Pompe Flashcards
pompe disease
1. overview
2. treatment
3. spectrum
4. genetic component
5. epidemiology
- neurometabolic disease with severe metabolic myopathy esp in cardioresp tissues caused by mutations in gene coding for acid alpha-glucosidase which is lysosomal enzyme used to break down glycogen, causing build up of glycogen which creates vaculoes of glycogen in all tissues, esp heart, muscle, and liver
- limited option but have enzyme replacement therapy (ERT) which replaces GAA but has problems
- infantile-onset (severe) and late-onset pompe disease (anyone w/o infantile pres) have wide variability in the amount of cardiac and SM dysfunction
- autosomal recessive inheritance on chromosome 17 on locus17q25
- 1/40000 incidence with 75% LOPD and 25% IOPD, without ERT IOPD lifespan is 2 yrs and LOPD is 55 yrs
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
pompe progression
1. overview
2. continuum
- mutation of GAA gene leads to GAA enzyme deficiency, accumulate glycogen causes pathological changes in myofibres, clinical manifestations and events, progressive decline lead to organ failure and loss of ambulation and respiratory mechanics for early mortality
- IOPD fatal at 1-2 years, late onset range from 25-55 years, large variability in age for physical events
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. pathogenesis in muscle
3. AMPK activation
- deficiency of GAA prevents breakdown of glycogen into G1P for use, 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
ERT for IOPD
use alglucosidase alfa (rhGAA) to decrease LV cardiac abnormalities in infants only less improvement in more severe cases and must start as soon as possible to retain muscle and limit glycogen accumulation as much as possible
ERT for LOPD
algucosidase alfa small improvement in FVC and large increase in 6 minute walk test; improve walking and respiratory function
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
Pompe disease next interventions
1. early diagnosis
2. second gen GAA
- early screening to preserve newborn muscle, cross reactive immunologic material negative dev reaction to exogenous protein rhGAA but look ot treat in utero to bypass immunological sys since blood supply shared with mom
- ATB200 is rhGAA with better binding affinity to M6P and neoGAA has synthetic chem that cannto be broken down by immune cells providing some improvement but similar problems
exercise in pompe
1. endurance
2. resistance
3. exercise outcomes on bracing
- 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
- able to walk better and prevent contractures, more independent, less dependent on mobility aids
