Pompe disease is traditionally considered a lysosomal myopathy. However, increasing experimental and clinical evidence suggests involvement of the entire motor unit, including motor neurons, peripheral nerves, neuromuscular junctions, and skeletal muscle. Respiratory impairment is a major cause of morbidity and mortality, and diaphragm dysfunction is frequently observed.

Clinical observations at IRCCS Fondazione Mondino have highlighted neurophysiological abnormalities of the phrenic nerve and diaphragm in patients with Pompe disease and respiratory involvement, sometimes occurring even in the absence of clinically significant limb muscle weakness. These findings suggest that respiratory motor unit dysfunction may represent an important component of the disease phenotype.

This observational study aims to systematically characterize phrenic nerve conduction parameters and diaphragm electromyographic findings in adult patients with genetically confirmed Pompe disease and in patients with unexplained respiratory failure. Retrospective and prospective clinical, neurophysiological, and respiratory data collected during routine clinical care will be analyzed to explore whether phrenic nerve and diaphragm abnormalities may serve as markers of respiratory motor unit involvement in Pompe disease.

This is a non-interventional observational study with a mixed retrospective and prospective cohort design. No experimental treatments, additional diagnostic procedures, or study-specific interventions are introduced. All data derive exclusively from routine clinical evaluations performed as part of standard patient care. Two main populations are included: 1) Adult patients with genetically confirmed Pompe disease undergoing routine neurophysiological and respiratory assessments; 2) Patients with restrictive respiratory failure or unexplained hypoventilation who previously underwent phrenic nerve conduction studies and/or diaphragm electromyography as part of clinical workup, identified retrospectively. The retrospective component consists of systematic review of phrenic nerve conduction studies and diaphragm electromyography performed over previous years in patients with suspected neuromuscular respiratory failure. The prospective component involves standardized collection of neurophysiological and respiratory data obtained during routine follow-up of patients with confirmed Pompe disease.

Neurophysiological assessments include bilateral phrenic nerve motor conduction studies and evaluation of peripheral nerves and limb muscles. Diaphragm needle electromyography is performed only when clinically indicated. Respiratory evaluations include spirometry with forced vital capacity in seated and supine positions, maximal inspiratory and expiratory pressures (MIP/MEP), and, when clinically required, overnight ventilation studies.

The primary outcome is the characterization of phrenic nerve conduction parameters, including motor latency, compound muscle action potential amplitude, and presence or absence of diaphragmatic responses. Secondary outcomes include diaphragm electromyographic patterns, comparison between phrenic nerve and other peripheral nerves, and correlations between neurophysiological parameters and respiratory function.

Data are collected retrospectively from medical records and prospectively during routine clinical visits, pseudonymized, and analyzed descriptively and exploratorily. The study aims to improve characterization of respiratory motor unit involvement in Pompe disease and to evaluate the potential diagnostic contribution of phrenic nerve and diaphragm electrophysiology in patients with unexplained respiratory failure.

Inclusion Criteria:

Age ≥ 18 years.

For the prospective cohort:

• Genetically confirmed diagnosis of Pompe disease.
• Ability to undergo routine neurophysiological and respiratory assessments.
• Written informed consent provided.

For the retrospective cohort:

• History of restrictive respiratory failure or unexplained hypoventilation.
• Availability of previous phrenic nerve conduction studies and/or diaphragm electromyography performed as part of routine clinical evaluation.

Exclusion Criteria:

- Age < 18 years.

For the prospective cohort:

• Conditions preventing completion of neurophysiological assessments (e.g., inability to maintain required positioning or relevant clinical contraindications).
• Known primary phrenic nerve injury (e.g., postsurgical phrenic palsy or documented traumatic phrenic neuropathy).
• Presence of other neuromuscular disorders potentially confounding data interpretation.
• Refusal or inability to provide informed consent.

For the retrospective cohort:

• Incomplete or technically non-interpretable neurophysiological examinations.
• Previously established respiratory or neuromuscular diagnoses fully explaining respiratory impairment.
• Cases requiring additional clinical information for study purposes when patient consent for contact or data completion cannot be obtained.

Approximately 20 adult patients with genetically confirmed Pompe disease are expected to be prospectively included. In addition, a retrospective review of approximately 150 previously performed phrenic nerve conduction studies and diaphragm electromyography examinations in patients with unexplained respiratory failure will be conducted. The prospective enrollment refers exclusively to newly evaluated Pompe disease patients, while the retrospective component is based on existing clinical records and neurophysiological data