Hereditary neuropathies: A pathological perspective

Abstract

Hereditary neuropathies may result from mutations in genes expressed by Schwann cells or neurons that affect selectively the peripheral nervous system (PNS) or may represent a minor or major component of complex inherited diseases that involve also the central nervous system and/or other organs and tissues. The chapter is constantly expanding and reworking, thanks to advances of molecular genetics; nextgeneration sequencing is identifying a plethora of new genes and is revolutionizing the diagnostic approach. In the past, diagnostic sural nerve biopsies paved the way to the discovery and elucidation of major genes and molecular pathways associated to most frequent hereditary motor-sensory neuropathies. Nowadays, a sural nerve biopsy may prove useful in selected cases for the differential diagnosis of an acquired neuropathy when clinical examination, nerve conduction studies, and molecular tests are not sufficiently informative. Skin biopsy has emerged as a minimally invasive window on the PNS, which may provide biomarkers of progression and clues to the physiopathology and molecular pathology of inherited neuropathies. The aim of our review is to illustrate the pathological features of more frequent and paradigmatic hereditary neuropathies and to highlight their correlations with the roles of the involved genes and functional consequences of related molecular defects.

A novel TRMT5 mutation causes a complex inherited neuropathy syndrome: The role of nerve pathology in defining a demyelinating neuropathy

“…These features have not been thoroughly analysed in the other reported mitochondrial demyelinating neuropathies; thus, we cannot conclude whether these abnormalities are specifically associated with the TRMT5 mutations harboured by our patients. Though we observed shared features with diverse CMT de‐or‐dys‐myelinating neuropathies particularly those associated with congenital hypomyelinating phenotypes, such as PMP , MZP and others, 24 our cases differ from many of them by the absence of common features like onion bulbs or basal lamina reduplication.…”

Conduction slowing, conduction block and temporal dispersion in demyelinating, dysmyelinating and axonal neuropathies: Electrophysiology meets pathology

“…102 Six patients had neuropathic pain or prominent sensory symptoms and three showed partial motor CB that, in one case, was reversed by immunomodulation. Nerve biopsy demonstrated, besides 56 the classical CMT changes, excess of lymphocytic infiltration (>100 CD4 + per section) in all patients, active or recent demyelination in four and extensive supepineurial edema in one. Four patients were treated with steroids and/or intravenous immunoglobulin, with variable positive response.…”

“…CMT1X, the second most common form of CMT, is due to mutations of gap junction protein beta-1 (GJB1) gene on chromosome Xq13 that 56 ). (F and G) Mouse model with one of the two PMP22 alleles deleted.…”

“…(D) On teased fibers tomacula (arrows) with a globular or fusiform shape and a length of 30–50 μm are localized to paranodes, bar = 30 μm. (E) At electron microscopy a tomaculum characterized by an abnormally large number of myelin lamellae that fold irregularly surrounding a constricted axon, bar = 2 μm (Reproduced from Cavallaro et al 56 ). (F and G) Mouse model with one of the two PMP22 alleles deleted.…”

“…(E) Teased fibers showing randomly distributed paranodal (arrow) and internodal (arrowheads) demyelination interposed with normally myelinated internodes, (bar = 40 μm). Reproduced with permission from Cavallaro et al 56 …”