AUTHOR INFORMATION

Section 1 of 11

Authored by Jennifer Ibrahim, MD, Fellow, Department of Pediatrics, Division of Genetics, Children's Hospital of New Jersey and Mount Sinai School of Medicine

Coauthored by Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine

Jennifer Ibrahim, MD, is a member of the following medical societies: American Society of Human Genetics

Edited by Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Jennifer Ibrahim, MD
Editor's Email:	Edward Kaye, MD

eMedicine Journal, May 2 2006, VOLUME 7, Number 5

INTRODUCTION

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Background: Glycogen-storage disease type II (GSDII), also referred to as Pompe disease, is an autosomal recessive disorder that results from the deficiency of acid alpha-glucosidase, a lysosomal hydrolase. Pompe first described the disease in 1932 when he was presented with a 7-month-old girl who died after developing idiopathic hypertrophic cardiomyopathy. Pompe observed the abnormal accumulation of glycogen in all tissues examined and described the cardinal pathologic features.

Three major forms of the disorder exist: infantile, juvenile, and adult-onset. The infantile form usually presents by age 6 months and is marked by a progressive and rapidly fatal course. In this form, involvement of cardiac, skeletal, and respiratory muscles exists. Respiratory and cardiac failure are the usual proximate causes of death. The adult form is a slowly progressive disease in which the heart is not affected. Patients with adult-onset GSDII typically present with proximal muscle weakness between the second and sixth decades of life. Similar to the infantile form, patients with the adult form ultimately succumb to respiratory failure. The juvenile (intermediate) form includes infants and children older than 6 months who present with weakness but generally have no cardiac disease, and the clinical features overlap those of the other forms. In general, the older the age of onset, the less the likelihood of cardiac involvement.

Pathophysiology: Acid alpha-glucosidase is a lysosomal hydrolase that is required for the degradation of a small percentage (1-3%) of cellular glycogen. Because the main pathway for glycogen degradation is not deficient in GSDII disease, energy production is not impaired, and hypoglycemia does not occur. However, the deficiency of this enzymatic activity 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 leads to cellular injury. In turn, this leads to enlargement and dysfunction of the entire organ involved (eg, cardiomyopathy).

In the infantile form, clinically significant storage occurs in the heart, resulting in progressive cardiomegaly with left ventricular (LV) thickening that eventually leads to outflow tract obstruction. Storage in skeletal muscle leads to hypotonia and weakness. The respiratory muscles are also affected, resulting in hypoventilation and progressive respiratory compromise. CNS involvement primarily is limited to the anterior horn cells of the spinal cord and brain stem nuclei, although intellectual performance remains normal. While skeletal and respiratory involvement is frequently present in the juvenile form, cardiac involvement is variable. Cardiac involvement is not observed in the adult form.

Frequency:

• In the US: Frequency is estimated at 1 per 40,000 people (total) for all 3 variants of GSDII. This calculation is from estimated gene frequencies in healthy individuals from various ethnic groups. The highest frequency has been observed in the African American population, in which the frequency of the infantile onset type may be as high as 1 per 14,000.

• Internationally: The frequency in Taiwan and southern China is estimated at 1 per 50,000 individuals. The frequency in the Dutch population is estimated at 1 per 40,000 individuals (1:138,000 for the infantile category). In this affected population, 63% carry at least 1 of the 3 common mutations.

Mortality/Morbidity:

• The infantile form usually is fatal during the first year of life. As the weakness progresses, patients develop feeding difficulties and respiratory insufficiency. Enlargement of the left ventricle leads to outflow tract obstruction and ventricular failure. Death results from cardiopulmonary failure.

• The juvenile (intermediate) form progresses more slowly and is uniformly fatal. Patients generally do not survive beyond the second or third decade of life. All patients have involvement of respiratory muscles, and most die of respiratory failure. Several patients are reported to have died of basilar artery aneurysm. All were found to have abnormal storage within the lysosomes of arterial smooth muscle fibers. Age of onset does not predict age of death.

• Patients with the adult form may survive for decades following diagnosis. Muscle weakness may interfere with normal daily activities, and respiratory insufficiency often is associated with sleep apnea. Death usually results from respiratory failure.

Race:

• Common mutations associated with the infantile-onset form have been found in the Taiwanese, Dutch and African-American populations. A common mutation associated with the adult onset form has been found in Caucasians.

Sex:

• This is an autosomal recessive disease; therefore, it affects males and females equally.

Age:

• As noted above, age of onset usually distinguishes the 3 types. Age of onset in the juvenile form may overlap both the adult and infantile forms.

CLINICAL

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History:

• Infantile form


• • These patients typically present with weakness and hypotonia in the first 6 months of life, which may manifest as respiratory and feeding difficulties.
  
  
  
  • Early cardiac failure due to LV enlargement and outflow obstruction may lead to respiratory and feeding difficulties as well.
  
  
  
  • In 1 infant described, the presenting sign was Wolff-Parkinson-White syndrome.
  
  
  
  • The birth and family history usually are noncontributory, although some families may be consanguineous. Rare familial cases are reported.
  
  
  
• Juvenile form


• • These children present with delayed motor milestones, weakness, and hypotonia.
  
  
  
  • Their intelligence is normal.
  
  
  
• Adult form


• • These patients present with symptoms related to proximal muscle weakness, such as difficulty climbing stairs.
  
  
  
  • Respiratory symptoms present in approximately one third of adult-onset cases.
  
  
  
  • Symptoms may include exercise intolerance, orthopnea, somnolence, and headache at night or upon waking.
  
  
  

Physical:

• Infantile form


• • Readily observed evidence of storage (eg, macroglossia, hepatomegaly, normal or increased muscle bulk)
  
  
  
  • Involvement of respiratory muscles manifest as respiratory distress (eg, tachypnea)
  
  
  
  • Cardiomegaly or cardiomyopathy leading to murmur and signs of cardiac failure
  
  
  
  • Profound diffuse hypotonia
  
  
  
• Juvenile form


• • Respiratory distress
  
  
  
  • Hypotonia (typically more proximal than distal)
  
  
  
  • Macroglossia and hepatomegaly typically absent
  
  
  
  • No associated cardiomegaly or cardiomyopathy
  
  
  
• Adult form


• • Proximal muscle weakness
  
  
  
  • Decreased bulk of involved muscles
  
  
  
  • Diminished deep tendon reflexes
  
  
  

Causes:

• GSDII is an autosomal recessive disease caused by the inheritance of 2 defective copies of the gene encoding acid alpha-glucosidase (GAA), which has been localized to band 17q23. Carriers (ie, individuals with 1 normal copy and 1 defective copy of the gene) have no clinical manifestations. Several types of deleterious mutations are identified, including missense, nonsense, deletion, and splice site mutations. These mutations can result in the following:


• • No detectable messenger ribonucleic acid (mRNA) and complete absence of enzymatic protein
  
  
  
  • A normal amount of enzyme with reduced activity (eg, reduced affinity for glycogen)
  
  
  
  • A reduced amount of enzyme with normal activity
  
  
  
  • No detectable enzyme activity in infantile form; varying amounts of residual enzyme activity in juvenile and adult forms
  
  
  

DIFFERENTIALS

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Noonan Syndrome

Other Problems to be Considered:

Organic acidurias
Mitochondrial disorders

WORKUP

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Lab Studies:

• Serum CK


• • General reflection of muscle disease
  
  
  
  • Greatest elevation among infants with GSDII
  
  
  
  • Up to 10 times normal level
  
  
  
• Serum aspartate aminotransferase


• • Highest among infants with GSDII
  
  
  
  • Reflects liver involvement
  
  
  
• Enzyme activity


• • Definitive diagnosis requires the measurement of acid alpha-glucosidase activity in cultured skin fibroblasts or peripheral blood lymphocytes. Testing in lymphocytes usually requires 10 cc of whole blood in heparinized tubes, from which a white cell pellet is generated. This may not be practical in an infant. A mixed leukocyte analysis may lead to errors since granulocytes also contain a renal isomer of acid maltase, which is active in an acidic pH.
  
  
  
  • A skin biopsy (3 mm diameter) is more likely to produce an adequate and reliable sample.
  
