eMedicine Specialties > Physical Medicine and Rehabilitation > Myopathy

Acid Maltase Deficiency Myopathy

Author: Michael Weinik, DO, Associate Chairman, Associate Professor, Physical Medicine and Rehabilitation, Temple University Hospital
Coauthor(s): Frank J King, MD, Clinical Instructor, Department of Physical Medicine and Rehabilitation, Georgia Pain Physicians/Emory School of Medicine
Contributor Information and Disclosures

Updated: Apr 15, 2009

Introduction

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 JC 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, GT Cori classified it as type II glycogenosis. (See image below and Image 1.)

• Infantile (Pompe disease)
• Late infantile
• Juvenile
• Adult

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 ages 6 months and 2 years. The other forms are somewhat milder and vary in clinical presentation.^1,2,3

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). (See images below and Images 1, 2.)

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; in muscle, however, 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,¹ 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

United States

Pompe disease, or infantile acid maltase deficiency, occurs in 1 out of 50,000 live births.

Mortality/Morbidity

Pompe disease is inherited as an autosomal recessive disease. In the infantile form, death usually occurs between ages 6 months and 2 years; however, a less severe infantile form, with a better prognosis and improved survival, has been identified. Patients with the late infantile form may survive for several years. Patients with either the juvenile or adult form of acid maltase deficiency (each of which is also known as late-onset 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 acid maltase deficiency.

Sex

Acid maltase deficiency occurs with equal frequency in males and females.

Age

The correlation of acid maltase deficiency with age depends on the form of the disease.

Clinical

History

Glycogenoses include the following:

• Type I - von Gierke disease (glucose-6-phosphatase deficiency)
• Type II - Pompe disease (acid maltase deficiency)^1,2,3
• Type III - Forbes disease (debrancher, amylo-1,6-glucosidase deficiency)
• Type IV - Andersen disease (brancher, amylo-transglucosidase deficiency)
• Type V - McArdle disease (myophosphorylase deficiency)
• Type VI - Hers disease (hepatophosphorylase deficiency)
• Type VII - Tarui disease (phosphofructokinase deficiency)

Other glycogenoses include the following:

• Smith disease (acid maltase deficiency) (late infantile form)
• Engel disease (acid maltase deficiency) (adult form)
• Hers disease (hepatophosphorylase deficiency)
• Hug disease (hepatic phosphorylase kinase deficiency)
• Satoyoshi disease (phosphohexose isomerase deficiency)
• Thomson disease (phosphoglucomutase deficiency)
• Glycogen synthase deficiency
• Bresolin disease (phosphoglycerate kinase deficiency)
• Tonin disease (phosphoglycerate mutase deficiency)
• Tsujimo disease (lactate dehydrogenase deficiency)

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.^1,2,3

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.^4,5,6,7,8 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

• Infantile AMD
  • Early hypotonia
  • Massive cardiomegaly, soft murmur, and heart failure
  • Weakness and depressed or absent muscle stretch reflexes
  • Macroglossia
  • Moderate hepatomegaly
  • Mental retardation
  • "Metabolic" anterior horn cell pathology (uncommon)
• Juvenile^4,5,6,7,8
  • Motor delay
  • Progressive myopathy
  • Signs and symptoms limited to skeletal muscles
  • Respiratory insufficiency
• Adult^4,5,6,7,8
  • Onset occurs in the second or third decade of life. Muscle weakness progresses in the third to sixth decades of life.
  • Proximal muscle weakness is greater than distal muscle weakness.
  • The pelvic girdle is more involved than the shoulder. Intercostal and diaphragmatic involvement is common.
  • No liver, heart, or tongue enlargement occurs, except sometimes in terminal stages.

Causes

Acid maltase deficiency is an inherited, autosomal condition characterized by a buildup of glycogen in the cells.

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