Genetics

HNPP is most often caused by the loss of one copy (a deletion) of the PMP22 gene on chromosome 17, but it may also be caused by a genetic change within this gene (point mutation). It is inherited in an autosomal dominant manner. Approximately 20% of individuals with HNPP have the disorder as the result of a de novo PMP22 pathogenic variant. The diagnosis is made based on the symptoms present, electrodiagnostic testing, and genetic testing.

HNPP is thought to be underdiagnosed, and it may be misdiagnosed. Cfr. prevalence, misdiagnoses

The disorder is inherited autosomal dominantly, which means that each child of an affected individual is at a 50% risk of inheriting HNPP.
Genetic counseling could be done for individuals having the disease and informing them that there is 50% risk of passing the mutation to offspring.

Source: https://www.ncbi.nlm.nih.gov/books/NBK1392/: Chrestian N. Hereditary Neuropathy with Liability to Pressure Palsies. 1998 Sep 28 [updated 2020 Aug 27]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 20301566.

You can only be sure of the diagnosis with a genetic test. Notice: Sometimes the deletion isn't well detected (with a technique called multiplex PCR (source: https://www.cmtausa.org/understanding-cmt/types-of-cmt/hereditary-neuropathy-with-liability-to-pressure-palsies/).

Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease (source: https://pubmed.ncbi.nlm.nih.gov/38481354/: Record CJ, Pipis M, Skorupinska M, Blake J, Poh R, Polke JM, Eggleton K, Nanji T, Zuchner S, Cortese A, Houlden H, Rossor AM, Laura M, Reilly MM. Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease. Brain. 2024 Mar 14:awae064. doi: 10.1093/brain/awae064. Epub ahead of print. PMID: 38481354. ) 

PMP22

The PMP22 gene provides instructions for making a protein called peripheral myelin protein 22. It is a component of myelin, the protective substance that covers nerves and promotes the efficient transmission of nerve impulses.

Within Schwann cells, PMP22 plays a crucial role in the development and maintenance of myelin. Studies suggest that the PMP22 protein is particularly important in protecting nerves from physical pressure, helping them restore their structure after being pinched or squeezed (compressed). Compression can interrupt nerve signaling, leading to the sensation commonly referred to as a limb "falling asleep." The ability of nerves to recover from normal, day-to-day compression, for example when sitting for long periods, keeps the limbs from constantly losing sensation. The PMP22 gene also plays a role in the growth of Schwann cells and the process by which cells mature to carry out specific functions (differentiation).

Source: https://medlineplus.gov/genetics/gene/pmp22/

Formation of tomacula

TO DO
Source: https://academic.oup.com/hmg/article-abstract/29/10/1689/5827383: Harrison Pantera, Bo Hu, Daniel Moiseev, Chris Dunham, Jibraan Rashid, John J Moran, Kathleen Krentz, C Dustin Rubinstein, Seongsik Won, Jun Li, John Svaren, Pmp22 super-enhancer deletion causes tomacula formation and conduction block in peripheral nerves, Human Molecular Genetics, Volume 29, Issue 10, 15 May 2020, Pages 1689–1699, https://doi.org/10.1093/hmg/ddaa082 

The peripheral nervous system

HNPP affects primarily the peripheral nervous system. What it is, is well explained in the video below: