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October 29, 2021

Multiple Mononeuropathy

Multiple mononeuropathy

This 25-year-old patient presented with clinical features of mononeuropathy multiplex (multifocal neuropathy). Serologic studies showed normal inflammatory markers. The nerve biopsy was performed to evaluate for vasculitis. The patient was treated with steroids prior to biopsy.

 

Based on the following images (see Figures 1 – 5) what additional testing would be most warranted?

A. ANCA

B. Del/Dup PMP22

C. Amyloid subtyping

D. Hemoglobin A1C

 

Multiple Mononeuropathy

Note the two axons that appear enlarged (thick arrows) compared to other myelinated axons within the nerve fascicle

 

Multiple Mononeuropathy

Note the several axons have thicker myelin sheaths (thick arrows) compared to other large-diameter myelinated axons within the nerve fascicle.

Also, note increased numbers of thinly myelinated large diameter axons (several marked by small arrows) scattered throughout the nerve fascicle.

An example of a normal large-diameter axon is marked by an asterisk.

 

Note single large diameter axon with abnormally thick (redundant) myelin sheath indicated by arrow.

 

Mononeuropathy

Many axons showed tomacula: segmental “sausage-like” areas of abnormally thick myelin.

 

Answer: Del/Dup PMP22

In the context of this patient’s clinical history, the morphologic features are most consistent with Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) most commonly caused by heterozygous PMP22 gene deletion (~80%). Small point mutations may less commonly cause this disorder (~20%). Patients with HNPP show recurrent motor and sensory mononeuropathies at sites of minor trauma or entrapment.  They can also present with multifocal conduction abnormalities (mononeuropathy multiplex) that mimic mononeuritis multiplex seen in vasculitis. 

In contrast to HNPP, Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by PMP22 gene duplication.

These two genetic conditions illustrate gene dosage or copy number as a mechanism of disease. Both follow an autosomal dominant pattern of inheritance.

The PMP22 gene encodes the protein “peripheral myelin protein 22” which is felt to be involved in the stability and organization of the myelin sheath.

Why were the other answers wrong?

ANCA (Anti-Neutrophilic Cytoplasmic Autoantibody) is associated with ANCA-Associated Vasculitis (AAV)

No amyloid-type material is seen in this case, and therefore amyloid subtyping would not be of utility

While peripheral neuropathy is very common in diabetes, the morphologic features shown in this case are not typical for diabetic polyneuropathy, and therefore Hemoglobin A1C would not be of utility

References

https://www.ncbi.nlm.nih.gov/books/NBK1392/pdf/Bookshelf_NBK1392.pdf

van Paassen BW, van der Kooi AJ, van Spaendonck-Zwarts KY, Verhamme C, Baas F, de Visser M. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies. Orphanet J Rare Dis. 2014;9:38. Published 2014 Mar 19. doi:10.1186/1750-1172-9-38

Salpietro V, Manole A, Efthymiou S, Houlden H. A Review of Copy Number Variants in Inherited Neuropathies. Curr Genomics. 2018 Sep;19(6):412-419. doi: 10.2174/1389202919666180330153316. PMID: 30258273; PMCID: PMC6128387

Li J, Parker B, Martyn C, Natarajan C, Guo J. The PMP22 gene and its related diseases. Mol Neurobiol. 2013 Apr;47(2):673-98. doi: 10.1007/s12035-012-8370-x. Epub 2012 Dec 7. PMID: 23224996; PMCID: PMC3594637

Mittendorf KF, Marinko JT, Hampton CM, et al. Peripheral myelin protein 22 alters membrane architecture. Sci Adv. 2017;3(7):e1700220. Published 2017 Jul 5. doi:10.1126/sciadv.1700220