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eMedicine Journal
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Physical Medicine and Rehabilitation
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Myopathy
Acid Maltase Deficiency Myopathy Synonyms, Key Words, and Related Terms: Pompe disease, acid maltase deficiency, Pompe’s disease, cardiomegalia glycogenica diffusa, type II glycogenosis, severe muscle weakness, cardiomegaly |
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Author Information | Introduction | Clinical | Differentials | Workup | Treatment | Medication | Follow-up | Test Questions | Pictures | Bibliography
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 | AUTHOR INFORMATION | Section 1 of 11    |
Authored by Michael Weinik, DO, Associate Chairman, Associate Professor, Physical Medicine and Rehabilitation, Temple University Hospital
Coauthored by Frank J King, MD, Consulting Staff, Community Orthopedic Medical Group; Daniel A Lee, MD, Intern, Department of Family Medicine, Contra Costa Regional Medical Center
Michael Weinik, DO, is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation
Edited by Elizabeth A Moberg-Wolff, MD, Associate Professor, Medical College of Wisconsin; Consulting Staff, Department of Physical Medicine and Rehabilitation, Children's Hospital of Wisconsin; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Kat Kolaski, MD, Assistant Professor, Departments of Orthopedics and Pediatrics, Wake Forest University School of Medicine; Kelly L Allen, MD, Consulting Staff, Department of Physical Medicine and Rehabilitation, Lourdes Regional Rehabilitation Center, Our Lady of Lourdes Medical Center; and Denise I Campagnolo, MD, MS, Director of Multiple Sclerosis Clinical Research, Investigator, Staff Physiatrist, Barrow Neurology Clinics, St Joseph's Hospital and Medical Center
| Author's Email: | Michael Weinik, DO |  |
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| Editor's Email: | Elizabeth A Moberg-Wolff, MD |
eMedicine Journal, June 2 2006, VOLUME 7,
Number 6
| INTRODUCTION | Section 2 of 11  |
Background: Acid maltase deficiency (AMD) is an autosomal recessive disease characterized by an excessive accumulation of glycogen within lysosome-derived vacuoles in nearly all types of cells. Excessive quantities of free extralysosomal glycogen also have been described. AMD first was described by J.C. Pompe in Amsterdam in 1932; Pompe reported the case of a 7-month-old girl who became fatally ill from what appeared to be pneumonia. An autopsy revealed an unusually enlarged heart with normal valves. Pompe called this condition cardiomegalia glycogenica diffusa and considered it a disease analogous to von Gierke syndrome. The first article by Pompe was followed by similar reports by 2 independent authors who described children with severe muscle weakness and cardiomegaly who died in early infancy. Their disease was attributed to an excessive deposition of glycogen in various tissues. This entity was named Pompe disease, and, in 1957, G.T. Cori classified it as type II glycogenosis.
The following clinical phenotypes of AMD have been identified:
Infantile acid maltase deficiency (Pompe disease) is the classic example of a metabolic myopathy and motor neuron disease that causes infantile hypotonia. This form of the disorder is the most severe and carries the worst prognosis with death ensuing between 6 months and 2 years of life. The other forms are somewhat milder and vary in clinical presentation.
Pathophysiology: Acid alpha-1,4 glucosidase (acid maltase), like other lysosomal enzymes, is synthesized as a precursor form (molecular weight 105,000) in the endoplasmic reticulum. The precursor molecule then is modified by the addition of a mannose-6-phosphate recognition signal that allows its transport to the lysosomes. Then, the acid maltase is partially degraded into a mature form with a molecular weight of 76,001. The gene for acid alpha-glucosidase is on chromosome band 17q23.
Acid maltase cleaves glycogen 1,4 and 1,6 alpha-glycosidic linkages. Its action gives rise to free glucose molecules (see History).
Nearly 35 distinct mutations have been identified in the q23-28 locus of chromosome 17, which encodes acid maltase. Establishing the genotype-phenotype correlation is difficult; however, the severity of mutation usually correlates with the severity of the disease. Deletions or missense mutations (mutations in which the base replacement changes the codon for one amino acid to another) usually are associated with the infantile variant (Pompe disease), whereas "leaky" (partial) mutations are associated with the childhood and adult forms of AMD.
The absence of acid maltase leads to an excessive accumulation of glycogen in lysosome-derived vacuoles. The presence of abnormal quantities of glycogen disrupts the normal architecture and function of the affected cells. The excess glycogen is expected to be, at least initially, in the vacuolar system. This has been found to be true in the liver and in other tissues; however, in muscle, most of the polysaccharide appears to be extravacuolar, possibly reflecting the fact that the glycogen is packed so densely in skeletal muscle that the surrounding membrane is difficult to see. Another possibility is that the intense pressure exerted on the vacuoles during muscular contracture causes them to rupture, allowing the contents to spill over into the cytosol.
Abnormal storage of glycogen occurs in many organs including the central nervous system (CNS), heart, liver, and skeletal muscles, thus leading to hypotonia, weak bulky muscles, macroglossia, cardiomegaly, and congestive heart failure. The intramuscular storage of glycogen is more severe in Pompe disease than in any other glycogenosis.
Frequency:
Mortality/Morbidity: Pompe disease is inherited as an autosomal recessive disease. In the infantile form, death usually occurs between 6 months and 2 years of age; however, a less severe infantile form has been identified with a better prognosis and improved survival. Patients with the late infantile form may survive for several years. Patients with the juvenile and adult forms of AMD have been known to survive into the sixth or seventh decade of life. The clinical presentation may vary considerably, and some cases may go undetected; hence, the life expectancy for these groups is not exactly known.
Race: No ethnic predilection exists in connection with AMD.
Sex: AMD occurs with equal frequency among males and females.
Age: The correlation of AMD with age depends on the form of the disease.
| CLINICAL | Section 3 of 11 |
History: Several forms of AMD have been observed. Clinical variation within siblings is uncommon; however, the occurrence of infantile or juvenile forms and adult forms in the same family has been reported, probably due to various compound heterozygous states.
Glycogenoses include the following:
Other glycogenoses include the following:
Infantile form of AMD
Pompe disease is characterized by hypotonia, weakness, areflexia, macroglossia, massive cardiomegaly, and moderate hepatomegaly. Development usually is normal for the first weeks or months of life, but as the disease progresses, spontaneous movements slowly decline and the infant's cry becomes weak and struggling. Swallowing becomes difficult. Skeletal muscle weakness and inability to handle pooled secretions lead to respiratory difficulty. Pulmonary atelectasis may be seen. Cardiomegaly then results, and a soft murmur sometimes is heard over the left sternal border. Ultimately, hepatomegaly appears, and the tongue may become enlarged and may protrude awkwardly. Skeletal muscles are small and firm, and the stretch reflexes are depressed. A sharp contrast can be seen between the gross motor dysfunction and the normal mental development.
Although the liver becomes progressively enlarged, neither hypoglycemia nor ketosis is noted, and the mobilization of glycogen by glucagon or epinephrine is normal. Death typically occurs as a result of heart failure within the first 2 years of life. When cardiac involvement is less severe, survival can extend beyond 2 years, depending on the degree of muscular and neurologic function.
Late infantile form of AMD
Difficulty walking usually is the first symptom to appear in the late infantile form of AMD. The signs and symptoms may simulate those of Duchenne muscular dystrophy but usually manifest during the first few months of life. In such patients, the gastrocnemius and deltoid muscles are firm and rubbery. Hypertrophy of the calf muscles is noted, and the Gower sign often is present. Toe walking develops with ankle contractures. Ambulation is unsteady and wobbly because of lumbar lordosis. The disease can progress for several years until death results from cardiorespiratory decompensation.
Juvenile and adult forms of AMD
Motor delay and progressive myopathy are the main features of the juvenile and adult forms of AMD. The disease is limited to skeletal muscle and leads to progressive weakness and respiratory insufficiency. Mental retardation may be present. Calf enlargement may be observed, and the Gower sign may be present. Muscle creatine kinase (CK) may range from 200-2000 IU/L, but CK usually is within the reference range in the adult form. Distinct electromyogram (EMG) findings usually can be found. Because enzymatic function is not entirely affected in the juvenile and adult forms, cardiac function in these groups usually is normal.
Patients with the adult form may have no complaints until the second or third decade of life. Progressive weakness occurs into the sixth decade of life. The legs are affected more than the arms, with proximal muscles involved earlier than distal ones, and the pelvic girdle is more involved than the shoulder. Hepatomegaly and cardiomegaly usually are not seen; however, these conditions are sometimes seen in the terminal phase. This form of the disease may be confused with limb-girdle dystrophy or chronic polymyositis. The heart, liver, and CNS generally are uninvolved in the juvenile and adult forms of AMD.
Manifestations of AMD Causes: AMD is an autosomal inherited condition characterized by a buildup of glycogen in the cells.
| DIFFERENTIALS | Section 4 of 11 |
Limb-Girdle Muscular Dystrophy
Other Problems to be Considered:
Other diseases must be ruled out before the diagnosis of AMD is definite. These other entities include spinal muscular atrophy and Duchenne muscle dystrophy, as well as most causes of floppy infant syndrome. Limb-girdle dystrophy and chronic inflammatory myopathy should be ruled out in the adult.
Differential diagnosis
| WORKUP | Section 5 of 11 |
Lab Studies:
Imaging Studies:
Other Tests:
Procedures:
| TREATMENT | Section 6 of 11 |
Rehabilitation Program:
In the juvenile and adult forms of AMD, it would seem intuitive to focus physiatric treatment on the systems involved.
The use of assistive devices and orthoses may prove beneficial in patients with AMD who develop ambulatory difficulties. The use of intermittent positive pressure ventilation in Pompe disease would seem appropriate; however, because the disease is limited not only to the respiratory muscles but also involves the heart, the final outcome is likely to be the same.
| MEDICATION | Section 7 of 11 |
Treatment for this fatal disorder is limited. A copious amount of research currently is exploring the possibility of replacing the deficient enzyme by means of gene therapy. Up to this point in time, the results have been frustratingly unfruitful. Future strategies may include in-vivo or ex-vivo gene therapy and/or mesenchymal stem cell or bone marrow transplantation approaches. Some results have been positive in animal models, but to extrapolate these results to the human form, new approaches to AMD must be determined and improvements in the access to cardiac and skeletal muscle must be made. Newer more efficacious and innocuous vectors also must be discovered. L-alanine supplementation in late-onset AMD has been shown to decrease resting energy expenditure.
Emerging research has shown that infusions of recombinant human alpha-glucosidase from rabbit milk is helpful for stabilizing pulmonary function and improving muscle fatigue in both early- and late-onset Pompe disease. The younger and least affected children showed the most improvement and delay in the progression of the disease process.
Originally described in the treatment of mice with glycogen storage disease, Ven den Hout et al have treated 4 babies with recombinant human alpha-glucosidase obtained from rabbit milk in an open-label study. Recombinant glucosidase was administered intravenously at a weekly dose of 15-20 mg/kg and later was increased to 40 mg/kg. Alpha-glucosidase activity normalized in muscle, the tissue morphology and motor and cardiac function improved, and the left ventricular mass index significantly decreased. Normal neurologic development was noted in all patients. The lessons learned from the research of this disease may lead to better understanding and treatment of other genetic disorders.
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 lysosomes; 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. |
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| 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 | Section 8 of 11 |
Deterrence/Prevention:
Complications:
Prognosis:
Patient Education:
| TEST QUESTIONS | Section 9 of 11 |
CME Question 1: The underlying defect in Pompe disease is a deficiency of which of the following?
A: Acid alpha-glucosidase (acid maltase)
B: Muscle phosphorylase
C: L-carnitine transferase
D: Glucose-6-phosphatase
E: None of the above
The correct answer is A: Muscle phosphorylase deficiency also is known as McArdle disease (type V glycogenosis). L-carnitine transferase deficiency leads to accumulation of fatty acids, not glucose products. Glucose-6-phosphatase also is known as Von-Gierke disease (hepatic glycogenosis) and does not involve the heart or muscles. The metabolic derangement in Pompe disease is acid maltase deficiency.
CME Question 2: Which of the following statements can be made about Pompe disease?
A: Pompe disease (also known as acid maltase deficiency [AMD]) is a metabolic myopathy caused by a deficiency in lysosomal acid maltase. Pompe disease affects the skeletal muscle, heart, liver, and central nervous system and usually is fatal by age 2 years. Other forms of acid maltase deficiency are known.
B: AMD is an inherited neuropathy, caused by an excessive accumulation of urokinase in the peripheral nerves that may or may not affect the central nervous system.
C: AMD is an inherited muscular dystrophy with a defect in chromosome band Xp21. AMD is characterized by limb-girdle weakness, hypertrophy of the calves, and progressive difficulty with ambulation.
D: AMD usually is mild. Patients with AMD usually survive into adulthood.
E: All of the above
The correct answer is A: Although motor neuron disease has been seen in AMD, it is not an inherited neuropathy per se, and urokinase is not involved in its pathophysiology. Duchenne muscular dystrophy is an X-linked muscular dystrophy characterized by limb-girdle weakness, calf hypertrophy, and progressive ambulation dysfunction. The chromosome band Xp21 is involved in Duchenne muscular dystrophy. Patients with acid maltase deficiency can survive into adulthood; however, the disease is far from mild.
Pearl Question 1 (T/F): Acid maltase deficiency (AMD) is an X-linked inherited disease.
The correct answer is False: AMD is an inherited autosomal recessive disease. The genetic defect is found in the q23-28 locus of chromosome 17. It produces an abnormal `spill over` accumulation of glycogen in nearly every tissue in the body, including the liver, heart, and central nervous system. The infantile type almost invariably leads to an early death, usually between 6 months and 2 years. Adults with AMD generally do not have liver involvement. Pulmonary complications are common in this group.
Pearl Question 2 (T/F): Acid maltase deficiency (AMD) affects the liver, heart, and brain.
The correct answer is True: The spill-over accumulation of glycogen in patients with AMD affects nearly every tissue in the body, including the liver, heart, and CNS.
Pearl Question 3 (T/F): Adult acid maltase deficiency (AMD) is always associated with fulminant liver failure.
The correct answer is False: Adults with AMD generally do not have liver involvement. Instead, adults tend to have pulmonary complications.
Pearl Question 4 (T/F): Infants with acid maltase deficiency (AMD) usually die before aged 2 years from heart failure.
The correct answer is True: Children with AMD exhibit severe muscle weakness and cardiomegaly and generally die at 6 months to 2 years of age. Autopsy findings may include an enlarged heart.
| PICTURES | Section 10 of 11 |
| Caption: Picture 1. Acid maltase deficiency myopathy. | |
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| BIBLIOGRAPHY | Section 11 of 11 |
| NOTE: |
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| Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER |
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Author Information | Introduction | Clinical | Differentials | Workup | Treatment | Medication | Follow-up | Test Questions | Pictures | Bibliography
|
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