Glycogen Storage Disease Type II (Pompe Disease)

[Acid Alpha-Glucosidase Deficiency, Acid Maltase Deficiency, GAA Deficiency, GSD II, Glycogenosis Type II]

Clinical Diagnosis

The two general subtypes of glycogen storage disease type II (GSD II), also known as Pompe disease, are suspected in individuals with the following findings:

Infantile-onset Pompe disease is suspected in infants with the following [van den Hout et al 2003, Kishnani et al 2006a]:

• Poor feeding/failure to thrive (44%-97% of cases)

• Motor delay/muscle weakness (20%-63% of cases)

• Respiratory concerns (infections/difficulty) (27%-78% of cases)

• Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy) (50%-92%).

  Note: The characteristic ECG changes indicate accelerated atrioventricular conduction and may be considered diagnostic of Pompe disease [Ansong et al 2006].

Late-onset (i.e., childhood, juvenile, and adult-onset) Pompe disease is suspected in individuals with proximal muscular weakness and respiratory insufficiency without cardiac involvement.

Testing

Nonspecific tests used to support of the diagnosis of Pompe disease

• Serum creatine kinase (CK) concentration is uniformly elevated (as high as 2000 IU/L; normal: 60-305 IU/L) in classic infantile-onset Pompe disease and in the childhood and juvenile variants, but may be normal in adult-onset disease [Laforet et al 2000, Kishnani et al 2006b]. However, serum CK concentration is elevated in many conditions and must be considered nonspecific.

• Urinary oligosaccharides. Elevation of a certain urinary glucose tetrasaccharide is highly sensitive in Pompe disease but is also seen in other glycogen storage diseases [An et al 2000, Kallwass et al 2007].

Testing used to establish the diagnosis of Pompe disease. For laboratories offering biochemical testing, see :

• Acid alpha-glucosidase (GAA) enzyme activity. Measurement of GAA enzyme activity is most reliably performed using cultured skin fibroblasts. It may take four to six weeks to obtain results:

  • Complete deficiency (activity <1% of normal controls) of GAA enzyme activity is associated with classic infantile-onset Pompe disease.

  • Partial deficiency (activity that is 2%-40% of normal controls) of GAA enzyme activity is associated with the non-classic infantile-onset and the late-onset forms [Hirschhorn & Reuser 2001].

    Note: (1) As a general rule, the lower the GAA enzyme activity the earlier the age of onset of disease. (2) GAA enzyme activity can be assayed in muscle; however, this invasive procedure usually requires anesthesia, which may not be tolerated in those who have infantile Pompe disease and cardiopulmonary compromise. (3) Peripheral leukocytes have been used to measure GAA enzyme activity but alternate isoenzymes such as maltase-glucoamylase may interfere with the assay. (4) GAA enzyme activity analysis can be performed on dried blood spots [Chamoles et al 2004, Zhang et al 2006], thus permitting rapid and sensitive analysis that is potentially useful for newborn screening [Kishnani et al 2006b].

• Acid alpha-glucosidase protein quantitation can be performed by an antibody-based method in dried blood spot samples. On occasion, such testing can be of value in interpreting the assay of GAA enzyme activity by evaluating the amount of protein present.

• Muscle biopsy. In contrast to the other glycogen storage disorders, GSD II is also a lysosomal storage disease. In GSD II glycogen storage may be observed in the lysosomes of muscle cells as vacuoles of varying severity that stain positively with periodic acid-Schiff. However, 20%-30% of individuals with late-onset Pompe disease with documented partial enzyme deficiency may not show these muscle-specific changes [Laforet et al 2000, Winkel et al 2005].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene. GAA is the only gene known to be associated with GSD II.

Clinical testing

• Sequence analysis. Depending on ethnicity and phenotype, an individual could be tested first for one of the three common mutations — p.Asp645Glu, p.Arg854X, and IVS1 -13T>G — before proceeding to full sequence analysis.

  In 83%-93% of individuals with confirmed reduced or absent GAA enzyme activity, two mutations can be detected by sequencing genomic DNA [Hermans et al 2004, Montalvo et al 2006].

• Deletion/duplication analysis. One of the more common pathogenic alleles involves the deletion of exon 18, seen in approximately 5%-7% of alleles [Van der Kraan et al 1994]. Single-exon deletions as well as multi-exonic deletions have been seen. With the exception of deletion exon 18, such deletions are rare except among consanguineous matings [McCready et al 2007; Pittis et al 2008; Authors, unpublished data].

