Successful pregnancy outcome in patient with Pompe disease despite discontinuation of enzyme replacement therapy

Dunja Leskovar Lemešić1, Dražen Perica1, Gordan Zlopaša2,3, Biserka Knezić Frković2, Nediljko Šućur1, Željko Reiner1, Ivan Pećin1,3

1 Division for Metabolic Diseases, Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, Croatia

2 Department of Obstetrics and Gynecology, University Hospital Centre Zagreb, Zagreb, Croatia

3 School of Medicine, University of Zagreb, Zagreb, Croatia

Corresponding author’s e-mail: dunja.leskovar@gmail.com

Received: 16/04/2025
Accepted: 22/04/2025
Published: 21/05/2025

Conflicts of Interests: The Authors declare that there are no competing interests.
Patient Consent: Written informed consent for the publication of her clinical data was obtained from the patient.
Acknowledgments: We would like to thank the staff of Division for Metabolic Diseases and the Clinic for Women’s Diseases and Childbirth, whose support enabled our patient with a complex illness to have a normal pregnancy and delivery.
This article is licensed under a Commons Attribution Non-Commercial 4.0 License

How to cite this article: Leskovar Lemešić D, Perica D, Zlopaša G, Knezić Frković B, Šućur N, Reiner X, Pećin I. Successful pregnancy outcome in patient with Pompe disease despite discontinuation of enzyme replacement therapy. EJCRIM 2025;12:doi:10.12890/2025_005456

ABSTRACT

Background: Pompe disease (PD), is an autosomal recessive metabolic disorder caused by mutations in the acid alpha-glucosidase (GAA) gene, resulting in a deficiency of the same enzyme and glycogen buildup in tissues. Late onset PD (LOPD) is characterized by muscle illness, accompanied by diaphragmatic involvement and leading to respiratory insufficiency. Fortunately, the disease progresses slowly, and treatment with enzyme replacement therapy can further delay its development. Pregnancy in women with LOPD requires special caution because musculoskeletal changes and greater physical demands may worsen muscular weakness and endanger both the mother and unborn child. Although several cases of pregnant women with LOPD that continued enzyme replacement therapy (ERT) during pregnancy have been reported, there is still a lack of data regarding teratogenicity and safety of the foetus.
Case report: We present a case of a 31-year- old pregnant women with a mild form of LOPD who discontinued ERT during whole pregnancy. During the whole pregnancy there were no clinical signs of progression of muscle or pulmonary weakness. With careful monitoring of the patient and foetus, and planned delivery, a healthy baby girl was born. ERT was reintroduced 6 months after delivery with premedication (corticosteroids and antihistamines) for the first application, with no allergic reaction noted.
Conclusion: In this patient with well-controlled LOPD, ERT was safely discontinued during pregnancy without disease worsening. The risks of ERT in pregnancy outweighed the potential complications of well-controlled disease. The final decision should be made with an individual approach for each patient by a multidisciplinary team.

KEYWORDS

Late onset Pompe disease, pregnancy, enzyme replacement therapy, muscle weakness

LEARNING POINTS

INTRODUCTION

Pompe disease (PD), or glycogen storage disease type II, is an autosomal recessive metabolic disorder caused by mutations in the acid alpha-glucosidase (GAA) gene, resulting in a deficiency of the same enzyme and glycogen buildup in tissues[1]. The disease has two forms: infantile onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). IOPD has more severe cardiac involvement with hypertrophic cardiomyopathy, hypotonia, and respiratory insufficiency, and is generally fatal within the first year of life if not treated. LOPD is largely a muscle illness that progresses slowly. LOPD can appear anytime from childhood to late adulthood. It has a pattern of symmetric limb-girdle muscular weakness. The weakness is accompanied by diaphragmatic involvement, leading to respiratory insufficiency early in the course of the disease. The estimate of the incidence is roughly 1/40,000 overall with around 3/4 of the cases being LOPD and 1/4 being IOPD[2]. The therapeutic options for LOPD are primarily aimed at treating the underlying enzyme deficit and managing symptoms. The mainstay of treatment is enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase, such as alglucosidase alfa, which reduces glycogen buildup in tissues and delays disease development. Supportive therapies such as physical therapy, respiratory care, and nutritional support are critical for improving muscular function, maintaining mobility, and controlling respiratory difficulties[1,3]. Adjunctive experimental therapies, such as next-generation ERTs, chaperone therapy, and gene therapy, are being investigated to improve therapeutic efficacy and address present ERT limitations, such as the inability to pass the blood-brain barrier[3]. The combination of LOPD with pregnancy presents distinct complications for both patients and healthcare professionals. Given that most women give birth before the diagnosis, pregnancy in women with active LOPD treatment is a relatively rare and could increase disease symptoms. Pregnancy is associated with increased metabolic needs, changes in respiratory mechanics and could impact skeletal muscle function[4]. LOPD during pregnancy necessitates a multidisciplinary approach due to the unique physiological changes that can exacerbate disease symptoms. Key considerations include regular monitoring of respiratory function, since diaphragmatic weakness may deteriorate due to increased intra-abdominal pressure in later trimesters, necessitating pulmonary function testing and, if necessary, nighttime ventilator assistance. Furthermore, musculoskeletal changes and greater physical demands may worsen muscle weakness, emphasizing the need for physical therapy and mobility support. A complete delivery plan should include considerations for specialized anaesthetic methods and respiratory support during labour and postpartum recovery[4].

