Pompe

Question 1

pompe as a genetic disease

Answer 1

autosomal recessive inheritance on chromosome 17 on locus17q25

Question 2

IOPD clinical manifestations

Answer 2

1. severe phenoype, diagnosis cogenitally or as infant
2. hypertrophic cardiomyopathy in LV due to buildup of glycogen can be detected using chest x-ray
3. hypotonia (little muscle contraction) resulting in floppy baby syndrome (baby reflexively raise head when prone, floppy baby is weakness in neck and spinal muscles)
4. respiratory insufficiency causes nasal flaring to increase airflow
5. dysphagia (trouble swallowing) and macroglossia

Question 3

LOPD clinical manifestations

Answer 3

1. delayed diagnosis at 7-10 y/o since early symptoms not obv
2. first symptoms are difficulting running with greater weakness in legs compared to arm,
3. by mid 20s mean onset age, by mid 40s wheelchair use and ventilatory support, 5-10% have cardiomyopathy, forced vital capacity decreases 1.5% per year

Question 4

diagnosing pompe

Answer 4

no single test, must use a battery of tests; enzyme test to measure GAA activity but has large variation, genetic testing id pompe disease causing mutations in GAA in self and parents, other non-specific test id signs and symptoms such as muscle, heart, and lung function test

Question 5

general clinical manifestations of Pompe

Answer 5

significant atrophy of quads and hip adductors, since type II fibres accumulate more glycogen vastus lat (more type II) exp greater atrophy than rec fem, scapular winging from degradation of scapular muscle, ptosis, lordosis due to paraspinal weakness, waddling gait since adductors can’t bring legs in line

Question 6

muscular degeneration in pompe

Answer 6

abdominal, paraspinal, and hip adductors have the greatest weakness, weakness in lower back and chest, glycogen builds up, lysosomes full of glycogen breakdown and leave large vacuoles in myofibres

Question 7

pathophysiology of pompe disease
1. lysosomes
2. Why LOPD goes undetected
3. AMPK activation

Answer 7

1. Glycogen accumulation leads to hypertrophy and increase muscle dmg and leaves less space for contractile proteins, bursting lysosome leaves big vacuoles of glycogen (glycogen lake); poor glycogen to glucose conversion impair lysosomal function, lysosomes cannot breakdown mitochondria, dysfunctional mitochondrial will continue to produce ROS causing dmg
2. healthy myofibrils gradually (long time over course of LOPD) replaced with glycogen impairing muscle function, LOPD onset often coincides with life changes (25-35 y/o decrease PA and muscle strength, increase sedentarism) thus goes undiagnosed since effects of weakness comparable to sedentary peers
3. Low glucose creates E deficit, constant activation of AMPK to produce G1P prevents protein synthesis, pompe muscle smaller

Question 8

autophagy

Answer 8

sys degrading intracellular comp into biochem building blocks
1. isolation membrane (phagophore) starts to form a vesicle around the intracellular components
2. vesicle elongates to form autophagosome
3. lysosome docks and fuses to autophagosome formins autolysosome, low pH and release enzymes breakdown components and degrade vesicle

Question 9

ERT for Pompe mechanism

Answer 9

recombinant human GAA myozyme replaces GAA, dose of 20-40 mg/kg biweekly, enters the body via IV and bind to mannose-6-phosphate receptors to form complex, myozyme/M6P complex internalized into cells and dissociates, myozyme breakdowns glycogen in glucose to restore autophagy and increases muscle and improve PRO homeostasis, greatly increase lifespan

Question 10

when should ERT be started?

Answer 10

must start as soon as possible to retain muscle and limit glycogen accumulation as much as possible

Question 11

issues with ERT in pompe
1. overview
2. muscle biopsy post ERT
3. problems with drug action in pompe
4. autoimmune response
5. in brain

Answer 11

1. majority of patients with pompe have mobility and FVC benefit from long-term ERT but many exp secondary decline after 3-5 yrs, treatment is very expensive and prescription only, is life-long
2. biopsies show sig interpersonal variability in myofibre glycogen, some patients show sig clearance of glycogen other almost no change
3. delivered via IV, therefore it enters through circulation, most cleared by liver and are dependent on capillaries to deliver to muscle; even though type II lots of glycogen accumulation, a low number of M6P receptors in muscle results in poor activation of rhGAA
4. cross-reactive immunological material associated with poor clinical outcomes since bioavailability of rhGAA reduced due to autoimmune response dev antiGAA antibodies
5. cannot bypass BBB glycogen, accumulate in the brain causing Alzheimer like cog deficit and does not address build-up of ROS