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Glycogen Storage Disease Type II (Pompe Disease)

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method	Test Availability
GAA	Sequence analysis	p.Arg854X	~50%-60% 1	Clinical
		p.Asp645Glu	~40%-80% 2
		IVS1 -13T>G	~50%-85% 3
		Other GAA sequence variants	83%-93% 4
	Deletion/duplication analysis 5	Exonic, multi-exonic and whole gene deletions/duplications	5%-13%

1. In African Americans with infantile-onset Pompe disease [Becker et al 1998, Hirschhorn & Reuser 2001]

2. In individuals of Chinese ancestry with infantile Pompe disease [Shieh & Lin 1998, Ko et al 1999, Hirschhorn & Reuser 2001]

3. In adults with late-onset disease (typically this mutation occurs in the compound heterozygous state) [Laforet et al 2000, Hirschhorn & Reuser 2001, Winkel et al 2005, Montalvo et al 2006]

4. Detection rate of two mutations in sequencing of the genomic DNA in patients with confirmed reduced or absent GAA enzyme activity [Hermans et al 2004, Montalvo et al 2006]

5. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods may be used including restriction fragment length polymorphism, PCR fragment length, quantitative PCR, real-time PCR, multiplex ligation dependent probe amplification (MLPA), array CGH. (see ), or high-density SNP array analysis.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Guidelines for the diagnosis of Pompe disease have been put forth by an expert panel from the American College of Medical Genetics [Kishnani et al 2006b].

To establish the diagnosis of Pompe disease in a proband. Clinical evaluation alone is not sufficient to establish the diagnosis of any of the forms of Pompe disease:

• Assay of acid alpha-glucosidase (GAA) enzyme activity in cultured skin fibroblasts or muscle, considered the gold standard for diagnosis, is the diagnostic test of choice if feasible, but it may take weeks to obtain results.

• Assay of GAA enzyme activity in whole blood or dried bloodspot reliably detects GAA enzyme deficiency; confirmation by a second method is preferred prior to initiation of therapy [Kallwass et al 2007].

• Urinary tetrasaccharide levels are elevated in nearly 100% of individuals with infantile Pompe disease, but may be normal in late-onset disease.

Note: Histochemical evidence of glycogen storage in muscle is supportive of a glycogen storage disorder but not specific for Pompe disease.

To confirm the diagnosis of Pompe disease in a proband. Identification of two disease-causing GAA alleles using molecular genetic testing provides additional confirmation of the diagnosis, but should not be used in place of biochemical testing.

Predictive testing for at-risk asymptomatic family members using molecular genetic testing requires prior identification of the GAA disease-causing mutations in the family.

Carrier testing for at-risk relatives using molecular genetic testing requires prior identification of the disease-causing GAA mutations in the family.

Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies using molecular genetic testing require prior identification of the disease-causing mutations in the family.

Genetically Related (Allelic) Disorders

No other phenotypes have been associated with mutations in the GAA gene.

Natural History

Glycogen storage disease type II (GSD II; Pompe disease) has been classified based on age of onset, organ involvement, severity, and rate of progression. As a general rule, the earlier the onset of symptoms, the faster the rate of progression. Although the accuracy and usefulness of the sub-types of late-onset disease may be in question, they are presented below as general categorizations.

Non-classic infantile-onset Pompe disease typically presents in the first year of life.

Although "late-onset" Pompe disease has been divided into childhood, juvenile, and adult-onset forms, many persons with the adult-onset type recall symptoms beginning in childhood and thus, "late-onset" is often the preferred term for those presenting after the first few years of life [Laforet et al 2000]. Most likely, late-onset Pompe disease represents a clinical continuum in which subtypes cannot be reliably distinguished by age of onset.

Feeding difficulties may result from facial hypotonia, macroglossia, tongue weakness, and/or poor oromotor skills.

Hearing abnormalities are common, possibly reflecting a cochlear or conductive pathology or both [Kamphoven et al 2004].

Without treatment by enzyme replacement therapy (ERT), the cardiomegaly and hypertrophic cardiomyopathy that are often identified at birth by echocardiography progress to left ventricular outflow obstruction. Enlargement of the heart can also result in diminished lung volumes, atelectasis, and sometimes bronchial compression. Progressive deposition of glycogen results in conduction defects as seen by shortening of the PR interval on ECG.

