The build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and nervous system.
Pompe disease has historically been divided into three forms defined by age of onset and progression of symptoms (see below). More recently there has been a trend to divide the disease into two groups: infantile onset (involving the massive enlargement of the heart) and late onset (no heart enlargement).Classification
Infantile, or early onset, is noticed shortly after birth. Symptoms include severe lack of muscle tone, weakness, an enlarged liver (hepatomegaly), and an enlarged heart (cardiomegaly). Mental function is not affected. Development appears normal for the first weeks or months but slowly declines as the disease progresses. Swallowing may become difficult and the tongue may protrude and become enlarged. Most children die from respiratory or cardiac complications before 2 years of age.
Juvenile onset symptoms appear in early to late childhood and include progressive weakness of respiratory muscles in the trunk, diaphragm and lower limbs, as well as exercise intolerance. Intelligence is normal.
Adult onset symptoms also involve generalized muscle weakness and wasting of respiratory muscles in the trunk, lower limbs, and diaphragm. Many patients report respiratory distress, headache at night or upon waking, diminished deep tendon reflexes, and proximal muscle weakness, such as difficulty in climbing stairs. Intellect is not affected. A small number of adult patients live without major symptoms or limitations.
Pompe's disease is one of the infiltrative causes of restrictive cardiomyopathy.
Signs and symptoms
The infantile form usually comes to medical attention within the first few months of life. The usual presenting features are cardiomegaly (92%), hypotonia (88%), cardiomyopathy (88%), respiratory distress (78%), muscle weakness (63%), feeding difficulties (57%) and failure to thrive (53%).
The main clinical findings include floppy baby appearance, delayed motor milestones and feeding difficulties. Moderate hepatomegaly may be present. Facial features include macroglossia, open mouth, wide open eyes, nasal flaring (due to respiratory distress), and poor facial muscle tone. Cardiopulmonary involvement is manifest by increased respiratory rate, use of accessory muscles for respiration, recurrent chest infections, decreased air entry in the left lower zone (due to cardiomegaly), arrhythmias and evidence of heart failure.
Median age at death in untreated cases is 8.7 months and is usually due to cardiorespiratory failure.
The usual initial investigations of this form of the disease include chest X ray, electrocardiogram and echocardiography. Typical findings are those of an enlarged heart with non specific conduction defects. Biochemical investigations include serum creatine kinase (typically increased 10 fold) with lesser elevations of the serum aldolase, aspartate transaminase, alanine transaminase and lactic dehydrogenase. Diagnosis is made by estimating the acid alpha glucoside activity in either skin biopsy (fibroblasts), muscle biopsy (muscle cells) or in white blood cells. The choice of sample depends on the facilities available at the diagnostic laboratory.
[edit]Late onset form
This form differs from the infantile principally in the relative lack of cardiac involvement. The onset is more insidious and has a slower progression. Cardiac involvement may occur but is milder than in the infantile form. Skeletal involvement is more prominent with a predilection for the lower limbs.
Late onset features include impaired cough, recurrent chest infections, hypotonia, progressive muscle weakness, delayed motor milestones, difficulty swallowing or chewing and reduced vital capacity.
Prognosis depends on the age of onset on symptoms with a better prognosis being associated with later onset disease.
The findings on investigation are similar to those of the infantile form with the caveat that the creatinine kinases may be normal in some cases. The diagnosis is by estimation of the enzyme activity in a suitable sample.
Cause
The disease is caused by a mutation in a gene (acid alpha-glucosidase: also known as acid maltase) on long arm of chromosome 17 at 17q25.2-q25.3 (base pair 75,689,876 to 75,708,272). The number of mutations described is currently (in 2010) 289 with 67 being non-pathogenic mutations and 197 pathogenic mutations. The remainder are still being evaluated for their association with disease.
The gene spans approximately 20 kb and contains 20 exons with first exon being noncoding. The coding sequence of the putative catalytic site domain is interrupted in the middle by an intron of 101 bp. The promoter has features characteristic of a 'housekeeping' gene. The GC content is high (80%) and distinct TATA and CCAAT motifs are lacking.
Most cases appear to be due to three mutations. A transversion (T → G) mutation is the most common among adults with this disorder. This mutation interrupts a site of RNA splicing.
