Glycogen Storage Disease, Type II

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Type II glycogen storage disease (GSD) is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme acid α-glucosidase (acid maltase). Incidence is esti- mated at 1 in 50,000 in most populations implying a carrier frequency of 1 in 100.

GENETICS/BASIC DEFECTS

1. Inheritance: autosomal recessive

2. Caused by deficiency of acid maltase (acid α-glucosidase), leading to the pathological accumulation of glycogen in lysosomes, predominantly in the skeletal muscle, heart, and liver

a. Virtual absence of α-glucosidase activity in infantile form (Pompe disease)

b. Considerable residual enzyme activity in the great majority of patients with the adolescent or adult form 3. Identification of various mutations in the α-glucosidase (GAA) gene (mapped on 17q23-25), leading to the disease a. Types of mutations

i. Point mutations ii. Deletions iii. Insertions

b. Compound heterozygotes in most patients

c. Relatively common mutations among European patients

i. The single base pair deletion ΔT525 causing pre- mature termination at nucleotide 658–660 ii. Deletion of exon 18

4. Genotype-phenotype correlation

a. The nature of the mutation is generally considered a good predictor of a clinical phenotype

b. Homozygosity for either Δexon 18 or ΔT525 mutation or compound heterozygosity for these two mutations results in a severe infantile form of GSDII c. Combination of either of these mutations with leaky

IVS1t-13g mutation results in the majority of cases in the adult phenotype

d. A splicing defect (IVS6 t-22g) results in a removal of exon 6 and insertion of 21 nucelotides of the intronic sequence defined the juvenile phenotype in a compound heterozygote patient who carries a silent second allele. Homozygosity for the same splicing defect resulted in a milder adult phenotype

e. Growing number of cases in recent years where the genotype does not match the phenotype

CLINICAL FEATURES

1. Infantile form

a. Classical infantile form

i. Onset within first weeks or months of life or even at birth

ii. Characterized by complete or near complete deficiency of α-glucosidase

iii. Poor feeding and failure to thrive, early complaints iv. Cyanosis and attacks of dyspnea beginning early v. Cardiomyopathy: the important finding suggest-

ing diagnosis

a) Marked cardiomegaly b) Congestive heart failure vi. Striking hypotonia

a) Increasing generalized weakness b) Affecting bulbar musculature c) Without muscle atrophy vii. Macroglossia

viii. Mild hepatomegaly ix. Calf hypertrophy

x. Depressed or absent reflexes due to glycogen accumulation in spinal motor neurons

xi. Impaired alertness

xii. Accumulation of glycogen in the lysosomes rapidly disrupts cellular function in the most severe form a) Rapidly disrupts cellular function

b) Leading to intractable cardiorespiratory failure c) Most patients die by 1 year of age

b. Nonclassical infantile form i. Onset in infancy ii. Slower progression

iii. Involving primarily skeletal muscle with minimal or no cardiac involvement (without cardiomegaly) iv. May present with delayed motor milestones if

onset is in early preschool age

v. May present with a decrease in motor skills if onset is later in childhood

vi. Usually demonstrate progressive proximal weakness with different degrees of respiratory muscle involvement

vii. Presence of respiratory complications often con- tributing to early death

2. Juvenile form

a. Juvenile onset (first decade)

b. Characterized by presence of reduced but residual α- glucosidase activity

c. Clinical boundaries between juvenile and adult forms not precisely defined

d. Clinical manifestations

i. Predominantly skeletal muscle weakness with respiratory muscle involvement and mild hepatomegaly

ii. Cardiac involvement: absent or mild a) Arrhythmia

b) Mild ventricular dysfunction

iii. Death results from respiratory failure after a course lasting several years

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Glycogen Storage Disease, Type II

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462 GLYCOGEN STORAGE DISEASE, TYPE II

3. Adult form

a. Onset: second to sixth decades

b. Characterized by higher levels of residual α-glucosidase activity

c. Slower progression of the skeletal muscle weakness i. Upper arms

ii. Pectoral muscles

iii. Asymmetry of affected muscle groups iv. Limb girdle weakness, a prominent finding

v. Respiratory muscle involvement (weakness of the diaphragm) (about 33%): a hallmark of the disease vi. Little or no cardiac abnormality

d. Acute respiratory failure

DIAGNOSTIC INVESTIGATIONS

1. Elevated serum creatine kinase in most patients

2. Elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactic dehydrogenase (LDH) 3. Radiography: tremendous cardiomegaly