  
  
  • A muscle biopsy can help establish a diagnosis, but it is unnecessarily invasive
  
  
  
  • Clinical analysis of the acid alpha-glucosidase (GAA) gene is available. However, the assay may fail to reveal both mutations in an affected individual. Therefore, DNA testing cannot be used in place of enzyme assay to establish the diagnosis. DNA analysis can be helpful in the identification of carriers in a family with an affected individual.
  
  
  

Imaging Studies:

• Echocardiography


• • This establishes the degree of cardiac involvement. It may also allow one to distinguish between the infantile and juvenile forms of GSDII.
  
  
  
  • It may show overall enlargement of the heart, isolated LV thickening, biventricular thickening, or outflow obstruction in advanced disease.
  
  
  

Other Tests:

• ECG


• • This test also establishes the presence and degree of cardiac involvement.
  
  
  
  • The characteristic finding is shortening of the PR interval.
  
  
  
  • Enlargement of the QRS complex also may occur.
  
  
  
• Electromyography


• • The electromyography (EMG) of all patients affected by GSDII reveals a myopathic pattern.
  
  
  
  • Many affected patients exhibit pseudomyotonic discharges (ie, myotonic discharges in the absence of clinical myotonia), fibrillation potentials, and positive waves due to the anterior horn cell involvement.
  
  
  

Procedures:

• A skin biopsy reveals acid alpha-glucosidase activity in cultured fibroblasts.

TREATMENT

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Medical Care:

• Limited medical treatment of the underlying disorder is currently available.



• Symptomatic treatment of cardiac and respiratory failure is available but does not significantly alter the clinical course.



• Anecdotal evidence that a high-protein diet can provide temporary improvement exists; however, such a diet does not alter the disease course.



• Enzyme replacement therapy is in development. Phase 2 and 3 trials have been completed in affected infants. The FDA has recently designated alglucosidase alfa (Myozyme), a recombinant human alpha-glucosidase as an orphan drug.



• Preclinical investigation of gene therapy is ongoing.

Consultations:

• Genetics: A clinical geneticist is advised to counsel families regarding risk to future pregnancies.



• Neurology: Because all patients require an EMG, involve the neurology service.



• Pediatric cardiology: A cardiologist can provide assessment of all infants, children, and adolescents suspected of having GSDII disease. Experienced interpretation of echocardiography findings is necessary.

Diet:

• As noted above, alterations in diet do not provide lasting improvement. Weakness can contribute to feeding difficulty in all patients. Infants ultimately may require tube feeding to provide adequate caloric intake; however, nutritional support does not change the disease course, and some families may choose not to pursue tube feeding when facing such a fatal illness.

Activity:

• Weakness may interfere with the normal daily activities of adult patients. Physical and occupational therapy may prove beneficial.

MEDICATION

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Drug Category: Enzyme replacement -- Recombinant human enzyme alpha-glucosidase has recently been designated an orphan drug.

Drug Name	Alglucosidase alfa (Myozyme) -- Recombinant human enzyme alpha-glucosidase (rhGAA) indicated as an orphan drug for treatment of Pompe disease. Replaces rhGAA, which is deficient or lacking in persons with Pompe disease. Alpha-glucosidase is essential for normal muscle development and function. Binds to mannose-6-phosphate receptors and then is transported into Iysosomes; undergoes proteolytic cleavage that results in increased enzymatic activity and ability to cleave glycogen. Improves infant survival without requiring invasive ventilatory support compared with historical controls without treatment.
Adult Dose	Data limited; administer as in pediatrics
Pediatric Dose	20 mg/kg IV q2wk; initial infusion rate not to exceed 1 mg/kg/h; may increase infusion rate by 2 mg/kg/h q30min to a maximum of 7 mg/kg/h if tolerated
Contraindications	None known
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Serious adverse effects reported include heart and lung failure; infusion-related reactions are common (51%) and include life-threatening anaphylaxis, shock, or respiratory or cardiac events (eg, bronchospasm, dyspnea, arrhythmias, hypotension, hypertension); medical support measures must be readily available; discontinue or temporarily stop infusion if reaction occurs; common adverse effects include pneumonia, respiratory failure and distress, infection, and fever

FOLLOW-UP

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Further Outpatient Care:

• Counsel the parents regarding the 25% recurrence risk for each subsequent pregnancy, and provide options for prenatal diagnosis. Chorionic villus sampling and amniocentesis both can be used to determine enzyme activity in a fetus. Prenatal diagnoses with as early as 10-week gestation are reported. Emphasize the genetic basis to family members, and encourage communication within the family in order to identify additional carriers.

