New insights into GI manifestations in late-onset Pompe disease: Lessons from the bench and bedside

Abstract

There is growing evidence of smooth muscle involvement in Pompe disease with reports of life-threatening basilar artery and ascending aorta aneurysms, difficulties in swallowing and speech, and gastrointestinal (GI) involvement. We studied the histopathology of the GI tract in Pompe mice (GAAKO 6neo/6neo), and impact of enzyme replacement therapy (ERT) with alglucosidase alfa. We evaluated adult patients with late-onset Pompe disease (LOPD) using Patient-Reported Outcomes Measurements Information System - Gastrointestinal (PROMIS-GI) symptom scales, and a GI-focused medical history. Pompe mice showed extensive and progressive glycogen accumulation in the smooth and striated muscles throughout the GI system (from tongue to rectum), and in the Aurbach's plexus, as early as age 3 months. Long-term (6 months) enzyme replacement therapy (ERT; 20 mg/kg biweekly, age at initiation 2 months) was more effective to clear the glycogen accumulation than short-term (5 weeks) ERT (20 mg/kg weekly, age at initiation 3 months) in Pompe mice. We enrolled 58 patients with LOPD (median age: 51.55 ± 15.5 years, range: 18–79 years; 35 females; 53 on ERT, 4 ERT naïve, 1 off ERT for 3 years; median duration of ERT: 5.5 years; range: 2 months-13 years). The PROMIS-GI (cross-sectional) data from 52 patients suggested a high prevalence of gas/bloating (98%), reflux (94%), constipation (84%), diarrhea (72%), belly pain (68%), nausea/vomiting (61%), disrupted swallowing (54%), and bowel incontinence (40%). Onset of GI symptoms ranged from childhood to seventh decade of life. Longitudinal data (n = 19, followed over 16 months) revealed that most patients had either no change or worsening GI symptoms over time, even after ERT initiation. This study sheds light on the significant disease burden caused by GI manifestations. Clinicians should evaluate GI manifestations during routine clinical visits, and use quantitative tools such as PROMIS-GI measures. The study also highlights the need for next generation therapies that target the smooth muscles.