Question 12

exercise in pompe
1. endurance
2. resistance

Answer 12

1. improve CV health and obesity, activate autophagy, activate mitochondrial biogen, increase capillarization to increase ERT delivery to muscle
2. increase strength, bone mineral density, FFM (muscular hypertrophy), M6P receptor

Question 13

clinical outcomes of exercise and ERT in LOPD patients

Answer 13

combined AET, RT, and core training 3x/week for 12 weeks show sig improvements in VO2, FVC, and 6 min walk distance increased by 16m (2x change in ERT), strength improvements in shoulder abductors and hip flexors, sig improvements in balance indicative of improved core strength

Question 14

murine model of exercise and ERT on Pompe
1. muscle
2. glycogen clearance
3. autophagy
4. polytherapy (exercise and ERT)

Answer 14

1. exercise group showed prevention of hindlimb muscle atrophy compared to control, ERT, and combined therapy
2. exercise increase whole body glycogen clearance whereas ERT not much of an effect, control group had high glucose in urine due to explosion and leak of glycogen filled lysosome into the blood (not actually clearance)
3. increase in autophagic clearance in exercise and combined group
4. combined therapy reduced autophagic buildup, decrease glycogen, improve mitcondrial antioxidant capacity to reduce ROS, improved mitochondrial morphology by improving mitophagy

Question 15

exercise prescription for Pompe
1. Frequency and time
2. intensity
3. type

Answer 15

1. typical ACSM guidelines of 150 mins/week of mod intensity aerobic, duration that won’t excessively fatigue
2. low impact or submax since high intensity too much muscle dmg
3. combined training, respiratory muscle therapy no change in FEV1, FVC, but some muscular improvement but aerobic improve all; res core strengthening sig improve endurance and balance and strengthen and increase muscle mass of one of the main muscle groups affected

Question 16

exercise safety for pompe

Answer 16

be aware of muscle dmg (CK lvl) cardiopulmonary surveillance for hypertrophy, watch for balance and stability since waddling gait cause biomech issue; graded assistance since free weight offer high ROM but machine can limit ROM to what is needed, progress intensity and modify exercise, neurological retraining of gait for efficiency; be cautious of overhead exercises since scapular winging unstable, proximal lower body movement isolate for lower body to prevent hurting low back, core and balance is poor so need to build up

Question 17

adherence to exercise in pompe

Answer 17

adherence is relatively high, exercise have effect on subjective measures by decreasing fatigue and pain and increasing vitality, general health, and QoL

Question 18

SRT
1. mechanism
2. combined SRT and ERT in murine model
3. cons

Answer 18

1. substrate reduction therapy reduces the amount of glycogen formed by inhibiting PPP1R3A (activates GYS1 enzyme by dephosphorylating to convert glu to glycogen), phosphorylating GYS1 enzyme; 65% less muscle glycogen has no differences in exercise capacity, cardiac function, or serum glu or correlation with T2DM
2. in diaphragm and soleus SRT as effective as ERT but combined SRT and ERT sig reduction in glycogen to point that it is not sig different from WT
3. exogenous therapy like ERT

Question 19

gene therapy for Pompe
1. mechanism
2. benefits
3. cons

Answer 19

1. adeno-associated virus mediated therapy takes functional GAA gene and inserts it into virus to carry, then infuse virus body and liver can then produce the GAA functional protein
2. able to cross BBB therefore improve cognitive function and has reduced immune response since virus is able to bypass it
3. must time between ERT non-response and extreme progression of decline, significant inflammatory response so significant immunosuppression req, likely have AAV antibodies since it is similar to common cold

Question 20

Nutrition for Pompe
1. diet
2. nutrition exercise therapy

Answer 20

1. maintaining a constant state of ketogenesis from low carb diet causing increased lipid breakdown to produce ketones which are converted to acetyl-CoA to fuel ATP production without carbs, can supplement ketones for direct ketosis
2. nutrition means nothing if you don’t exercise since muscle deteriorates but combined lifestyle intervention see large improvement in muscle function