Inherited neuropathies: clinical overview and update

Abstract

Inherited neuropathy is a group of common neurologic disorders with heterogeneous clinical presentations and genetic causes. Detailed neuromuscular evaluations, including nerve conduction studies, laboratory testing, and histopathologic examination, can assist in identification of the inherited component beyond family history. Genetic testing increasingly enables definitive diagnosis of specific inherited neuropathies. Diagnosis, however, is often complex, and neurologic disability may have both genetic and acquired components in individual patients. The decision of which genetic test to order or whether to order genetic tests is often complicated, and the strategies to maximize the value of testing are evolving. Apart from rare inherited metabolic neuropathies, treatment approaches remain largely supportive. We provide a clinical update of the various types of inherited neuropathies, their differential diagnoses, and distinguishing clinical features (where available). A framework is provided for clinical evaluations, including the inheritance assessment, electrophysiologic examinations, and specific genetic tests.

Keywords: ataxia; cerebellum; neuropathy; spinocerebellar; triplet repeats.

FIGURE 1

Molecular targets of inherited neuropathy illustrate the diverse pathogenesis of inherited neuropathies.

FIGURE 2

Demyelinating neuropathy in the absence of dispersion and conduction block favors an inherited PMP22 duplication over acquired chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The electrophysiologic differences relate to the observed pathologic findings in each case where uniform myelin lamella collagen thickening (onion bulbs) with PMP22 duplications differs from the mixed onion bulbs of CIDP; the latter produces variable conduction velocities between fibers with observed dispersion and potential conduction blocks.

FIGURE 3

The pattern of inheritance and nerve conduction details are useful in limiting the candidate genes in genetic testing of varieties of motor and sensory neuropathies. Retrospective cohort studies with comprehensive gene sequencing support the utility of some genetic tests (bold) as having the highest probability of positive testing.^,,

FIGURE 4

Nerve biopsy assists diagnosis of familial amyloid polyneuropathy. Paraffin-embedded sural nerve stained with (A) methyl violet with characteristic metachromatic staining of amyloid, (B) Congo red with amyloid congophilia, and (C) apple-green birefringence shown under polarized light, later determined by laser dissection of the infiltrate and mass spectro-photometric analysis to be transthyretin amyloidosis due to the Val30Met mutation.

FIGURE 5

A sural nerve biopsy in a child that led to genetic testing and discovery of the gigaxonin mutation in giant axonal neuropathy, which had not been considered previously. (A) Osmium-stained teased nerve fiber preparation demonstrates neurofilament accumulations characteristic of the disorder with (B) light microscopy epoxy-embedded methyl blue–stained nerve showing the characteristic axonal enlargements (C) confirmed on electron micrographs to be localized to intermediate filament inclusions and myelin lamella thickening.

FIGURE 6

Histopathologic evaluation of sural nerve in a patient with an unexplained axonal polyradiculoneuropathy where frequent polyglucosan bodies led to enzymatic and DNA confirmation of autosomal recessive adult-onset polyglucosan-body disease (APBD). (A) Teased-fiber nerve preparation stained by osmium showing the characteristic homogeneous axonal glycogen deposits of APBD. (B) Basophilic staining of polyglucosan by hematoxylin and eosin. (C) Epoxy-embedded nerve having the characteristic targetoid features of APBD.

FIGURE 7

Myelin abnormalities are distinct between patients with HMSN 1A caused by duplications of PMP22 [onion bulbs (A) teased fibers and (B) high-power electron micrograph] and those found in HNPP [tomaculae (C) teased fibers and (D) high-power electron micrograph] caused by deletions in PMP22. In (A) and (C), the top teased fiber shown is a normal control. Onion bulbs have characteristic generalized nerve fiber thickening from exuberant collagen lamellae with loss of nodal definition. In contrast, tomaculae have focal myelin thickening caused by localized redundant loops of myelin, creating the typical tomaculous swellings.