Which nerve biopsy findings are characteristic of hereditary neuropathy with predisposition to pressure palsies (HNPP)?

Updated: Feb 19, 2019
  • Author: Francisco de Assis Aquino Gondim, MD, PhD, MSc, FAAN; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Both motor and sensory fibers in most nerves show segmental demyelination and remyelination; variable, secondary, and axonal loss; and focal thickening of the myelin sheath or tomaculae. [26, 27, 28, 29] Outside of tomaculae, the ratio of axon and fiber diameter (g ratio) is normal. Onion bulb formation and increase in endoneurial connective tissue are limited. Tomaculae are more often perinodal than internodal. Nodes of Ranvier are often obscured, probably by transnodal myelin. Branching and duplication of the mesaxons may be present, and more than one Schwann cell may participate in myelination. [27] Ultrastructurally, tomaculae appear as redundant myelin loops, both external and internal, with intramyelinic folds. Uncompacted myelin is typically rare.

A teased fiber analysis of 37 biopsies found features of demyelination and remyelination as well as tomaculae in all cases. About 23% of fibers were normal, and 52% showed evidence of demyelination or remyelination; 54% had tomaculae with a mean diameter and length of 16.3 µm and 83.7 µm, respectively.

Focal myelin thickening, although a hallmark of HNPP, is not restricted to this condition but occurs to varying degrees with CMT1B, immune-mediated neuropathies, hereditary neuropathies with myelin outfolding, and others, and it can occur experimentally from pressure injury. An issue with important implications for the molecular pathogenesis is the reason for tomaculae formation. In 1971, Ochoa and colleagues explained pressure-induced myelin abnormalities with slippage of myelin lamellae. In HNPP, the genetic defect may disturb adhesion of myelin lamellae and make them susceptible to displacement. The susceptibility of nerve biopsies from patients and PMP22 deletion transgenic mice to artifacts supports the exquisite sensitivity to mechanical forces. Findings suggest that tomaculae are accumulated because of everyday injuries that patients may not notice, whereas more intense or longer injuries displace sufficient myelin lamellae to cause demyelination and conduction block with palsies.

Interestingly, several conditions in which tomaculae occur result from either antibodies binding to proteins in compact myelin carrying the L2/HNK-1 epitope or from genetic defects in the proteins themselves. This is the case for myelin protein zero, PMP22, and myelin-associated glycoprotein; myelin protein zero may be a binding partner for L2/HNK-1. Mutations in these genes and myelin-associated glycoprotein antibodies are also associated with widening of the myelin lamellae. Although altered PMP22 function may play a role in some mutations, PMP22 deletion results in underexpression of PMP22 mRNA that correlates with disease severity, axon diameter, and g ratio but not with myelin thickness, number of tomaculae, or nerve conduction parameters. Mutations of the CX32 gene that are not expressed in compact myelin and do not carry the L2/HNK-1 epitope are not associated with tomacula formation in CMTX.

Myelin proteins expressing or reacting with HNK-1 are crucial in myelin adhesion and tomacula formation. However, why tomaculae, indistinguishable histologically, are associated with liability to pressure palsies in some conditions but not others remains unexplained. Additional genes expressed in peripheral nerve are likely to also be involved because the genes in 2 other conditions with focal myelin thickening, hereditary neurologic amyotrophy, and hereditary motor and sensory neuropathy with myelin outfolding have not been identified, although gene linkages have been established to chromosome arms 17q25 and 11q23, respectively.

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