Acid Maltase Deficiency Myopathy

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).[12, 13] See the images below.

Glycogen molecule; by cleaving glycogen's 1,4 and 1,6 alpha-glycosidic linkages, the enzyme acid maltase gives rise to free glucose molecules.

Metabolic pathways of carbohydrates.

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 that for another) usually are associated with the infantile variant (Pompe disease), whereas "leaky" (partial) mutations are associated with the childhood and adult forms of acid maltase deficiency.

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,[2] 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.

Several forms of acid maltase deficiency (AMD) have been observed. Clinical variation between siblings is uncommon; however, the occurrence of infantile or juvenile forms and adult forms in the same family has been reported, probably owing to various compound heterozygous states.[14]

Glycogenoses include the following:

• Type I - von Gierke disease (glucose-6-phosphatase deficiency)

• Type II - Pompe disease (acid maltase deficiency)[2, 3, 4]

• 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.[2, 3, 4]

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 Gowers 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.[5, 6, 7, 8, 9, 15] Mental retardation may be present. Calf enlargement may be observed, and the Gowers 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.

A study by Jones et al indicated that tongue characteristics may aid in differentiating late-onset AMD from other myopathies. Compared with patients suffering from other myopathies, acquired or hereditary, the tongues of those with late-onset AMD were weaker and had reduced muscle thickness, with ultrasonographic results suggesting fibrofatty replacement and atrophy.[16]

Manifestations of AMD

See the list below:

• 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[5, 6, 7, 8, 9]

  • Motor delay

  • Progressive myopathy

  • Signs and symptoms limited to skeletal muscles

  • Respiratory insufficiency

• Adult[5, 6, 7, 8, 9]

  • 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.

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

Measurement of acid alpha-glucosidase enzyme activity in dried blood specimens is an optimal and reliable diagnostic test for acid maltase deficiency.[10]

Serum CK usually is elevated in the forms of the disease that affect younger patients, but CK can be within the reference range in the adult variety. CK levels can be as high as 2000 IU/L.[10]

Serum aspartate aminotransferase and lactic dehydrogenase can also be elevated.

The tissue concentration level of acid maltase helps to establish a definite diagnosis.[11]

In patients with acid maltase deficiency, chest radiographs reveal an enlarged, globular heart associated with pulmonary vascular congestion. Atelectasis can also be seen.

See the list below:

• EMG

  • Brief, small-amplitude, polyphasic potentials or myopathic features, excessive electrical irritability, and pseudomyotonic discharges usually are seen on EMG.

  • A myopathy is demonstrated.

  • Neuropathic findings may be revealed.

  • Pseudomyotonia may be seen in the absence of myotonia.

• Electrocardiographic findings include extremely tall and broad QRS complexes (representing ventricular depolarization) with a short PR interval (time between P wave and the beginning of the QRS complex), commonly less than 0.009 seconds. The short PR interval may be due to facilitated atrioventricular conduction as a result of myocardial glycogen deposition. A distinct left ventricular trabeculation can be seen on selective angiography.

• Prenatal/postnatal testing

  • Prenatal diagnosis using chorionic villi or amniocentesis is available for the fatal infantile form. Decreased serum levels of acid maltase can be detected. Acid phosphatase levels also can be measured and will be elevated.

  • Newborn screening for Pompe disease can be performed by determining the total acid alpha-glucosidase in plasma or dried blood spots. The sensitivity of these tests is 82-95%, and the specificity is 100%.

See the list below:

• Biopsy

  • The diagnosis of acid maltase deficiency (AMD) usually is made based on the absence or reduction in the levels of alpha–acid maltase in muscle tissue or cultured skin fibroblasts. This deficiency usually is more pronounced in the infantile form than in the juvenile and adult forms.[10]

  • Muscle biopsy shows the presence of vacuoles that stain positive for glycogen. The large vacuoles contain material that is positive for the periodic acid-Schiff stain (typical of lysosomal glycogen storage). Acid phosphatase is increased, most likely because of a compensatory increase in the production of lysosomal enzymes. Electron microscopy reveals glycogen accumulation within the vacuoles and in the cytoplasm.

  • Brain tissue samples from patients with AMD reveal swelling of the perinuclear space (perikaryal edema) caused by excessive storage of glycogen. These cells usually display absence or dispersion of Nissl substance. The cytoplasm may be foamy or stained irregularly, and the nucleus may not be displaced to the periphery. Storage-induced changes tend to be more diffuse or multifocal rather than localized.

