ERT Found Effective for Baby With Pompe, Neutropenia in Case Report
Screening enables timely treatment in boy with ERT antibodies, low neutrophils
Enzyme replacement therapy (ERT) was effective in a newborn with infantile-onset Pompe disease (IOPD) who developed treatment antibodies and had low blood levels of a type of immune cell called neutrophils, according to a case report.
Researchers stressed the importance of including Pompe disease in newborn screening programs and the impact of low neutrophil counts — called neutropenia — in treatment decisions for infantile-onset disease.
The case study, “Infantile-onset Pompe disease with neutropenia: Treatment decisions in the face of a unique phenotype,” was published in the journal JIMD Reports.
Pompe disease is caused by a toxic buildup of the sugar molecule glycogen inside cells, mainly affecting muscle cells. Since glycogen normally serves as a main source of energy to power muscle movements, the condition can lead to symptoms such as weakness and poor muscle tone.
The condition is caused by mutations in the GAA gene, which encodes instructions for producing an enzyme called acid alpha-glucosidase (GAA). As this enzyme is normally responsible for breaking down glycogen, GAA mutations result in a toxic buildup of this sugar molecule. ERT delivers a working version of the GAA enzyme that can get into the cells and break down glycogen.
Classic infantile-onset Pompe is the most severe type of the disease, being characterized by symptoms within the first few months after birth and by the presence of cardiomyopathy, or disease of the heart muscle, in early life.
Newborn screening for Pompe disease is included in the recommended screening panel in some U.S. states. Early diagnosis of Pompe would enable a timely start to ERT.
Case report of newborn boy with infantile-onset Pompe disease
A team of researchers from University at Buffalo reported a case of a baby boy with infantile-onset Pompe disease. His mother had a history of obesity and gestational diabetes, or high blood sugar that develops during pregnancy.
During pregnancy, the fetus had an abnormal fast heart rate (tachycardia) that was consistent with a condition called atrial flutter, which occurs when the heart’s upper chambers (atria) beat too quickly. This prompted an emergency caesarian section.
At birth, the baby was cyanotic (had a bluish color that results from oxygen deficiency) and persistent tachycardia. To normalize his heart rate, the baby underwent low-energy shocks in a procedure called cardioversion. Heart scans showed heart enlargement. Based on these findings, the researchers suspected that the mother’s gestational diabetes may have been the cause of the baby’s cardiomyopathy.
Newborn screening showed a decrease in GAA enzyme activity and genetic testing revealed two disease-causing mutations in the GAA gene — c.953T>C and c.1710C>G — confirming the diagnosis of Pompe.
The baby also had neutropenia and high levels of an enzyme called creatine kinase, a marker of muscle damage.
He was discharged home with further outpatient monitoring. A lab test showed he was CRIM-positive, which means he had residual GAA enzyme activity. High urinary levels of glucotetrasaccharides — a marker of excess glycogen — was also observed.
The boy was admitted to the ICU soon after he was one month old to start ERT with Lumizyme (alglucosidase alfa) at a dosage of 40 mg/kg of body weight. Since his CRIM was positive and neutrophils remained low, the boy was started on ERT without first using immune modulating therapies.
“The initiation of ERT in an IOPD patient with profound and persistent neutropenia of unknown origin presented our team with a unique challenge not previously described in the medical literature,” the scientists wrote. “The results of newborn screening drastically changed treatment decision making for our patient.”
ERT was first well-tolerated without side effects and the baby was discharged home and started on antibiotics. No antibodies, or inhibitors, against the treatment were developed. (Inhibitors neutralize ERT activity, decreasing the therapy’s efficacy.)
On the third ERT administration, he experienced an allergic reaction that resolved by stopping the infusion and taking an antihistamine called diphenhydramine.
Neutropenia resolved after fourth ERT administration
Before he started his fourth session, the baby was given anti-inflammatory and anti-allergy medications. No allergic reactions were observed during ERT. At that point, the researchers observed that his neutropenia was resolved.
During his fifth ERT session, the baby developed a severe allergic reaction that resolved with medication.
He then underwent three infusions of Lumizyme at a lower dose of 10 mg/kg once a week. As this regimen was well-tolerated by the boy, the dose was changed to 20 mg/kg every other week.
Although CRIM-positive patients are less likely to develop anti-therapy antibodies, the baby developed antibodies against ERT. Neutrophil levels fluctuated over time, and was low when the boy was 6 months old.
“We are continuing to monitor for IgG anti-drug antibody development monthly while exploring strategies to understand the etiology [cause] of the patient’s neutropenia,” the scientists wrote.
Despite these results, the efficacy of ERT in the boy was shown through heart and motor function tests.
“This case highlights the importance of screening and early detection, as a positive newborn screen prompted appropriate additional testing and treatment with enzyme replacement therapy rather than delay of care,” the researchers wrote.
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