pompe as a genetic disease
autosomal recessive inheritance on chromosome 17 on locus17q25
IOPD clinical manifestations
- severe phenoype, diagnosis cogenitally or as infant
- hypertrophic cardiomyopathy in LV due to buildup of glycogen can be detected using chest x-ray
- hypotonia (little muscle contraction) resulting in floppy baby syndrome (baby reflexively raise head when prone, floppy baby is weakness in neck and spinal muscles)
- respiratory insufficiency causes nasal flaring to increase airflow
- dysphagia (trouble swallowing) and macroglossia
LOPD clinical manifestations
- delayed diagnosis at 7-10 y/o since early symptoms not obv
- first symptoms are difficulting running with greater weakness in legs compared to arm,
- 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
diagnosing pompe
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
general clinical manifestations of Pompe
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
muscular degeneration in pompe
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
pathophysiology of pompe disease
1. lysosomes
2. Why LOPD goes undetected
3. AMPK activation
- 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
- 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
- Low glucose creates E deficit, constant activation of AMPK to produce G1P prevents protein synthesis, pompe muscle smaller
autophagy
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
ERT for Pompe mechanism
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
when should ERT be started?
must start as soon as possible to retain muscle and limit glycogen accumulation as much as possible
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
- 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
- biopsies show sig interpersonal variability in myofibre glycogen, some patients show sig clearance of glycogen other almost no change
- 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
- cross-reactive immunological material associated with poor clinical outcomes since bioavailability of rhGAA reduced due to autoimmune response dev antiGAA antibodies
- cannot bypass BBB glycogen, accumulate in the brain causing Alzheimer like cog deficit and does not address build-up of ROS
exercise in pompe
1. endurance
2. resistance
- improve CV health and obesity, activate autophagy, activate mitochondrial biogen, increase capillarization to increase ERT delivery to muscle
- increase strength, bone mineral density, FFM (muscular hypertrophy), M6P receptor
clinical outcomes of exercise and ERT in LOPD patients
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
murine model of exercise and ERT on Pompe
1. muscle
2. glycogen clearance
3. autophagy
4. polytherapy (exercise and ERT)
- exercise group showed prevention of hindlimb muscle atrophy compared to control, ERT, and combined therapy
- 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)
- increase in autophagic clearance in exercise and combined group
- combined therapy reduced autophagic buildup, decrease glycogen, improve mitcondrial antioxidant capacity to reduce ROS, improved mitochondrial morphology by improving mitophagy
exercise prescription for Pompe
1. Frequency and time
2. intensity
3. type
- typical ACSM guidelines of 150 mins/week of mod intensity aerobic, duration that won’t excessively fatigue
- low impact or submax since high intensity too much muscle dmg
- 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
exercise safety for pompe
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
adherence to exercise in pompe
adherence is relatively high, exercise have effect on subjective measures by decreasing fatigue and pain and increasing vitality, general health, and QoL
SRT
1. mechanism
2. combined SRT and ERT in murine model
3. cons
- 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
- 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
- exogenous therapy like ERT
gene therapy for Pompe
1. mechanism
2. benefits
3. cons
- 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
- able to cross BBB therefore improve cognitive function and has reduced immune response since virus is able to bypass it
- 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
Nutrition for Pompe
1. diet
2. nutrition exercise therapy
- 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
- nutrition means nothing if you don’t exercise since muscle deteriorates but combined lifestyle intervention see large improvement in muscle function
