and neurons
            -knock-out mice (have no Necdin) had smaller muscle mass and muscles
don’t repair well (while mice with increased necdin repair muscle faster)
-necdin inactivation (from genes) probably plays a role in hypotonia/muscle
weakness for PWS à what can be therapeutically done?

Physical Therapy
-increases tone, increases strength
-combination of PT & OT most helpful
-multidisciplinary care to ensure that low tone/weakness doesn’t cause additional problems
            -GI issues
-should meet individual needs of the patient
-stretch legs to prevent/treat toe walking – happens when tendons in the ankles shorten because of weak calves
-aquatic therapy and hippotherapy also fantastic for building strength & balance

Recommends CoQ10, carnitine, and creatine
-creatine can be helpful even for those who are not deficient

Session 2: Orthopedic Issues in PWS
Harold J.P. van Bosse, M.D., Orthopedic Surgeon, Shriner’s Hospital Philadelphia

Scoliosis: curves over 10 degrees: 40% to 90% in PWS
-“severe” or “significant” cases: 15%
-incidence actually underreported

F:M ratio typically 1:3; in PWSA survey, 2:1
-females have slightly increased risk for progression to surgery
-compared to 8:1 F:M in idiopathic scoliosis (in general population)

Age at diagnosis: 5.8 +/- 4.3 years

If diagnosed before 4th birthday – severe progression unlikely (15%) vs. those diagnosed 4+ yrs. (41% with severe progression)
-early diagnosis associated with hypotonia

Etiology of scoliosis
-no difference in BMI, and 50% develop before obesity – so obesity not the cause
-probably a combination of obesity and hypotonia

People with PWS and scoliosis have less rotation of curves, so harder to detect and diagnose in an exam

In PWS, many of infantile cases (0-3 yo) resolve spontaneously

Effects of Scoliosis
-cardiopulmonary compromise
            -80-90 degrees and above
            -pulmonary insufficiency
-cor pulmonale
            -heart thickens as body struggles to pump blood to smooshed lungs
-early onset curves and death

-yearly screenings/x-rays starting when the child is sitting
                        -even if exam looks ok
-Casting à for patients under 3yo
            -for de-rotating chest, correct the curve           
            -done under anesthesia
            -change every few months
-Bracing à for curves 20 degrees and larger
            -prevent curve progression when upright
            -can’t make curve smaller, only stop it from getting larger
-Surgery for curves over 45 degrees
            -high complication rate à infections (related to skin picking), anesthesia
concerns, hardware failure/pseudoarthrosis
-spinal fusion for older kids
            -avoid the anterior approach – go through back instead
            -done for curves 50 degrees + at maturity
-Physical Therapy
            -truncal strengthening
            -sensory integration
            -don’t rush upright activities à otherwise poor posture
            -Any exercises good for increasing balance and propioception are helpful for

People with PWS also have lots of kyphotic (front to back) curves
-Cervico-thoracic kyphosis  - characteristic PWS posture
No studies show that scoliosis worsens with GH, neither in terms of developing or worsening a curve
-however, early GH may actually delay curve onset, and may protect against progression
-Dr. van Bosse thinks scoliosis progresses with amount of growth, regardless of speed of growth

Session 3: NIH Research Strategy Workshop Report and Follow-Up
Theresa Strong, Ph.D., Associate Professor of Medicine, University of Alabama at Birmingham; Chair, Scientific Advisory Board, FPWR

Best place to learn about this is the handout of the full report from the workshop

Recruiting patients is one of the biggest hurdles with rare syndromes

Drug companies not as interested in PWS because is a small market and risky patient population

NIH trying to push the research process along; good to have their support as a rare disease

Early diagnosis is good, but not sure how early diagnosis does/doesn’t affect later (adult) outcome

Some priorities for research:
-low tone
-sleep issues
-GI issues
-Central adrenal insufficiency
-how does “no appetite” progress to hyperphagia

Discovery of leptin was a big deal, but now know that hunger/appetite a much more complicated ordeal
-leptin – more overall signals for hunger
-ghrelin – hour-to-hour signals (‘is it time to eat yet?’)

Oxytocin – trials in autism, maybe in PWS?

Difference between behavioral issues and acute psychiatric problems – some have both

Snord116 critical region
-but don’t know what it is modifying
-affects other RNAs

When PWCR (Prader-Willi critical region) duplicated in “normal” individuals, risk for autism increases – why?

Important next steps:
**Pluripotent stem cells
-tissue repositories
-clinical databases
-clinical trials in obesity & psychiatry


Session 5: An Improved Mouse Model of PWS
Jim Resnick, Ph.D., Associate Professor of Genetics, University of Florida

Ok, I have to admit that this one was over my head a lot, so I didn’t get much!

Imprinting defect – paternal chromosome 15 is there, but it acts like the maternal one (silent)

Made a new mouse model where they can turn on/off PWS genes at different times in development
-potential advantages: bypass early failure-to-thrive, better expose late onset trials (I have no clue what that means – lol)

Session 6: Behavior, Development, and Family Stress
Elizabeth Roof, M.A., Senior Research Specialist, Vanderbilt University

Early behavior issues – hypotonia, FTT, delayed milestones, decreased appetite, sleepy, low energy, weak cry, passive

Trying to find out which genes affect which behaviors

-type I deletion – 500 genes missing
-type II deletion – 1000 genes missing
-imprinting defect

Some behaviors might be neurotransmitter-driven

Poor emotional regulation – outbursts & mood swings

Behaviors get stronger over time à tend to emerge around time of food-seeking

Aberrant serotonin, ghrelin, oxytocin in PWS à implications?

Many people with PWS say they know what can/can’t eat, BUT their behavior doesn’t reflect that
-seem to know what adults want them to say

Trying to do studies to find out how much people with PWS think about food

People with PWS not disgusted by odd food combinations or contaminated food
-limited understanding of “disgust,” particles and germs

Rigid, repetitive behaviors
-lots of questions about schedules
-collecting/hoarding items (often not food)
-certain way of doing tasks
-items in certain place
-may erase/rewrite things over and over
-sensory – touching, twirling, etc.
-finish something before moving on
-demand others to do things certain way
-scripted, repetitive speech

Other difficult behaviors:
-may hold grudges
-once behavior starts, very hard to stop

Some tendencies with subtypes (just generalizations, obviously there are exceptions!)
-deletion – increased skin picking, tantrums, puzzle ability
-UPD – increased verbal IQs, vulnerable to autistic & psychotic symptoms

Behavioral issues highest in 20s (particularly looking at skin-picking and externalizing behaviors)
-big drop-off into middle adulthood

“Compulsive” behaviors make them happy, but not like typical compulsions in people with OCD à more repetitive in nature too

Generally, behaviors ebb & flow a lot

Cortisol levels (stress hormone) high in parents with PWS (also ASD)
-Importance of taking care of yourself as a person first (airplane oxygen mask analogy)
-mindfulness-based stress reduction

Keep diary of behaviors and note in particular any deteriorations in behavior

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