Case of In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease: A report

A case report published in the New England Journal of Medicine is the first case of in-utero enzyme-replacement therapy (ERT) in a fetus with cross-reactive immunologic material (CRIM) –negative infantile-onset Pompe's disease.

Pompe disease (PD) is an autosomal recessive glycogen storage disorder. This is caused due to the deficient activity of lysosomal enzyme acid alpha-1,4-glucosidase.

The deficiency leads to the accumulation of glycogen in lysosomes and the cytoplasm, which ultimately results in tissue destruction. The two most important cells affected are muscle and cardiac tissues.

The manifestations of PD include hypotonia, weakness which gradually progresses, macroglossia and hepatomegaly.

The most typical characteristic finding that alarms the physicians of the PD is an electrocardiogram (EKG) revealing high voltages, repolarization abnormalities, and PR intervals are short. In PD, myocardial thickening affects ventricles which can lead to obstruction of the ventricular outflow tract. Respiratory failure may also occur due to respiratory muscle involvement.

Patients of infantile-onset PD cannot survive without treatment. One treatment which showed benefits includes Enzyme replacement therapy (ERT) with recombinant human GAA. This shows the best motor outcomes when used early, so early diagnosis is critical to successful treatment outcomes.

The most crucial point here to be noted is that CRIM-positive infants have residual GAA enzyme activity, so exposure to native enzymes develops immune tolerance to the GAA protein.

However, CRIM-negative patients do not have immune tolerance to GAA, and an antibody response to the native enzyme is mounted on ERT administration. These patients have poor responses to ERT, which could be improved with immunomodulatory therapy.

The present report is of a 37-year-old woman. Two of her children died early on and were affected by CRIM-negative infantile-onset Pompe disease. She electively terminated one pregnancy. The diagnosis of PD was confirmed in the current pregnancy via CVS (chorionic villus sampling).

The researchers conducted six in-utero ERT infusions at 2-week intervals. This treatment started at 24 weeks and five days of gestation and continued through 34 weeks and five days of gestation.

The researchers, during infusions, administered alglucosidase alfa at a dose of 20 mg per kg of estimated fetal weight. This was made through the umbilical vein.

The baby was delivered vaginally at 37 weeks and four days of gestation.

The treatment was planned so the infant was treated with immune tolerance induction after birth. This started on the first day of life.

From day four onwards, the infant was treated with ERT infusion every week at 20 mg per kg, which increased at ten months and then at 11 months.

The researchers confirmed the investigations like creatine kinase levels, glucose tetrasaccharide levels and IgG antidrug antibodies.

The researchers also identified the cardiac outcomes and placental pathology. The ventricular mass index was normal on day 1. EKG was normal.

The infant had normal creatine kinase levels up to 13 months.

The results obtained in this case were compared to the small cohorts. The immune benefit was achieved because the treatment was initiated prenatally. There was an insignificant lower immune response after birth in this case compared to those who were treated postnatally.

Dr Chakraborty, the co-researcher explained that prenatal therapy is essential in cases like PD because the organ damage begins in utero. The study confirmed the safety and efficacy of in-utero ERT in CRIM-negative infantile onset PD. The researchers said, "We reported the safety and effectiveness for in utero (ERT) in a fetus with CRIM negative infantile-onset Pompe's disease. The family history, in this case, was positive, and cardiomyopathy was reported in two previously affected deceased siblings. They wrote that in-utero ERT and standard postnatal therapy offer immune benefits. The outcome in the current case was normal cardiac and improved motor function postnatally. The biomarkers (normal level of creatine kinase) were normal, and the patient had normal feeding behaviour with good growth. The patient grew well at 13 months of age.The procedure was completely safe, and there was no harm to the mother and the child.

Dr Cohen said, The baby started walking around 11.5 months and responded well to physical therapies, which were assessed regularly.

The main expected result of the case report is better long-term results with survival rate. More research is required to confirm the immune benefit.

Further reading:

In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease. Jennifer L. Cohen, et al.November 9, 2022 DOI: 10.1056/NEJMoa2200587