In untreated infants, death commonly occurs in the first year of life from cardiopulmonary insufficiency [van den Hout et al 2003, Kishnani et al 2006a].

The non-classic variant of infantile-onset Pompe disease usually presents within the first year of life predominantly with motor delays and/or muscle weakness. Muscles are firm and rubbery as a result of glycogen deposition. Pseudohypertrophy of the calf muscles and a Gower sign simulate Duchenne muscular dystrophy (DMD), but these findings typically occur at an earlier age in Pompe disease than in DMD. Muscular weakness progresses more slowly than in classic infantile-onset Pompe disease.

Although cardiomegaly can be seen with or without left ventricular outflow obstruction, it is not a major source of clinical morbidity [Slonim et al 2000].

Death from ventilatory failure typically occurs in early childhood.

Late-onset Pompe disease can present at various ages with muscle weakness and respiratory insufficiency. Progression of the disease is often predicted by the age of onset as progression is more rapid if symptoms present in childhood.

Late-onset Pompe disease presenting in infancy or early childhood may be difficult to differentiate from the non-classic infantile form. Cardiomegaly is not typically seen but progressive muscle weakness resulting in motor delays, swallowing difficulties, and respiratory insufficiency usually occurs as in the infantile form, but at a slower rate.

Initial symptom presentation in late childhood to adolescence is typically not associated with heart complications. Progression of skeletal muscle involvement is slower than in the infantile forms and eventually involves the diaphragm and accessory respiratory muscles [Winkel et al 2005].

Affected individuals often become wheelchair dependent because of lower limb weakness. Respiratory failure causes the major morbidity and mortality of this form of the disease. Death commonly occurs in the second or third decade of life [Hirschhorn & Reuser 2001, Hagemans et al 2005].

Late-onset Pompe disease may present as late as the second to the seventh decade of life with progressive proximal muscle weakness primarily affecting the lower limbs, as in a limb-girdle muscular dystrophy or polymyositis. Affected adults often describe symptoms beginning in childhood with difficulty participating in sports. Later, fatigue and difficulty with rising from a sitting position, climbing stairs, and walking prompt medical attention.

Evidence of advanced osteoporosis in adults with Pompe disease is accumulating and likely secondarily to decreased ambulation for the most part but other pathologic processes cannot be overlooked [Oktenli 2000, Case et al 2007].

Respiratory failure causes the major morbidity and mortality of this form of the disease [Hagemans et al 2005].

Clinical manifestations of late-onset Pompe disease [Hirschhorn & Reuser 2001]

• Progressive proximal muscle weakness (95%) [Winkel et al 2005]

• Respiratory insufficiency

• Exercise intolerance

• Exertional dyspnea

• Orthopnea

• Sleep apnea

• Hyperlordosis and/or scoliosis (childhood and juvenile onset)

• Hepatomegaly (childhood and juvenile onset)

• Macroglossia (childhood onset)

• Difficulty chewing and swallowing

• Increased respiratory infections

• Decreased deep tendon reflexes

• Gower sign

• Joint contractures

• Cardiac hypertrophy (childhood onset)

Electrophysiologic studies. Myopathy can be documented by electromyography (EMG) in all forms of Pompe disease although some muscles may appear normal.

Nerve conduction velocity (NCV) studies are normal for both motor and sensory nerves.

Genotype-Phenotype Correlations

GAA enzyme activity may correlate with age of onset and rate of progression as a "rough" general rule:

• It is assumed that a combination of two mutated alleles that encode essentially no enzyme activity results in infantile-onset Pompe disease.

• Various combinations of other alleles resulting in some residual enzyme activity likely cause disease but the age of onset and progression are most likely directly proportional to the residual GAA enzyme activity.

Although a number of mutations seen in homozygosity may suggest a genotype-phenotype correlation, the existence of a number of case reports of both infantile and late-onset Pompe disease in the same family suggests strong caution in extrapolation of these observances [Hoefsloot et al 1990].

Mutations that introduce mRNA instability, such as nonsense mutations, are more commonly seen in the infantile-onset form of Pompe disease as they result in nearly complete absence of GAA enzyme activity.

