Glycogen storage disease type II (Pompe Disease)

Glycogen storage disease type II (Pompe Disease)


Glycogen storage disease type II (also called Pompe disease or acid maltase deficiency) is an autosomal recessive metabolic disorder[1] which damages muscle and nerve cells throughout the body. It is caused by an accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme. It is the only glycogen storage disease with a defect in lysosomal metabolism, and the first glycogen storage disease to be identified, in 1932.
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.
Glycogen storage disease type II
Classification and external resources
ICD-10
E74.0

ICD-9
271.0

OMIM
232300

DiseasesDB
5296

eMedicine
med/908 ped/1866

MeSH
D006009


Variants
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).[citation needed]
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).[citation needed] 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.[citation needed]
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.[citation needed]
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.[citation needed]
Pompe's disease is one of the infiltrative causes of restrictive cardiomyopathy.[citation needed]


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.[citation needed] Genetic counseling can provide families with information regarding risk in future pregnancies.
On April 28, 2006 the US Food and Drug Administration approved a biologics license application (BLA) for Myozyme (alglucosidase alfa, rhGAA),[2] the first treatment for patients with Pompe disease. This was based on enzyme replacement therapy work pioneered by Drs Arnold Reuser and Ans van der Ploeg at Erasmus University, Rotterdam.[3] Myozyme falls under the FDA Orphan Drug designation and was approved under a priority review.
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) under development. In November 2001 Genzyme chief executive Henri Termeer organised a systematic comparison of the various potential drugs in transgenic mice. It was found that Myozyme was the most efficatious and easiest to manufacture. Work on the other products was then discontinued.
The FDA has approved Myozyme for administration by intravenous infusion of solution into a vein. 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 costs an average of $300,000 a year, and must be taken for the patients' entire life. The treatment is not without side effects which include fever, cardiac failure, pneumonia, respiratory failure and rarely shock. Some insurers have refused to pay for it.[4] The treatment is better at stabilizing the clinical condition than reversing the pathological changes that have already occurred. Early diagnosis leads to better outcomes.
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).[5] The vast majority of developed countries are providing access to therapy for all diagnosed Pompe patients.[6]
In June 2007 it was reported that ZyStor Therapeutics was in the process of developing an enzyme replacement therapy for Pompe disease by leveraging their glycosylation independent lysosomal targeting technology (GILT).[7]
Prognosis
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 combined form of the human enzyme acid alpha-glucosidase, and is also currently being used to replace the missing enzyme. In a study[8] 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.
On December 13, 2007, Genzyme released the initial results of its Late Onset Treatment Study (LOTS). The study was undertaken to evaluate the safety and efficacy of Myozyme 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 Myozyme 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 Myozyme on pulmonary function as measured by percent predicted forced vital capacity.
The results showed that, at 18 months, patients treated with Myozyme increased their distance walked in six minutes by an average of approximately 30 meters as compared with the placebo group (P=0.0283; Wilcoxon test). 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 Myozyme increased by 1 percent at 18 months. In contrast, it declined by approximately 3 percent in the placebo group (P=0.0026; Wilcoxon test). The average baseline percent predicted forced vital capacity in both groups was approximately 55 percent.
The results for both efficacy endpoints were consistent across various prospectively defined subgroups.


Epidemiology


Glycogen storage disease type II has an autosomal recessive pattern of inheritance.
The disorder is estimated to occur in about 1 in 40,000 births. Worldwide there are thought to be about 5,000 to 10,000 suffers of this disease.
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.[9][10] 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. Despite this work at Erasmus MC University Medical Center, Rotterdam began in the '70s. In the early 1990s two Dutch scientists, Arnold Reuser and Ans van der Ploeg a PhD student, had the idea that phosphorylated enzyme would be taken via by the mannose-6-phosphate receptors in lysosomes thus allowing the enzyme to be targeted. Using alpha-glucosidase containing phosphorylated mannose residues they were able to show that an increase in the enzyme's activity in the muscles.[11] The increases reported - 43% increase in skeletal muscle and 70% in the heart - were likely to be clinically significant.
They cloned the acid alpha-glucosidase gene and then made the first mouse model of Pompe's disease. A second model was developed by Yuan-Tsong Chen and colleagues at Duke University using the quail. (Dr. Chen is the director of the Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.) The results of the work at Dukes were impressive with one treated animal recovering to the point of being able to fly again.[12]
This was followed by production of alpha-glucosidase in Chinese hamster ovary (CHO) cells and in the milk of transgenic rabbits.[13] This work eventually culminated in the start of clinical trials with the first clinical trial including 4 babies taking place at Erasmus MC Sophia Children’s Hospital in 1999. This was organised by Pharming in the Netherlands. A second trial in 2001 organised by Dr Chen and Synpac, a Taiwan-based company, used enzyme grown in CHO cells[14] (陳垣崇) while he was at Duke University. Both trials were successful.
Genzyme which had an existing enzyme replacement therapy for Gaucher's disease became involved at this point. They developed a product of their own for Pompe's disease also grown in CHO cells. This is now marketed as Myozyme.
Much of the funding for research in this field was provided by the Association of Glycogen Storage Disorders. This association was founded by a Scotsman - Kevin O’Donnell - whose son Calum aged eight months died from Pompe's disease in 1993. A grant from the AGSD-UK in 1996 funded the work that showed that replacement treatment could work. A second fund-raising group was formed in 1999 - 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.

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v • d • e
Inborn error of carbohydrate metabolism: monosaccharide metabolism disorders (including glycogen storage diseases) (E73-74, 271)


Sucrose, transport
(extracellular) Disaccharide catabolism Lactose intolerance • Sucrose intolerance


Monosaccharide transport Glucose-galactose malabsorption • Inborn errors of renal tubular transport (Renal glycosuria) • Fructose malabsorption



Hexose → glucose
Monosaccharide catabolism fructose: Essential fructosuria • Fructose intolerance
galactose/galactosemia : GALK deficiency • GALT deficiency/GALE deficiency



Glucose ⇄ glycogen
Glycogenesis
GSD type 0, glycogen synthase • GSD type IV, Andersen's, branching


Glycogenolysis
extralysosomal: GSD type V, McArdle, muscle glycogen phosphorylase/GSD type VI, Hers', liver glycogen phosphorylase • GSD type III, Cori's, debranching
lysosomal/LSD: GSD type II, Pompe's, glucosidase



Glucose ⇄ CAC
Glycolysis
MODY 2 • GSD type VII, Tarui's, phosphofructokinase • Triosephosphate isomerase deficiency • Pyruvate kinase deficiency


Pyruvate catabolism PDHA • Fumarase deficiency


Gluconeogenesis
PCD • Fructose bisphosphatase deficiency • GSD type I, von Gierke, glucose 6-phosphatase



Pentose phosphate pathway
Glucose-6-phosphate dehydrogenase deficiency • Pentosuria


Other Hyperoxaluria (Primary hyperoxaluria)