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Glycogen Storage Disease Type II (Pompe Disease).

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.
2007 Aug 31 [updated 2013 May 9].

Excerpt

CLINICAL CHARACTERISTICS:

Glycogen storage disease type II (GSD II), or Pompe disease, is classified by age of onset, organ involvement, severity, and rate of progression. Classic infantile-onset Pompe disease may be apparent in utero but more often presents in the first two months of life with hypotonia, generalized muscle weakness, cardiomegaly and hypertrophic cardiomyopathy, feeding difficulties, failure to thrive, respiratory distress, and hearing loss. Without treatment by enzyme replacement therapy (ERT), classic infantile-onset Pompe disease commonly results in death in the first year of life from progressive left ventricular outflow obstruction. The non-classic variant of infantile-onset Pompe disease usually presents within the first year of life with motor delays and/or slowly progressive muscle weakness, typically resulting in death from ventilatory failure in early childhood. Cardiomegaly can be seen, but heart disease is not a major source of morbidity. Late-onset (i.e., childhood, juvenile, and adult-onset) Pompe disease is characterized by proximal muscle weakness and respiratory insufficiency; clinically significant cardiac involvement is uncommon in the late-onset form.

DIAGNOSIS/TESTING:

Measurement of acid alpha-glucosidase (GAA) enzyme activity is diagnostic. GAA is the only gene in which mutation is known to cause GSD II.

MANAGEMENT:

Treatment of manifestations: Management guidelines from the American College of Medical Genetics: individualized care of cardiomyopathy as standard drugs may be contraindicated and risk for tachyarrhythmia and sudden death is high; physical therapy for muscle weakness to maintain range of motion and assist in ambulation; surgery for contractures as needed; nutrition/feeding support. Respiratory support may include inspiratory/expiratory training in affected adults, CPAP, BiPAP and/or tracheostomy. Prevention of primary manifestations: Begin enzyme replacement therapy (ERT) with Myozyme® or Lumizyme® (alglucosidase alfa) as soon as the diagnosis is established. Infants at high risk for development of antibodies to the therapeutic enzyme are likely to need an immunomodulatory protocol early in the treatment course. In the pivotal trial, a majority of infants in whom ERT was initiated before age six months and before the need for ventilatory assistance demonstrated improved survival, ventilator-independent survival, improved acquisition of motor skills, and reduced cardiac mass compared to untreated controls. In affected individuals with late-onset disease, ERT may stabilize ventilatory function and motor ability, measured by six-minute walk and upright pulmonary function testing. ERT can be accompanied by treatable infusion reactions as well as anaphylaxis. Prevention of secondary complications: Aggressive management of infections; keeping immunizations up to date; annual influenza vaccination of the affected individual and household members; respiratory syncytial virus (RSV) prophylaxis (palivizumab) in the first two years of life; use of anesthesia only when absolutely necessary. Surveillance: Routine monitoring of respiratory status, cardiovascular status, musculoskeletal function (including bone densitometry), nutrition and feeding, renal function, and hearing. Agents/circumstances to avoid: Digoxin, ionotropes, diuretics, and afterload-reducing agents, as they may worsen left ventricular outflow obstruction in some stages of the disease; hypotension and volume depletion; exposure to infectious agents. Evaluation of relatives at risk: Evaluate at-risk sibs by GAA enzyme activity or molecular genetic testing (if the pathogenic variants have been identified in an affected family member) to permit early diagnosis and treatment with ERT.

GENETIC COUNSELING:

GSD II (Pompe disease) is inherited in an autosomal recessive manner. In most instances, the parents of a proband are heterozygotes and thus carry a single copy of a GAA pathogenic variant. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Historically, children with classic infantile Pompe disease have not survived to reproduce, whereas many individuals with later-onset disease survive into their 50s and 60s. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

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