Missense and splicing mutations may result in either complete or partial absence of GAA enzyme activity and therefore may be seen in both infantile-onset and late-onset Pompe disease.

• c.525delT is an especially common mutation among the Dutch [Van der Kraan et al 1994]. It results in negligible GAA enzyme activity and must be considered one of the more severe alterations. Either in the homozygous state or in the compound heterozygous state with another severe mutation, c.525delT predicts the infantile-onset form of Pompe disease, although the correlation is not absolute.

• Deletion of exon 18 is also a common mutation, particularly among the Dutch [Van der Kraan et al 1994]. It results in negligible GAA enzyme activity and must be considered one of the more severe mutations. Deletion of exon 18, either in the homozygous state or in the compound heterozygous state with another severe mutation, predicts the infantile-onset form.

• IVS1 -13T>G is seen in 36% to 90% of late-onset Pompe disease and is not associated with the infantile-onset form [Hermans et al 2004, Montalvo et al 2006]. The mutation leads to a leaky splice site resulting in greatly diminished, but not absent, GAA enzyme activity.

Anticipation

There is no known or predicted clinical or genetic anticipation in GAA deficiency.

Prevalence

p.Asp645Glu, seen among a high proportion (up to 80%) of infantile cases in Taiwan and China, is associated with a haplotype, suggesting a founder effect [Shieh & Lin 1998].

p.Arg854X is frequently associated with infantile-onset Pompe disease. Although found among different ethnicities, the mutation has been observed in up to 60% of individuals of African descent who had a common haplotype, suggesting a founder effect [Becker et al 1998].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with glycogen storage disease type II (GSD II; Pompe disease), the following guidelines for the initial evaluation of Pompe disease put forth by an expert panel from the American College of Medical Genetics [Kishnani et al 2006b] are recommended:

• Chest radiography. In infantile-onset Pompe disease nearly all affected infants have cardiomegaly on chest x-ray [van den Hout et al 2003]. Further, evaluation of apparent lung volume reduction, areas of atelectasis, and any pulmonary fluid may be helpful in directing other therapies.

  In late-onset disease, baseline radiographic evaluation of the lungs and heart silhouette is indicated but only rarely reveals cardiomegaly.

• Electrocardiography (ECG). In infantile Pompe disease the majority of affected infants have left ventricular hypertrophy and many have biventricular hypertrophy [van den Hout et al 2003]. Conduction disturbance is often seen.

• Echocardiography. Typically in the infantile forms, echocardiography demonstrates hypertrophic cardiomyopathy with or without left ventricular outflow tract obstruction in the early phases of the disease process. In later stages, dilated cardiomyopathy may be seen.

• Pulmonary assessment. Most infants have varying degrees of respiratory insufficiency. Respiratory status should be established with regard to cough, presence of wheezing or labored breathing, and/or feeding difficulties. Diaphragmatic weakness caused by excessive glycogen deposits results in mild to moderate reduction of vital capacity; however, objective assessment of pulmonary functions in infants is difficult at best. Most infants display respiratory difficulty with feeds or sleep disturbance [Kravitz et al 2005].

  Persons with late-onset disease should be evaluated for cough, wheezing, dyspnea, energy level, exercise tolerance, and fatigability. Formal pulmonary function tests in the late-onset forms show pulmonary insufficiency. Pulse oximetry, respiratory rate, and venous bicarbonate and/or pCO₂ should be obtained to assess for alveolar hypoventilation.

• Nutrition/feeding. Patients should be evaluated for possible feeding difficulties (e.g., facial hypotonia, macroglossia, tongue weakness, and/or poor oromotor skills).

  Assessment of growth (i.e., height, weight, head circumference), energy intake, and feeding (including video swallow study) is appropriate.

  All infants should be evaluated for gastroesophageal reflux.

• Audiologic. Baseline hearing evaluation including tympanometry is appropriate. See Hereditary Deafness and Hearing Loss Overview for a discussion of age-related methods of hearing evaluation.

• Bone densitometry. Dual energy x-ray absorptiometry (DXA) should be obtained once an individual is medically stabilized.

• Disability inventory. All patients should undergo assessment of their motor skills and overall functioning to guide subsequent therapies and monitor progression of the disease.

