PMP22 – Hereditary neuropathy with liability to pressure palsies

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant episodic neuropathy characterized by recurrent focal nerve palsies, often precipitated by minor compression or trauma. Clinically, patients present with transient sensory loss, muscle weakness, and electrophysiological evidence of multifocal demyelination with tomacula formation in myelinated fibers. The underlying pathology is attributable to reduced dosage of peripheral myelin protein 22 (PMP22), a key structural component of compact myelin in the peripheral nervous system.

Genetic evidence for PMP22 in HNPP is robust. A European collaborative study identified a heterozygous 1.5-Mb deletion encompassing PMP22 in 84% of 156 unrelated HNPP probands (PMID:8800924). Point mutations account for approximately 15% of cases, with diverse variant classes including frameshift, nonsense, splice-site, and missense alleles such as c.297del (p.Gly100fs) in PMP22 (PMID:19830275).

Multiple families demonstrate segregation of PMP22 deletions with HNPP. In a cohort of 13 French families, 28 symptomatic individuals carried the PMP22 deletion, and electrophysiological abnormalities were present even in asymptomatic carriers (PMID:7501152). These data confirm high penetrance and support autosomal dominant inheritance.

Mechanistic studies corroborate haploinsufficiency as the primary mode of pathogenicity. Heterozygous Pmp22 knockout mice (pmp22+/–) exhibit focal hypermyelination and tomacula analogous to human HNPP, with reduced PMP22 expression leading to Schwann cell dysfunction (PMID:9335255). Cellular models further demonstrate impaired PMP22 trafficking and increased proteasomal degradation of mutant protein, reinforcing loss-of-function effects.

Rare variants in PMP22 have elicited debate on pathogenicity. The Thr118Met substitution, once proposed as a recessive CMT1 locus, is found at low frequency in controls and does not consistently correlate with neuropathy, arguing against its role as a primary HNPP marker (PMID:11081809).

Taken together, genetic and functional data establish a definitive association between PMP22 haploinsufficiency and HNPP. The high prevalence of PMP22 deletion, segregation in multiple pedigrees, and concordant animal and cellular phenotypes underpin diagnostic guidelines recommending deletion testing by FISH or multiplex ligation-dependent probe amplification, followed by sequencing for point mutations when deletion is absent.

Key Take-home: Genetic testing for PMP22 copy-number loss and point mutations provides a definitive diagnosis of HNPP, guiding management and genetic counseling.

References

• European Journal of Human Genetics • 1996 • Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study PMID:8800924
• Neurology • 1995 • Clinical, electrophysiologic, and molecular correlations in 13 families with hereditary neuropathy with liability to pressure palsies and a chromosome 17p11.2 deletion PMID:7501152
• Journal of Neuroscience Research • 1997 • Analysis of compound heterozygous mice reveals that the Trembler mutation can behave as a gain-of-function allele PMID:9335255
• Acta Biochimica Polonica • 2009 • A newly identified Thr99fsX110 mutation in the PMP22 gene associated with an atypical phenotype of the hereditary neuropathy with liability to pressure palsies PMID:19830275
• Journal of Neurology • 2000 • PMP22 Thr118Met is not a clinically relevant CMT1 marker PMID:11081809

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