4. EKG: can readily observe the signs of cardiac glycogenosis (indicators of relative myocardial ischemia)

a. Very large QRS complex in all leads

b. Short P-R interval: pathognomonic of infantile Pompe disease

c. Left axis deviation or absence of the normal right axis deviation (presence of biventricular hypertrophy) d. Inverted T wave

e. S-T segment depression

5. Echocardiography: Biventricular hypertrophy without outflow obstruction

6. EMG

a. Infantile form: nonspecific myopathic changes or normal finding

b. Adult form

i. Pseudomyotonia

ii. High-frequency discharges iii. Fibrillations

7. Muscle biopsy

a. Presence of vacuoles that stain positive for glycogen (PAS) as well as for the lysosomal enzyme acid phosphatase

b. A typical lacework appearance of histologic sections from the myocardium resulting from deposition of stored material in the cardiac fibrils

c. Electron microscopy

i. Membrane-bound glycogen

ii. Glycogen accumulation within the lysosome 8. Glycogen accumulation

a. Infantile form i. Muscle ii. Liver

iii. Motor nuclei in the brain stem iv. Anterior horn cells of the spinal cord

v. Placenta

a) Amniotic storage cells identified and shown histochemically to contain glycogen b) Pathognomonic accumulation of lysosomal

glycogen in the placenta by electron microscopy in the second trimester

c) Confirmation of the prenatal diagnosis made by enzyme assay

vi. Other tissues a) Endothelial cells b) Kidneys

c. Skin

b. Adult form: not seen in the heart, liver, or brain 9. Diagnostic enzymatic test: deficient acid maltase in

leukocytes, muscle, and skin fibroblasts 10. DNA analysis by targeted mutation analysis

11. Newborn screening by determining the total α-glucosidase in plasma or dried blood spots

12. Heterozygote detection

a. Reduced α-glucosidase activity: not reliable

b. DNA based detection more appropriate and definitive within families

GENETIC COUNSELING

1. Recurrence risk a. Patient’s sib: 25%

b. Patient’s offspring: not increased unless the spouse is a carrier in which cases 50% of offspring will be affected and 50% will be carriers

2. Prenatal diagnosis

a. Rapid prenatal diagnosis by electron microscopy of uncultured amniocytes

b. Deficient activity of lysosomal acid α-glucosidase in cultured amniocytes or CVS

c. Electron microscopic study of chorionic villus biop- sies for the pregnancy at risk: fibrocytes with typical vacuoles filled with glycogen

d. Mutation analysis on amniocytes or CVS: 100% reliable prediction of the genetic status of the fetus, including heterozygosity

3. Management

a. Supportive therapy to manage symptoms and mini- mize complications whenever possible

i. Respiratory therapy ii. Physical therapy iii. Dietary therapy

iv. Infection prevention

v. A high protein diet to improve muscle function vi. Ventilator support

b. Administration of purified α-glucosidase not effective c. Bone marrow transplantation presumably to provide

enzyme secreted by the normal cells continuously i. Results not promising

ii. Transitory engraftment of the haploidentical transplant

iii. No enzyme detected in muscle cells

iv. Patient died of complications of the transplant d. Enzyme replacement therapy with recombinant

human α-glucosidase from rabbit milk in Pompe patients in an open-label study

i. Intended to directly address the underlying metabolic defect via intravenous infusions of recombinant human GAA (rhGAA) enzyme

ii. The enzyme generally well tolerated

iii. Normalization of muscle α-glucosidase activity

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GLYCOGEN STORAGE DISEASE, TYPE II 463

iv. Improved tissue morphology and motor and cardiac function

v. Significantly decreased left ventricular mass index

vi. Recommend early treatment (before irreversible damage) and follow-up of long-term effects vii. Anti-rhGAA antibody may limit the efficacy of

the treatment.

viii. Extensive muscle damage may be unrefractive to therapy

e. Gene therapy aiming at providing a permanent endogenous source of enzyme for the affected tissues:

not available currently

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464 GLYCOGEN STORAGE DISEASE, TYPE II

Fig. 1. An infant with massive cardiomegaly and hypotonia. Diagnosis of Pompe disease was confirmed by deficient acid maltase in the leukocytes.

Fig. 2. Different patient with Pompe disease. (A) Myocardium. Note numerous vacuolated fibers (arrows) due to glycogen accumulation.

HE, X40. (B) Smooth muscle from GI tract. Note clear areas represent glycogen deposition (arrows).