Pompe disease is an inherited metabolic disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase. The mode of inheritance is autosomal recessive and the disease has a predicted frequency of 1 in 40,000 newborns. The clinical spectrum is wide, including at one end neonates with generalized muscle weakness and hypertrophic cardiomyopathy who die within the first year of life, and at the other end adults with a slowly progressive limb girdle weakness with or without respiratory failure.
Authors
A.T. Van der Ploeg. MD, PhD
A.J.J. Reuser, MD, PhD
P.A. van Doorn, M.D, PhD
N.A.M.E. van der Beek, M.D.
Clinical features
In the past, different nomenclature has been used to describe clinical subtypes. Names found in literature are: infantile, infantile-onset, non-typical infantile, childhood, adolescent, juvenile, adult, late-onset, classic, non-classic, muscular variant. We now conclude Pompe disease presents a continuous spectrum of phenotypes with variation in age of onset, rate of disease progression and severity of symptoms 1 . For clinical practice it is useful to divide the spectrum in the classic infantile subtype of Pompe disease and the non-classic or late-onset subtype of Pompe disease (which then comprises all clinical phenotypes other than the classic infantile subtype). Classic infantile Pompe disease: The classic infantile form of Pompe disease presents shortly after birth, at a median age of 1. Read more
Natural course and prognosis
In the classic infantile form of Pompe disease, important motor milestones like turning over, sitting and standing are not achieved. The median age of death is 6-8 months; patients rarely survive beyond the first year. 2,3 In the non-classic or late-onset form of Pompe disease, the course of the disease can vary substantially between patients with respect to age of onset and rate of disease progression. Disease severity, as measured by the percentage of patients requiring a wheelchair or ventilator, is mainly determined by disease duration and not by age. 8 In the course of the disease approximately one third of patients finally requires artificial ventilation. Read more
Epidemiology
The enzyme deficiency in Pompe disease is caused by pathogenic mutations in the acid -glucosidase gene (GAA) located on chromosome 17 (region 17q25.2-q25.3). The mode of inheritance is autosomal recessive. The reported frequency varies depending on the ethnic group and geographic area studied. The estimated frequency in the Western world is 1: 40.000.9-11
Pathophysiology / etiology
Pompe disease is characterized by a total or partial deficiency of the enzyme acid -glucosidase. This enzyme is needed to break down glycogen that is stored within the lysosome, a cytoplasmic organelle involved in cellular recycling and tissue remodeling (figure 1). This results in accumulation of lysosomal glycogen in virtually all cells of the body, but the effects are most notable in muscle. The pathologic mechanisms by which glycogen accumulation eventually causes muscle malfunction are not fully understood. Muscle wasting in Pompe disease has been explained by increased tissue breakdown by autolytic enzymes released from ruptured lysosomes and by a combination of disuse atrophy and muscle oxidative stress, reflected in the appearance of lipofuscin.12,13 Another hypothesis is that glycogen-filled lysosomes and clusters of non-contractile material disturb the myofibrillar morphology and thus the transmission of force in the muscle cells.14
Differential diagnosis
Differential diagnosis of classic infantile Pompe disease
- Werdnig-Hoffman disease (Spinal Muscular Atrophy type I)
- Hypothyroidism
- Congenital muscular dystrophy
- Glycogen storage diseases:
- IIIa (Debrancher deficiency/Cori or Forbes disease)
- IV (Branching enzyme deficiency/Anderson disease) - Michondrial/respiratory chain disorders
- Danon disease
- Idiopathic hypertrophic cardiomyopathy
- Endocardial fibroelastosis
- Myocarditis
- Peroxisomal disorders
Differential Diagnosis of late-onset/non-classic Pompe Disease
- Limb girdle muscular dystrophy (LGMD)
- Becker muscular dystrophy (BMD)
- Scapuloperoneal syndromes
- Rigid spine syndrome
- Myasthenia gravis
- Spinal muscular atrophy
- Polymyositis/dermatomyositis
- Glycogen storage diseases:
- IIIa (Debrancher deficiency/Cori or Forbes disease)
- IV (Branching enzyme deficiency/Anderson disease)
- V (Muscle phosphorylase deficiency/McArdle disease)
- VII (Muscle phosphofructokinase deficiency/Tauri disease) - Danon disease
- Mitochondrial myopathies
Ancillary investigations
Diagnostic procedures in patients with suspected Pompe disease can include aspecific measurements like serum Creatine Kinase (CK) activity and evaluation of muscle tissue, or specific diagnostic procedures like measurement of alpha-glucosidase activity in various tissues (leukocytes, fibroblasts, muscle tissue) and DNA analysis. In patients with classic infantile Pompe disease, chest X-ray and echocardiography can be used to demonstrate the characteristic cardiomegaly. Echocardiography reveals an increased thickness of the left ventricular posterior wall and inter-ventricular septum, which may lead to outflow tract obstruction and subsequent cardiac failure. In general, attention should also be paid to pulmonary status by means of pulmonary function testing and blood gas analysis to diagnose (nocturnal) hypoventilation. Routine laboratory measurements: More than 90% of all patients with Pompe disease show an elevated CK value. Read more
Genetics
The enzyme deficiency in Pompe disease is caused by pathogenic mutations in the acid-glucosidase gene (GAA) located on chromosome 17 (region 17q25.2-q25.3). Basically, the nature of the mutations in the acid -glucosidase gene and the combination of mutant alleles determine the level of residual lysosomal acid -glucosidase activity and primarily the clinical phenotype of Pompe disease. Read more
Therapy
Pompe disease has long been an untreatable disorder, for which only supportive care was available. In March 2006, enzyme replacement therapy with Myozyme received marketing authorization in the European Union, followed in April 2006 by FDA approval in the United States. The rationale for this therapy is to treat the disease by intravenous administration of highly purified enzyme, finding its way to the lysosomes via endocytosis. The same type of treatment has been applied in other lysosomal storage disorders (e.g. Fabry disease, Gaucher disease, Mucopolysaccharidosis type I), whereby recombinant human enzymes are used and produced in genetically modified animal or human cells. Read more