The gene encodes a protein - acid alpha-glucosidase (EC 3.2.1.20) - which is a lysosomal hydrolase. The protein is an enzyme that normally degrades the alpha -1,4 and alpha -1,6 linkages in glycogen, maltose and isomaltose and is required for the degradation of 1-3% of cellularglycogen. The deficiency of this enzyme results in the accumulation of structurally normal glycogen in lysosomes and cytoplasm in affected individuals. Excessive glycogen storage within lysosomes may interrupt normal functioning of other organelles and lead to cellular injury.
A putative homologue - acid alpha-glucosidase-related gene 1 - has been identified in the nematode Caenorhabditis elegans.
[edit]Treatment
Cardiac and respiratory complications are treated symptomatically. Physical and occupational therapy may be beneficial for some patients. Alterations in diet may provide temporary improvement but will not alter the course of the disease. Genetic counseling can provide families with information regarding risk in future pregnancies.
On April 28, 2006 the US Food and Drug Administration approved a Biologic License Application (BLA) for Myozyme (alglucosidase alfa, rhGAA), the first treatment for patients with Pompe disease. This was based on enzyme replacement therapy using biologically active recombinant human alglucosidase alfa produced in Chinese Hamster Ovary cells. Myozyme falls under the FDA Orphan Drug designation and was approved under a priority review.
The FDA has approved Myozyme for administration by intravenous infusion of the solution. The safety and efficacy of Myozyme were assessed in two separate clinical trials in 39 infantile-onset patients with Pompe disease ranging in age from 1 month to 3.5 years at the time of the first infusion. Myozyme treatment clearly prolongs ventilator-free survival and overall survival. Early diagnosis and early treatment leads to much better outcomes. The treatment is not without side effects which include fever, flushing, skin rash, increased heart rate and even shock; these conditions, however, are usually manageable.
Myozyme costs an average of $300,000 a year, and must be taken for the patients' entire life. Some American insurers have refused to pay for it. On August 14, 2006, Health Canada approved Myozyme for the treatment of Pompe disease. On June 14, 2007 the Canadian Common Drug Review issued their recommendations regarding public funding for Myozyme therapy. Their recommendation was to provide funding to treat a very small subset of Pompe patients (Infants less one year of age with cardiomyopathy). The vast majority of developed countries are providing access to therapy for all diagnosed Pompe patients. On May 26, 2010 FDA approved Lumizyme, a similar version of Myozyme, for the treament of late-onset Pompe disease.
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The prognosis for individuals with Pompe disease varies according to the onset and severity of symptoms. Without treatment the disease is particularly lethal in infants and young children.
Myozyme (alglucosidase alfa), which helps break down glucose, is a recombinant form of the human enzyme acid alpha-glucosidase, and is also currently being used to replace the missing enzyme. In a study which included the largest cohort of patients with Pompe disease treated with enzyme replacement therapy (ERT) to date findings showed that Myozyme treatment clearly prolongs ventilator-free survival and overall survival in patients with infantile-onset Pompe disease as compared to an untreated historical control population. Furthermore, the study demonstrated that initiation of ERT prior to 6 months of age, which could be facilitated by newborn screening, shows great promise to reduce the mortality and disability associated with this devastating disorder. Taiwan and several states in the United States have started the newborn screening and results of such regimen in early diagnosis and early initiation of the therapy have dramatically improved the outcome of the disease; many of these babies have reached the normal motor developmental milestones.
Another factor affecting the treatment response is generation of antibodies against the infused enzyme, which is particularly severe in Pompe infants who have complete deficiency of the acid alpha-glucosidase . Immune tolerance therapy to eliminate these antibodies has improved the treatment outcome.
A Late Onset Treatment Study (LOTS) was published in 2010 . The study was undertaken to evaluate the safety and efficacy of aglucosidase alfa in juvenile and adult patients with Pompe disease. LOTS was a randomized, double-blind, placebo-controlled study that enrolled 90 patients at eight primary sites in the United States and Europe. Participants received either aglucosidase alfa or a placebo every other week for 18 months. The average age of study participants was 44 years. The primary efficacy endpoints of the study sought to determine the effect of Myozyme on functional endurance as measured by the six-minute walk test and to determine the effect of aglucosidase alfa on pulmonary function as measured by percent predicted forced vital capacity.