Physical Therapy

Little information has been published regarding the physiatric management of Pompe disease, probably owing to the lack of a specific treatment, the relentlessly progressive course, and the fatal outcome of the disease.

In the juvenile and adult forms of acid maltase deficiency (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 involves not just the respiratory muscles but also the heart, the final outcome is likely to be the same.

Due to extended survival and musculoskeletal involvement, physiatric and orthopedic treatment may gain in importance.

A study by Jones et al found that adult patients with late-onset AMD who underwent a 12-week respiratory muscle training program achieved large to very large increases in inspiratory and expiratory muscle strength, with these improvements enduring relatively well even after 3 months’ detraining. The study involved eight patients.[17]

Treatment for this fatal disorder is limited.[12, 18] A copious amount of research into acid maltase deficiency (AMD) is exploring the possibility of replacing the deficient enzyme by means of gene therapy.[13] Up to this point, 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 early onset and late-onset Pompe disease.[19, 20] The younger and least affected children have shown 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, in an open-label study, treated 4 babies with recombinant human alpha-glucosidase obtained from rabbit milk.[21] 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. Subsequent studies have involved the use of recombinant human alpha-glucosidase derived from Chinese hamster ovary cells.[3, 22]

In a 2009 open-label, multicenter study, Nicolino et al employed intravenous treatment with recombinant human alpha-glucosidase in 21 patients, aged 3-43 months, with advanced Pompe disease.[19] The drug was administered every 2 weeks for up to 168 weeks; the investigators found that, compared with an untreated reference cohort, the risk of death in the treated children was reduced by 79% (P < 0.001), and the risk that invasive ventilation would be required was decreased by 58% (P = 0.02).

A prospective cohort study by Kuperus et al reported that in adults with AMD, long-term enzyme replacement therapy has a beneficial impact on muscle strength, pulmonary function, and levels of daily life activity. The study had a median 6.1-year follow-up period, which included 5 years of enzyme replacement therapy, with the treatment having its greatest effect during approximately the first 2-3 years.[23]

Similarly, a study by Semplicini et al indicated that in adult AMD, improvements in walking ability and, probably, stabilization of respiratory function result from enzyme replacement therapy with alglucosidase alfa. Initially, treated patients showed a significant increase of 1.4% per year in the 6-minute walk test, with a subsequent decrease of 2.3% per year (cutoff point at 2.2 years). In addition, the motor function measure score improved by 6.6% per year, with a subsequent reduction of 1.1% per year after 0.5 years. Moreover, the maximum expiratory pressure remained stable throughout the follow-up period. The study’s results, according to the investigators, indicated a ceiling effect for the 6-minute walk test in the first 3 years for patients who undergo enzyme replacement therapy.[24]

The lessons learned from research into AMD may lead to better understanding and treatment of other genetic disorders.[25]

Class Summary

Used as replacement therapy. Recombinant human enzyme alpha-glucosidase has recently been designated an orphan drug.[26]

Previously, although the form of alglucosidase alfa known as Myozyme had been approved by the US Food and Drug Administration (FDA) for use in the treatment of patients younger than 8 years with infantile acid maltase deficiency (Pompe disease), the form known as Lumizyme had been approved only for patients with late-onset acid maltase deficiency who were aged 8 years or older. In 2014, however, the FDA also approved Lumizyme for patients younger than 8 years.[27]

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.

Acid maltase deficiency is an inherited, autosomal recessive disorder; therefore, there are no prevention measures for it.

Respiratory and heart complications are common in the infantile form of acid maltase deficiency (AMD). Severe muscle weakness, including weakness of the respiratory muscles, is a complication of all 3 types of AMD.

The infantile form of acid maltase deficiency has a very unfavorable prognosis. Death usually occurs between ages 6 months and 2 years. A less severe infantile form that exhibits a better prognosis and improved survival has been identified. Patients with the late infantile form may survive for several years.

Educating patients and family members thoroughly about this condition is important. Parents and caregivers need to be instructed in all aspects of taking care of an infant or child with acid maltase deficiency (AMD). Increasing public awareness of this disease also is important, as more research is needed to find a cure for AMD.