Treatment of Manifestations

Guidelines for the management of Pompe disease have been put forth by an expert panel from the American College of Medical Genetics [Kishnani et al 2006b]:

• Cardiomyopathy. Medical intervention needs to be individualized as use of standard drugs may be contraindicated in certain stages of the disease process (see Agents/Circumstances to Avoid) [Kishnani et al 2006b].

  Enzyme replacement therapy (ERT) reduces cardiac mass to varying degrees and improves the ejection fraction, although there may be a transient decrease in the ejection fraction after the first several weeks of ERT.

• Conduction disturbances. Patients with hypertrophic cardiomyopathy are at high risk for tachyarrhythmia and sudden death [Tabarki et al 2002]. Twenty-four hour Holter monitoring is useful in characterizing the type and severity of rhythm disturbance. Management includes avoidance of stress, infection, fever, dehydration, and anesthesia. Medical therapy, if indicated, often necessitates a careful balance of ventricular function and should be undertaken by a cardiologist familial with Pompe disease.

  Enzyme replacement therapy results in an increase of the PR interval and a decrease in the left ventricular voltage [Ansong et al 2006].

• Muscle weakness. Physical therapy is appropriate to maintain range of motion and assist in ambulation.

  Proximal motor weakness can result in contractures of the pelvic girdle in infants and children, necessitating aggressive management including surgery.

• Nutrition/feeding. Infants may need specialized diets and maximal nutrition, with some requiring gastric feedings. Persons with late-onset disease may also develop feeding concerns and are often managed on a soft diet, with a few requiring gastric or jejunal feedings.

• Respiratory insufficiency. Respiratory support including CPAP and BiPAP may be required.

  Macroglossia and severe respiratory insufficiency in the infantile form may necessitate tracheostomy.

Prevention of Primary Manifestations

Enzyme replacement therapy (ERT) should be initiated as soon as the diagnosis of Pompe disease is established.

The FDA approved the use of Myozyme^® (alglucosidase alfa) for use in infantile Pompe disease in 2006. Studies on later-onset forms of Pompe disease are ongoing.

Myozyme^® is administered by slow IV infusion at 20-40 mg/kg/dose every two weeks.

In clinical studies, infusion reactions were observed in half of the patients treated with Myozyme^®. The majority of treated children developed IgG antibodies to Myozyme^® within the first three months of treatment. Infusion reactions appear to be more common in individuals with IgG antibodies. Development of IgE antibodies is less common but may be associated with anaphylactic reaction. Some patients with high sustained IgG titers may have a poor clinical response to treatment. Most of these reactions could be modified by slowing the rate of infusion or administration of antipyretics, antihistamines, or glucocorticoids. However, anaphylaxis requiring life support measures has been reported. For these reasons, and because many individuals with Pompe disease have preexisting compromise of respiratory and cardiac function, careful infusion in centers equipped to provide emergency care is recommended.

In addition to drug-related reactions, children with infantile Pompe disease may have difficulty with anesthesia for procedures related to placement of venous access devices.

The relative resistance of skeletal muscle to effective glycogen depletion with administered alpha glucosidase has been observed in animals and humans, and varies with different enzyme preparations. Type II muscle fibers appear to be quite resistant to therapy. From a clinical viewpoint, the failure of most ventilator-dependent patients to achieve independence from invasive ventilation is not surprising. Perhaps more disappointing is that five of the 18 infants treated before age six months made no meaningful gains in motor function and six of 18 became dependent on ventilatory assistance. A variety of predictors of poor prognosis were observed, including increase in muscle glycogen during therapy, high IgG titers to alpha glucosidase, and CRM negativity. The relationship between GAA genotype and response to ERT is still under study.

In summary, when compared to an untreated cohort, a majority of those in whom ERT was initiated before age six months and before need for ventilatory assistance had improved survival, improved ventilator-independent survival, reduced cardiac mass, and significantly improved acquisition of motor skills. Factors predicting poor response are incompletely known and may only be deduced for any given individual by therapeutic trial. While the long-term prognosis is as yet unknown and many treated children are too young for cognitive evaluation, available studies suggest better cognitive outcomes than had been predicted.

Prevention of Secondary Complications

Infections need to be aggressively managed.

Immunizations need to be kept current.

The patient and household members should receive annual influenza vaccinations.

Respiratory syncytial virus (RSV) prophylaxis (palivizumab) should be administered in the first two years.

Anesthesia should be used only when absolutely necessary because reduced cardiovascular return and underlying respiratory insufficiency pose significant risks.

