Pompe Disease

Excerpt

Clinical characteristics: Pompe disease can be classified by age of onset, organ involvement, severity, and rate of progression into infantile-onset Pompe disease (IOPD) (i.e., individuals with onset before age 12 months with cardiomyopathy) and late-onset Pompe disease (LOPD) (i.e., individuals with onset before age 12 months without cardiomyopathy, and all individuals with onset after age 12 months). Untreated individuals with IOPD typically have hypotonia, generalized muscle weakness, feeding difficulties, poor growth, and respiratory distress. Cardiomegaly and hypertrophic cardiomyopathy is usually identified in the first weeks of life and progress to left ventricular outflow obstruction and diminished lung volume. Progressive deposition of glycogen results in conduction defects with shortening of the PR interval on EKG. In untreated infants, death commonly occurs in the first two years of life from cardiopulmonary insufficiency. In those in whom enzyme replacement therapy (ERT) is initiated before age six months and before the need for ventilatory assistance, a majority have improved survival, improved ventilator-independent survival, reduced cardiac mass, and significantly improved acquisition of motor skills compared to untreated individuals.

LOPD can manifest from the first decade to as late as the seventh decade of life with progressive proximal muscle weakness primarily affecting the lower limbs, which may require use of a wheelchair. Respiratory insufficiency progressing to respiratory failure is a significant cause of morbidity and mortality. Some adults have developed arteriopathy, including dilatation of the ascending thoracic aorta. Scoliosis is also frequent.

Diagnosis/testing: The diagnosis of Pompe disease is established in a proband who has deficiency of acid alpha-glucosidase (GAA) enzyme activity in isolated lymphocytes or mixed leukocytes and/or by identification of biallelic pathogenic (or likely pathogenic) variants in GAA by molecular genetic testing in a proband with an out-of-range newborn screening result and/or suggestive clinical features.

Management: Targeted therapies: Although ERT should be initiated as soon as the diagnosis of IOPD or symptomatic Pompe disease is established, it is appropriate to determine cross-reactive immunologic material (CRIM) status prior to initiating ERT, as individuals who do not produce CRIM (i.e., who are CRIM negative) generally develop high titer anti-rhGAA antibodies during ERT and require modified therapy protocols using immunomodulation early in the treatment course, optimally before the first infusion. ERT options include alglucosidase alfa for both IOPD and LOPD; avalglucosidase for individuals with LOPD who are older than age one year; and cipaglucosidase alfa with miglustat for adults with LOPD who weigh at least 40 kg and are not improving on their current ERT regimen.

Supportive care: Medical intervention for cardiomyopathy needs to be individualized as use of standard drugs may be contraindicated in certain stages of the disease process. Management of conduction disturbances 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 familiar with Pompe disease. Speech therapy and augmented communication devices may be helpful for those with communication difficulties. Feeding therapy and consideration of a gastrostomy tube is recommended for those who have feeding/nutritional difficulties. Respiratory support for those with respiratory insufficiency may include CPAP and BiPAP; tracheostomy may be considered in those with macroglossia and severe respiratory insufficiency. Standard treatment for arteriopathy, muscle weakness, scoliosis, osteoporosis, and hearing loss.

Surveillance: At each visit, measure growth parameters and evaluate nutritional status and safety of oral intake; monitor those with seizures as clinically indicated; assess for new manifestations (seizures, changes in tone, movement disorders); monitor developmental progress and educational needs; assess mobility and self-help skills; assess for scoliosis; monitor for evidence of aspiration and respiratory insufficiency; assess respiratory status with regard to cough, difficulty breathing, wheezing, fatigability, and exercise intolerance; obtain electrolytes, BUN, creatinine, liver function tests, CK level, and urine total glucotetrasaccharide (Hex4) level. At least annually, bone mineral density screening (DXA) in those with LOPD (in those with IOPD, DXA scan every two to three years until puberty, then every one to two years); pulmonary function tests; echocardiography (to include assessment for aortic dilatation in those with LOPD); EKG; audiology evaluation; BNP level (if there are concerns for evolving cardiomyopathy). At least every five years, MR cerebral angiography to evaluate for progressive dilation of cerebral vasculature. As clinically indicated, brain imaging to evaluate for intracranial vasculopathy (in those with LOPD); chest radiograph; whole-body MRI to evaluate muscle disease burden; polysomnography; videofluoroscopic swallow study; 24-hour ambulatory EKG (Holter monitoring).

Agents/circumstances to avoid: 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.

Evaluation of relatives at risk: Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment with ERT. If a molecular diagnosis has been established in the proband, molecular genetic prenatal testing of a fetus at risk may be performed; for at-risk newborn sibs (when prenatal testing was not performed), in parallel with newborn screening, either test for the familial GAA pathogenic variants or measure GAA enzyme activity.

Pregnancy management: Several women with LOPD have been treated with ERT during pregnancy and lactation with no reported adverse effects on the fetus and no adverse events during infusions.

Genetic counseling: Pompe disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GAA pathogenic variant, each sib of an affected individual has at conception 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 the GAA pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.