Multidimensional assessment of diaphragmatic dysfunction in late-onset Pompe disease: a prospective cohort study

Late-onset Pompe disease (LOPD) often leads to progressive respiratory failure due to diaphragmatic involvement. Conventional pulmonary function tests frequently fail to detect early respiratory muscle weakness. We conducted a five-year prospective cohort study of 15 genetically confirmed LOPD patients to evaluate diaphragmatic function using a multidimensional approach that included spirometry, inspiratory/expiratory pressures (MIP/MEP), sniff nasal inspiratory pressure (SNIP), arterial blood gases, and diaphragmatic ultrasound. Data were analyzed using generalized linear mixed models. Forced vital capacity (FVC) declined progressively (− 1.05% per visit, p = 0.010), while diaphragmatic thickening fraction (TF, − 3.46% per visit, p < 0.0001), SNIP (− 2.53 cmH₂O per visit, p = 0.003), and MIP (− 3.56% per visit, p < 0.001) showed earlier and steeper declines. TF and SNIP were significantly more sensitive than FVC in detecting early respiratory involvement (p < 0.05). Patients receiving enzyme replacement therapy (ERT) had slower functional decline, with significantly higher SNIP values (p = 0.003). One patient developed symptomatic diaphragmatic weakness despite preserved FVC. SNIP and TF are more sensitive than FVC for early detection of respiratory dysfunction in LOPD and may allow earlier initiation of enzyme replacement therapy and respiratory support.