Complications:

• The major complication among infant patients is aspiration pneumonia.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to counsel parents in regard to the 25% recurrence risk with each subsequent pregnancy

Special Concerns:

• Successful pregnancy in a woman with the adult form of GSDII disease has been reported.

TEST QUESTIONS

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CME Question 1: What is the most reliable method for confirming the diagnosis of glycogen-storage disease type II (Pompe disease)?

A: Measurement of serum CK
B: Measurement of blood glucose
C: Echocardiography
D: Enzyme activity measurement
E: Electromyography (EMG)

The correct answer is D: Measurement of enzyme activity is the criterion standard for establishing the diagnosis of glycogen-storage disease type II (Pompe disease).

CME Question 2: The parents of a child with glycogen-storage disease type II (GSDII), or Pompe disease, ask about the risk of having another affected child in a future pregnancy. What is the percentage risk of GSDII in each pregnancy?

A: 0%
B: 10%
C: 25%
D: 50%
E: 75%

The correct answer is C: The risk to each pregnancy is 25%. The fact that a couple already has an affected child in no way influences the outcome of future pregnancies.

Pearl Question 1 (T/F): Both chorionic villus sampling and amniocentesis can be used for prenatal diagnosis of glycogen-storage disease type II (Pompe disease).

The correct answer is True: Chorionic villi and amniocytes can be cultured and assayed for acid maltase activity.

Pearl Question 2 (T/F): The mode of inheritance for glycogen-storage disease type II (Pompe disease) is autosomal dominant.

The correct answer is False: Glycogen-storage disease type II is inherited in an autosomal recessive fashion. Carrier couples have a 25% recurrence risk with each pregnancy.

Pearl Question 3 (T/F): Age of onset is the same for all 3 types of glycogen-storage disease type II.

The correct answer is False: Age of onset is the clinical feature that most readily distinguishes the 3 forms of glycogen-storage disease type II (eg, infantile, juvenile, adult-onset).

Pearl Question 4 (T/F): Weakness and hypotonia in the first 6 months of life are the most common presentation of the infantile form of glycogen-storage disease type II.

The correct answer is True: Weakness and hypotonia in the first 6 months of life are the most common presentation of the infantile form of glycogen-storage disease type II. These symptoms may manifest as respiratory and feeding difficulties.

BIBLIOGRAPHY

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• Ausems MG, Verbiest J, Hermans MP, et al: Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet 1999 Sep; 7(6): 713-6[Medline].
• Ausems MG, Lochman P, van Diggelen OP, et al: A diagnostic protocol for adult-onset glycogen storage disease type II. Neurology 1999 Mar 10; 52(4): 851-3[Medline].
• Bulkley BH, Hutchins GM: Pompe's disease presenting as hypertrophic myocardiopathy with Wolff- Parkinson-White syndrome. Am Heart J 1978 Aug; 96(2): 246-52[Medline].
• Engel AG, Hirschhorn R: Acid maltase deficiency. In: Engel AG, Franzine-Armstrong C, eds. Myology: Basic and Clinical. New York: McGraw-Hill; 1996: 1533-53.
• Engel AG, Gomez MR, Seybold ME, Lambert EH: The spectrum and diagnosis of acid maltase deficiency. Neurology 1973 Jan; 23(1): 95-106[Medline].
• Hirschhorn R: Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Scriver CR, Beaudet AL, Sly W, Valle E, eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill; 1995: 2443-64.
• Hirschhorn R, Reuser AJJ: Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Scriver CR, Beaudet AL,et, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. 2001; 3389-3420.
• Isaacs H, Savage N, Badenhorst M, Whistler T: Acid maltase deficiency: a case study and review of the pathophysiological changes and proposed therapeutic measures. J Neurol Neurosurg Psychiatry 1986 Sep; 49(9): 1011-8[Medline].

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