The results showed that, at 78 weeks, patients treated with aglucosidase alfa increased their distance walked in six minutes by an average of approximately 25 meters as compared with the placebo group which declined by 3 meters (P=0.03). The placebo group did not show any improvement from baseline. The average baseline distance walked in six minutes in both groups was approximately 325 meters. Percent predicted forced vital capacity in the group of patients treated with aglucosidase alfa increased by 1.2 percent at 78 weeks. In contrast, it declined by approximately 2.2 percent in the placebo group (P=0.006).
Epidemiology
Glycogen storage disease type II has an autosomal recessive pattern of inheritance. The incidence of the disease is approximately 1 in 140,000 for infantile GSD II and 1 in 60,000 for adult GSD II. It has been reported in almost all ethnic populations. It has an autosomal recessive inheritance pattern. This means the defective gene is located on an autosome, and two copies of the gene—one from each parent—are required to be born with the disorder. As with all cases of autosomal recessive inheritance, children have a 1 in 4 chance of inheriting the disorder when both parents carry the defective gene, and although both parents carry one copy of the defective gene, they are usually not affected by the disorder.
History
The disease is named after Johann Pompe, who characterized it in 1932. Pompe described accumulation of glycogen in muscle tissue in some cases of a previously unknown disorder. This accumulation was difficult to explain as the enzymes involved in the usual metabolism of glucose and glycogen were all present and functioning.
The basis for the disease remained a puzzle until Christian de Duve's discovery of lysosomes in 1955 for which he won the Nobel Prize in 1974. His co-worker Henri G. Hers realised in 1965 that the deficiency of a lysosomal enzyme (alpha glucosidase) for the breakdown of glycogen could explain the symptoms of Pompe disease. This discovery lead to establishing the concept of lysosomal storage diseases of which 49 have been described (to date).
Despite recognizing the basis for the disease treatment proved difficult. Administration of the enzyme lead to its uptake by the liver and not the muscle cells where it is needed. In the early 1990s two Dutch scientists, Arnold Reuser and Ans van der Ploeg a PhD student using alpha-glucosidase containing phosphorylated mannose residues purified from bovine testes, they were able to show that an increase in the enzyme's activity in the normal mouse muscles. Later in 1998, Dr. Yuan-Tsong Chen and colleagues at Duke University ,Dr. Chen is currently the director of the Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.), using the enzyme produced in Chinese Hamster Ovary cells demonstrated for the first time that the enzyme can clear the glycogen and improved the muscle function in Pompe disease quail. The results of the work at Dukes were impressive with one treated bird recovering to the point of being able to fly again.
This was followed by production of clinical grade alpha-glucosidase in Chinese hamster ovary (CHO) cells and in the milk of transgenic rabbits. This work eventually culminated in the start of clinical trials with the first clinical trial including 4 babies receiving enzyme from rabbit milk at Erasmus MC Sophia Children’s Hospital and 3 babies receiving enzyme grown in CHO cells at Duke University in 1999. The currently approved Myozyme is manufactured by Genzyme Corp. in Cambridge, Massachusetts, USA. Its development was a complex process. Genzyme first partnered with Pharming Group NV who had managed to produce acid alpha-glucosidase from the milk of transgentic rabbits. They also partnered with a second group based at Duke University using Chinese hamster ovary cells. In 2001 it acquired Novazyme which was also working on this enzyme. Genzyme also had its own product (Myozyme) grown in CHO cells under development. In November 2001 Genzyme chief executive Henri Termeer organised a systematic comparison of the various potential drugs in a mouse model of Pompe disease. . It was found that Duke enzyme was the most efficacious, followed by Myozyme. However, due to easier manufacture of Myozyme, work on the other products was then discontinued.
Funding for research in this field was in part provided by Muscular Dystrophy Association and Acid Maltase Deficiency Association in USA and the Association of Glycogen Storage Disorders in UK and the International Pompe Association.
John Crowley became involved in the fund-raising efforts in 1998 after two of his children were diagnosed with Pompe's. He joined the company Novazyme in 1999 which was working on enzyme replacement treatment for Pompe's. Novazyme was sold to Genzyme in 2001 for over US$100 million. The movie Extraordinary Measures is based on his search for a cure.
