Study Examines Respiratory Muscle Weakness in Ambulatory CMT1A Patients

Even if not experiencing overt clinical signs, Charcot-Marie-Tooth Disease Type 1A (CMT1A) patients able to walk show respiratory muscle weakness associated with phrenic nerve damage, according to a new study.

The findings in that study also revealed that having lower diaphragm strength and function is associated with more advanced disease.

The research, “Phrenic nerve involvement and respiratory muscle weakness in patients with Charcot‐Marie‐Tooth disease 1A,” was published in the Journal of the Peripheral Nervous System.

Although both phrenic nerve involvement — referring to a nerve that descends from the neck to the diaphragm — and respiratory muscle weakness have been described in severe cases of CMT, evidence is still lacking,  particularly in ambulatory patients.

Researchers from Germany addressed these shortcomings by studying whether diaphragm dysfunction occurs without respiratory muscle weakness in ambulatory patients with CMT1A (the most common CMT subtype), while also determining if such dysfunction may be due to motor nerve damage (neuropathy) of the phrenic nerves.

Nineteen patients (13 women, mean age 47 years) underwent spiromanometry to assess lung function, diaphragm ultrasound, and magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots, an approach intended to overcome the limitations of previously used volitional tests (those dependent on one’s will).

Also, 15 patients underwent recordings of their diaphragm compound muscle action potentials (CMAP) — the muscle response to nerve fiber stimulation —  and of diaphragm motor-evoked potential (MEP) (electrical activity) after magnetic stimulation of the brain’s cortex. Twelve patients underwent invasive measurements of twitch transdiaphragmatic and gastric pressures, the gold standard for assessing diaphragm strength.

Disease severity was assessed with the CMT Neuropathy Scale version 2, which combines self-reported symptoms, motor signs, and electrical activity findings. All patients also completed the Medical Research Council Breathlessness Scale.

Ulnar nerve (arm) conduction measurements in 17 patients revealed marked reduction of nerve conduction velocity in comparison to controls. No patient revealed hypercapnia, which refers to increased blood levels of carbon dioxide and indicates lung disease.

Compared to the controls, CMT1A patients showed significantly lower forced vital capacity (FVC, the amount of air exhaled after a deep breath), peak expiratory flow, peak cough flow, and maximum inspiratory and expiratory pressures, all of which are lung function parameters.

Lower (worse) FVC scores correlated with greater disease severity. Higher maximum inspiratory pressure was associated with greater ulnar nerve CMAP amplitude, or signal strength.

Both CMAP and MEP latencies in the diaphragm were delayed in patients compared to controls. People with CMT1A also revealed lower diaphragm excursion, diaphragm thickening ratio (DTR) — calculated by dividing the thickness with the maximum amount of air filling the lungs by the air present at the end of expiration — and twitch gastric pressure. Of note, diaphragm excursion refers to its movement during breathing and may be impaired in people with phrenic nerve palsy.

The data further showed that lower DTR values were linked with greater disease severity.

“Thus, the present data underline that signs and symptoms of respiratory muscle involvement deserve special attention in patients with CMT1A, especially if advanced disease is present,” the researchers wrote.

The study was part of a clinical trial (NCT03032562) intended to assess respiratory muscle strength and function in neuromuscular disorders and chronic obstructive pulmonary disease.