Loss of function MPZ mutation causes milder CMT1B neuropathy

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• Charcot-Marie-Tooth disease type 1B (CMT1B), the second leading cause of CMT1, is primarily caused by over 200 mutations in Myelin Protein Zero (MPZ).
• Many MPZ mutations result in neuropathy through toxic gain-of-function mechanisms, including ER retention, Unfolded Protein Response (UPR) activation, and disrupted myelin compaction.
• While the loss-of-function effects of MPZ in heterozygous Mpz +/- null mice are well-documented, human MPZ haploinsufficiency consequences remain largely unknown.

Purpose of the Study:

• To investigate the clinical and electrophysiological consequences of MPZ haploinsufficiency in humans.
• To characterize the neuropathy resulting from heterozygous MPZ mutations predicted to cause premature termination and nonsense-mediated decay.
• To establish a human correlate to the neuropathy observed in heterozygous Mpz null mice.

Main Methods:

• Clinical evaluation of six patients from different families with heterozygous MPZ mutations (p.Tyr68Ter or p.Asp104fs).
• Electrophysiological assessments to evaluate nerve function.
• Analysis of clinical presentation, symptom onset, and neurological examination findings, including deep tendon reflexes and CMT Neuropathy Score (CMTNSv2).

Main Results:

• All six patients exhibited MPZ haploinsufficiency due to mutations predicted to cause premature termination.
• The predominant clinical feature was sensory ataxia, with only mild weakness in five patients.
• Symptoms manifested in adulthood, deep tendon reflexes were absent in all patients, and only one patient had a CMTNSv2 >5.

Conclusions:

• MPZ haploinsufficiency in humans results in a mild, predominantly large-fiber sensory neuropathy, consistent with loss-of-function.
• This neuropathy serves as a human model analogous to that observed in heterozygous Mpz null mice.
• Therapeutic strategies successful in Mpz-deficient mice may be applicable for clinical trials in patients with similar MPZ loss-of-function mutations.