CASE DESCRIPTION

We present the case of a 31-year-old pregnant patient with late-onset Pompe disease, diagnosed at the age of 16. She was born from a first pregnancy complicated by maternal hypertension, but had a nor-mal birth weight, height, and Apgar score. Her neonatal and infant periods were uneventful, and psy-chomotor development proceeded normally. During her early school years, she began to experience pronounced fatigue during prolonged running and noticed she lagged behind her peers. The initial sus-picion of disease arose following elevated liver transaminase levels (aspartate transaminase, AST 114 U/l, alanine transaminase, ALT 90 U/l) and significantly increased creatine kinase (CK) levels (~1000 U/l). A thorough neurological evaluation led to a diagnosis of metabolic myopathy. Laboratory results revealed severely reduced alpha-glucosidase activity in lymphocytes. Genetic testing confirmed com-pound heterozygosity for the IVS1-13T>G mutation on one allele and the 2501delCA mutation on the other. She began ERT with alglucosidase alfa in the summer of 2010. She transitioned to adult care and had since received biweekly ERT for 14 years without complications. Annual check-ups showed no signs of disease progression. Pulmonary function tests and the 6-minute walk test remained within normal ranges. Manual muscle testing revealed only mild involvement of the trunk muscles. CK levels remained between 300–500 U/l, and myoglobin levels were <90 ng/ml.

The patient experienced no fertility issues, had no history of miscarriage, and conceived naturally while on ERT. Upon pregnancy confirmation at 9 weeks, a mutual decision was made to pause ERT and closely monitor both the patient and foetus. A multidisciplinary team, including a gynaecologist, was formed to oversee the pregnancy. Throughout the pregnancy, no foetal abnormalities were detect-ed. The patient remained clinically stable, reporting no muscle weakness or respiratory difficulties, and did not require assistive devices or respiratory support. Despite her stable condition, a caesarean sec-tion was planned at 38 weeks due to the breech position of the foetus. A healthy baby girl was deliv-ered, weighing 2730 grams and measuring 48 cm, with an Apgar score of 10/10. The patient recovered well from general anaesthesia and had an uncomplicated postpartum course, including successful new-born care. She chose to breastfeed for 6 months. ERT was reintroduced 6 months postpartum, with premedication (corticosteroids and antihistamines) administered before the first infusion. No allergic reactions occurred.

DISCUSSION

Studies have not demonstrated a higher rate of pregnancy, delivery, or birth complications in women with LOPD compared to the general population[5]. However, pregnancy places increased demand on the respiratory system, which may pose challenges for women with PD, particularly those with underlying respiratory muscle weakness. Additionally, adequate muscle strength is essential for labour and delivery, and progressive muscle weakness associated with PD can compromise this process. In such cases, ERT plays a crucial role in stabilizing and improving muscle function. In most reported cases of LOPD, the diagnosis of the disease was made after pregnancy, so assessing the impact of the disease on pregnancy is difficult. Unfortunately, it is well known that the symptoms of the disease themselves begin a long time before the final diagnosis is made. Goker-Alpan et al.[4] described a cohort of 25 women with LOPD, 80% of whom were diagnosed post-pregnancy. Some of them reported postpartum fatigue as one of the earliest symptoms of the disease. One patient conceived on ERT and continued treatment throughout pregnancy. The pregnancy was complicated with worsening of muscle weakness during the third trimester, which led to the recommendation to continue ERT during a subsequent pregnancy as well[4].

To date, there are fewer than 30 reports in the literature of pregnancy outcomes in women with PD (Table 1). Most involve patients with LOPD who continued ERT throughout pregnancy[6-8]. These studies generally suggest that ERT is safe during pregnancy, though individual responses vary. Holbeck-Brendel et al.[6] reported the case of a 25-year-old woman with mildly symptomatic LOPD who discontinued ERT during the first trimester due to concerns about potential effects on organogenesis. The ERT was restarted again at 16 weeks and continued without complications. Despite that, at 37 weeks sudden muscle weakness and exhaustion appeared. Although caesarean section was planned, the patient spontaneously went into labour. A healthy baby was born, but the postpartum period was complicated by prolonged muscle weakness which persisted for 3 months[6].

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Table 1. Published case reports of pregnant women with Pompe disease.

On the other hand, most case reports describe continued ERT throughout pregnancy without clinical worsening[7,9]. De Vries et al.[9] addressed concerns about the safety of breastfeeding while on ERT. By measuring the concentration of alglucosidase alpha in the breast milk they concluded that 24 hours after ERT there is no enzyme activity in breast milk, indicating that breastfeeding during ERT is safe[9]. The European Reference Network for Metabolic Diseases recommends continuation of ERT during pregnancy as there are several reports on safe usage and the absence of embryo-foetal toxicity in animal studies[10]. It also reports that cessation of ERT during pregnancy may result with an increased risk of allergic reaction upon reintroduction[10]. However, more studies are needed to address safety for the foetus and potential teratogenicity of ERT during pregnancy.

CONCLUSION

Although the guidelines, based on several case reports, advise the continuation of ERT in the pregnant women with PD, given the still insufficient evidence, it is necessary to make the decision on a case-by-case basis. Our case report of a pregnant woman with mild clinical manifestations of LOPD demonstrates how ERT could be temporary discontinued with close monitoring of both mother and foetus, without clinical deterioration. It is important to emphasize that in this particular case, the potential risks associated with ERT were considered to outweigh the risks posed by a well-controlled form of the disease.

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