Clinical Guidance

Combinations of pathogenic variants that result in complete absence of acid alpha-glucosidase (GAA) enzyme activity are seen more commonly in IOPD, whereas combinations of pathogenic variants that result in partial enzyme activity are seen more commonly in LOPD.

• GAA pathogenic variants that introduce mRNA instability, such as nonsense pathogenic variants, are more commonly seen in IOPD, as they result in nearly complete absence of GAA enzyme activity.

• GAA pathogenic missense and splicing variants may result in either complete or partial absence of GAA enzyme activity and therefore may be seen in both IOPD and LOPD [Zampieri et al 2011].

Observations about genotype-phenotype correlations with specific pathogenic variants include:

Source: GeneReviews — "Pompe Disease"

Diagnostic Criteria

Pompe disease can be classified by age of onset, organ involvement, severity, and rate of progression:

• Infantile-onset Pompe disease (IOPD). Individuals with onset before age 12 months with cardiomyopathy

• Late-onset Pompe disease (LOPD)

• Individuals with onset before age 12 months without cardiomyopathy

• All individuals with onset after age 12 months

Suggestive Findings

A diagnosis of Pompe disease may be suspected due to an prior to onset of suggestive findings or may be considered because of .

Out-of-Range NBS Result

NBS for Pompe disease is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify acid alpha-glucosidase (GAA) enzyme activity. Pompe disease is included in the United States (US) Secretary of Health and Human Services Recommended Unifor...

Source: GeneReviews — "Pompe Disease"

Differential Diagnosis

Infantile-Onset Pompe Disease (IOPD) Table 5. Genes of Interest in the Differential Diagnosis of Infantile-Onset Pompe Disease

Management Guidelines

Clinical practice guidelines for Pompe disease have been published:

• Guidelines for individuals ascertained by newborn screening [Kronn et al 2017]

• Guidelines for infantile-onset Pompe disease (IOPD) [American College of Medical Genetics expert panel; see Kishnani et al 2006]

• Guidelines for late-onset Pompe disease (LOPD) [Cupler et al 2012]

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Pompe disease, the evaluations summarized in for IOPD and for LOPD (if not performed already) are recommended.

Table 7.

Infantile-Onset Pompe Disease: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Constitutional

| Measurement of weight, length, head circumference | To assess for poor growth

Respiratory

| Assess for signs/symptoms of respiratory insufficiency. | Incl for cough, wheeze, labored breathing, dyspnea, energy level, exercise tolerance, and fatigability feeding difficulties, or sleep disturbance

Chest radiograph | To assess for cardiomegaly, apparent lung volume reduction, areas of atelectasis, any pulmonary fluid

Consider pulmonary function tests. | • Most affected persons demonstrate pulmonary insufficiency.

• Assessing ventilatory capacity in supine position can detect early ventilatory insufficiency.

Pulse oximetry, respiratory rate, venous bicarbonate /or pCO2 should be obtained to assess for alveolar hypoventilation.1 |

Mouth

| Assess for macroglossia. |

Cardiovascular

| EKG echocardiog...

Source: GeneReviews — "Pompe Disease"

Clinical Guidance

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. Anesthesia should be used only when absolutely necessary because reduced cardiovascular return and underlying respiratory insufficiency pose significant risks. Exposure to infectious agents is to be avoided.

Source: GeneReviews — "Pompe Disease"

Therapies Under Investigation

In utero therapy. In utero alglucosidase alfa therapy (20 mg/kg of estimated fetal weight) was given to an affected fetus every two weeks from 24 5/7 weeks' gestation to 34 5/7 weeks' gestation as part of a clinical trial. After birth, the infant received immunotolerance induction and alglucosidase alfa ERT at various doses. Follow up through approximately age 12 months noted normal cardiac function and attainment of appropriate gross motor milestones [Cohen et al 2022]. Gene therapy to correct the underlying enzyme defect is under investigation [Raben et al 2002, DeRuisseau et al 2009, Mah et al 2010]. A Phase I/II trial to investigate the ability of adeno-associated virus (AAV)-mediated delivery of GAA to improve ventilation reported outcomes of children with IOPD treated with ERT.

Source: GeneReviews — "Pompe Disease"

Surveillance Guidelines

Updated management and surveillance guidelines have been published by the Pompe Disease Newborn Screening Working Group [Kronn et al 2017], summarized in . To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in are recommended. Given the wide age range in individuals with LOPD, most of the recommendations can be applied to both IOPD and LOPD; however, there are some differences highlighted in .

Table 11.

Pompe Disease: Recommended Surveillance

System/Concern | Evaluation | Frequency

Constitutional

| • Measurement of growth parameters

• Eval of nutritional status safety of oral intake

| At each visit

Neurologic

| Monitor those w/seizures as clinically indicated.

Assess for new manifestations such as seizures, changes in tone, movement disorders.

Brain imaging to evaluate for intracranial vasculopathy | As clinically indicated for persons w/LOPD

Development

| Monitor developmental progress educational needs. | At each visit

Musculoskeletal

| Physical medicine, OT/PT assessment of mobility, self-help skills

Clinical assessment for scoliosis

DXA scan | • IOPD: every 2-3 yrs until puberty, then every 1-2 yrs

• LOPD: Consider annual screening.

CK level | At each visit, particularly in those persons identified on NBS w/LOPD very early clinical symptoms

Respiratory

| Monitor for evidence of aspiration respiratory insufficiency.

Source: GeneReviews — "Pompe Disease"