Surveillance

Close follow-up is indicated. Management and surveillance guidelines have been proposed by the ACMG Work Group on Management of Pompe Disease [Kishnani et al 2006b]:

• Twice-yearly clinical review of development, clinical status, growth, and use of adaptive equipment

• Assessment of respiratory status with each visit with regard to cough, difficulty breathing, wheezing, fatigability, and exercise tolerance:

  • Chest x-rays at regular intervals

  • Annual pulmonary function tests or more frequently as indicated

  • Periodic sleep evaluation, which may include regular capnography and pulse oximetry

• Monitoring of overall musculoskeletal and functional status to guide therapies aimed at preventing or minimizing physical impairment and their complications

• Regular nutritional and feeding assessment

• At least annual renal function studies to monitor for secondary complications related to cardiac and/or pulmonary impairment as well as medication effects

• Annual cardiology evaluation in late-onset disease and as needed for infantile-onset disease:

  • Periodic echocardiography

  • Twenty-four-hour ambulatory ECG at baseline and at regular intervals [Cook et al 2006]

• Annual hearing evaluation

Agents/Circumstances to Avoid

Use of standard drugs for treatment of cardiac manifestations may be contraindicated in certain stages of the disease. The use of digoxin, ionotropes, diuretics, and afterload-reducing agents may worsen left ventricular outflow obstruction, although they may be indicated in later stages of the disease.

Hypotension and volume depletion should be avoided.

Exposure to infectious agents is to be avoided.

Over-the-counter medications used for acute respiratory illnesses may contain sympathomimetic agents and should be avoided.

Testing of Relatives at Risk

It is appropriate to offer sibs of a proband either testing of GAA enzyme activity or molecular genetic testing (if the disease-causing mutations have been identified in an affected family member) so that morbidity and mortality can be reduced by early diagnosis and treatment with ERT.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Gene therapy to correct the underlying enzyme defect is under investigation [Raben et al 2002].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Experience with bone marrow transplantation in both humans and cattle with acid alpha-glucosidase deficiency has been limited; to date, such treatment is not considered successful [Hirschhorn & Reuser 2001].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Glycogen storage disease type II (GSD II; Pompe disease) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• In most instances, the parents of a proband are heterozygotes and thus carry a single copy of a disease-causing mutation in the GAA gene.

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.

• Heterozygotes are asymptomatic.

Offspring of a proband

• Children with the more common infantile form of GSD II do not reproduce, although the availability of therapy may alter this expectation through improved fitness of those individuals who respond to enzyme replacement therapy.

• The offspring of an individual with a later-onset form of GSD II are obligate heterozygotes (carriers) for a disease-causing mutation in the GAA gene.

Other family members of a proband. Each sib of an obligate heterozygote is at a 50% risk of being a carrier.

Carrier Detection

Biochemical genetic testing. Measurement of acid alpha-glucosidase enzyme activity in skin fibroblasts, muscle, or peripheral blood leukocytes is unreliable for carrier determination because of significant overlap in residual enzyme activity levels between obligate carriers and the general (non-carrier) population.

Molecular genetic testing. Carrier testing for at-risk family members is available on a clinical basis once the mutations have been identified in the family.

Related Genetic Counseling Issues

See Management, Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Concordance/discordance of phenotype in family members

• The sib pair concordance in the infantile-onset form of Pompe disease is high in children with null mutations [Hirschhorn & Reuser 2001].

• Because intergenerational phenotypic variation has been reported in several families with Pompe disease, careful genetic counseling is advised [Hoefsloot et al 1990].

Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed. Results of prenatal testing cannot predict the age of onset, clinical course, or degree of disability.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Biochemical genetic testing. Prenatal testing is possible by measuring GAA enzyme activity in uncultured chorionic villi or amniocytes; however molecular genetic testing is clinically available and is the preferred method if the familial mutations are identified.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Literature Cited

Published Statements and Policies Regarding Genetic Testing

Suggested Reading

Author Notes

Web site: www.cincinnatichildrens.org/svc/alpha/l/lysosomal

Revision History

• 5 August 2008 (cd) Revision: deletion/duplication testing available clinically

• 22 April 2008 (cd) Revision: targeted mutation analysis no longer available clinically

• 31 August 2007 (me) Review posted to live Web site

• 8 January 2007 (btt) Original submission