Phrenic Nerve and Diaphragm Electrophysiology in Pompe Disease

Official title

Electrophysiological Study of the Phrenic Nerve and Diaphragm in Pompe Disease: Retrospective and Prospective Cohort Analysis

Overview

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.

Detailed description

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.

Primary outcome measures

• Motor latency (ms) [Time frame: Baseline (at first available assessment, retrospective or prospective)]
• Compound muscle action potential (CMAP) amplitude (millivolts) [Time frame: Baseline (at first available assessment, retrospective or prospective)]
• Presence or absence of diaphragmatic responses [Time frame: Baseline (at first available assessment, retrospective or prospective)]

Secondary outcome measures (4)

• Neurogenic pattern [Time frame: Baseline (at time of clinical assessment when EMG is performed)]
• Myopathic pattern [Time frame: Baseline (at time of clinical assessment when EMG is performed)]
• Mixed pattern [Time frame: Baseline (at time of clinical assessment when EMG is performed)]
• Normal pattern [Time frame: Baseline (at time of clinical assessment when EMG is performed)]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Study design

Observational model

Case-only

Study locations

Italy · 1 center

• Translational Neurophysiology — Pavia

Publications

• DeRuisseau LR, Fuller DD, Qiu K, DeRuisseau KC, Donnelly WH Jr, Mah C, Reier PJ, Byrne BJ. Neural deficits contribute to respiratory insufficiency in Pompe disease. Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9419-24. doi: 10.1073/pnas.0902534106. Epub 2009 May 27. PMID 19474295
• Falk DJ, Todd AG, Lee S, Soustek MS, ElMallah MK, Fuller DD, Notterpek L, Byrne BJ. Peripheral nerve and neuromuscular junction pathology in Pompe disease. Hum Mol Genet. 2015 Feb 1;24(3):625-36. doi: 10.1093/hmg/ddu476. Epub 2014 Sep 12. PMID 25217571
• ElMallah MK, Pagliardini S, Turner SM, Cerreta AJ, Falk DJ, Byrne BJ, Greer JJ, Fuller DD. Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines. Am J Respir Cell Mol Biol. 2015 Sep;53(3):326-35. doi: 10.1165/rcmb.2014-0374OC. PMID 25569118
• Turner SMF, Falk DJ, Byrne BJ, Fuller DD. Transcriptome assessment of the Pompe (Gaa-/-) mouse spinal cord indicates widespread neuropathology. Physiol Genomics. 2016 Nov 1;48(11):785-794. doi: 10.1152/physiolgenomics.00075.2016. Epub 2016 Sep 9. PMID 27614205
• Oliveira Santos M, Domingues S, de Campos CF, Moreira S, de Carvalho M. Diaphragm weakness in late-onset Pompe disease: A complex interplay between lower motor neuron and muscle fibre degeneration. J Neurol Sci. 2024 May 15;460:123021. doi: 10.1016/j.jns.2024.123021. Epub 2024 Apr 18. PMID 38653115
• Spiesshoefer J, Henke C, Kabitz HJ, Brix T, Gorlich D, Herkenrath S, Randerath W, Young P, Boentert M. The nature of respiratory muscle weakness in patients with late-onset Pompe disease. Neuromuscul Disord. 2019 Aug;29(8):618-627. doi: 10.1016/j.nmd.2019.06.011. Epub 2019 Jun 22. PMID 31327549

Identifiers

NCT: NCT07664930 · POMPE-PHRENIC

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