Four cases of infantile-onset Pompe disease recently reported in Australia help shed light on some of the unique challenges care providers face in diagnosing and managing this genetic disease.
Early recognition of the disease’s signs and prompt initiation of enzyme replacement therapy (ERT) are critical to ensuring the best patient outcome and to preventing irreversible clinical changes.
The study describing the four cases, “Infantile‐onset Pompe disease: A case series highlighting early clinical features, spectrum of disease severity and treatment response,” was published in the Journal of Paediatrics and Child Health.
Classical infantile-onset Pompe disease, which appears soon after birth, is characterized by reduced muscle tone and strength, respiratory insufficiency with an increased risk of pulmonary infections, feeding difficulties, failure to thrive, and cardiac problems.
This broad spectrum of generic clinical features can make the diagnostic process more difficult, often causing delays and leading to misdiagnosis.
The first case presented in the study discussed a girl described by her pediatrician as a “normal child,” despite having a droopy eyelid (a condition called ptosis) and an enlarged heart at the age of 9 months. The ptosis progressed, and at 13 months, she was admitted to the hospital. There, a physical examination revealed she had an abnormally enlarged heart, intermittent difficulty breathing due to respiratory infections, ptosis, an enlarged tongue and lips, and severely low muscle tone.
Developmental evaluations showed that she had lower body weight and significant delays in motor function, speech, and social skills. Blood analysis indicated that she had increased levels of creatinine kinase and liver enzymes, common biomarkers of muscle disorders.
At 15 months, the diagnosis of infantile-onset Pompe disease was suspected, and cross-reactive immunological material (CRIM) status was confirmed as negative, which is a prognostic factor linked to a worse Pompe treatment outcome.
Treatment with ERT was started at 16 months, resulting in clinically meaningful improvements. The child’s motor functions improved significantly with the therapy, and the size of her heart was within normal range. The girl currently is 7 years old and continues to make good progress on ERT. She did not require additional treatment or assistance.
The second patient in the study was first referred to the clinical team at the age of 3 months, due to a cardiac murmur. A physical examination noted that he had reduced limb movement, low muscle tone, feeding difficulties, slow weight gain, and an abnormally rapid breathing rhythm.
An evaluation of his heart showed severe enlargement of the heart walls, which was treated with Inderal (propranolol) three times a day.
Infantile-onset Pompe disease was confirmed after the boy was found to have significantly reduced GAA activity, the hallmark of Pompe disease. He was confirmed to be CRIM-negative and started ERT at 4 months of age.
Despite treatment, his developmental, respiratory, and cardiac conditions continued to progressively decline. Although he initially tolerated the ERT well, he began to develop secondary reactions, and blood analysis showed that he had begun to produce antibodies against the treatment. At 9 months, additional administration of Rituxan (rituximab) was started to prevent an adverse immune reaction. However, this strategy failed to improve the therapy’s effectiveness.
Although the clinical team continued to change the treatment strategy to improve response and reduce adverse side effects, the patient struggled to tolerate treatment. At that point, doctors decided to withdraw treatment. The boy died at the age of 19 months from cardiac failure.
The third case presented in the study discussed a girl who at 4 months already had developed two pulmonary infections for which she required respiratory support. In her last hospital admission, she was seen to have low muscle tone with no reflexes and 2.6 times higher levels of creatinine kinase. This indicated muscle or heart damage. Feeding difficulties and poor weight gain also were reported.
At 5 months, she had failed developmental milestones and did not recover muscle tone. A sleep study revealed that she had respiratory failure, and heart imaging showed structural alterations that impaired the heart’s functioning.
The girl started ERT at 7 months and her clinical condition gradually improved over time. Initially, she experienced several pulmonary and lower respiratory tract infections that required hospitalization. Now, at 5 years old, she continues ERT and remains in good general health but with borderline to low intellectual function.
The last patient discussed by researchers was a girl who at 9 months showed severely reduced muscle tone and marked respiratory distress due to pneumonia.
Her developmental records showed that she failed several milestones and had shortness of breath that caused feeding difficulties. Her heart was structurally normal but had significant thickening of the walls.
Infantile-onset Pompe disease was confirmed at 10 months, and CRIM status was reported as positive. One month later, she started ERT, experiencing frequent immune-mediated adverse reactions.
Despite the treatment, the girl continued to experience several episodes of pulmonary infections that required hospital admission. She also had chronic respiratory failure, mucus plugging, increasing oral secretions, and general muscle weakness.
Treatment with immunoregulatory drugs was started to counteract the enhanced immune response. But two months later, she experienced a viral lower respiratory tract infection that caused her death.
“ERT has greatly improved survival in infantile-onset Pompe disease,” the researchers stated. However, information and guidelines to support treatment decisions are still lacking in terms of management therapies for these patients.
“Treatment outcome is largely dependent on age at initiation with its benefits being the greatest when started early prior to sustained irreversible [muscle tissue] damage,” researchers added.
This underscores “the need for increased vigilance in recognizing the early signs,” which include increased thickness of the heart walls, respiratory insufficiency, and severe generalized muscle disorder, to promote early diagnosis.