The dominantly inherited motor and sensory neuropathies: Clinical and molecular advances

Abstract

The rapid advances in the molecular genetics and cell biology of hereditary neuropathy have revealed great genetic complexity. It is a challenge for physicians and laboratories to keep pace with new discoveries. Classification of hereditary neuropathies has evolved from a simple clinical to a detailed molecular classification. However, the molecular classification is not simple to use, as different mutations of the same gene produce a range of phenotypes. The logistics of testing for multiple gene mutations are considerable. This review gives a clinical overview of molecular and clinical advances in the dominant hereditary motor and sensory neuropathies [HMSNs, Charcot-Marie-Tooth (CMT) neuropathy], which account for some 60%-70% of families with CMT. The dominant forms of CMT have cellular mechanisms different from those of recessive forms and are a separate diagnostic challenge, so they are not included in this review. Diagnostic testing requires accurate clinical information and a selective approach to gene screening until the cost of multiple gene mutation screening falls. Accurate molecular diagnosis is critical to genetic counseling. This review concentrates on how molecular information can be used clinically, on how physicians can keep pace with new developments, and on the relevance of this new knowledge to patients.

Experimental Therapeutics in Hereditary Neuropathies: The Past, the Present, and the Future

“…[2][3][4] Particular genetic causes of CMT may also lead to hearing, respiratory, vocal cord, or autonomic impairment. The age of symptom onset and the degree of associated disability range widely, from a childhood requirement for a wheelchair to mild impairment of gait and balance in later life.…”

“…CMT1A stems from a duplication of a 1.5-Mb domain of the PMP22 gene, with PMP22 overexpression in peripheral nerves. [2][3][4] PMP22 overexpressing transgenic mice develop a demyelinating neuropathy, and the animal phenotype depends on the degree of PMP22 expression. 13 A toxic gain of function mediated by PMP22 overexpression is inferred in CMT1A.…”

“…[2][3][4] It influences axon-glial cell interactions and axonal integrity, loss of which is thought to be critical in the progression of CMT1A. [2][3][4] PMP22 overexpression produces ubiquinated PM22 aggregates, impaired proteosomal function, and autophagic profiles in rodent SC cytoplasm. 14 Correction of PMP22 levels in animals leads to improvement of the neuropathy, and is a rational strategy for CMT1A.…”

“…Among CMT, approximately 50% are accounted for by CMT type 1A (CMT1A), due to a duplication within the peripheral myelin protein 22 gene (PMP22). 2,3 Mutations in the gap junction beta 1 gene (GJB1), the myelin protein zero gene (MPZ), and the mitofusin 2 gene (MFN2) account for a substantial proportion of other genetically-definable CMT. 2,3 Some 15% of demyelinating CMT and 70% of axonal CMT await genetic clarification.…”

“…2,3 Mutations in the gap junction beta 1 gene (GJB1), the myelin protein zero gene (MPZ), and the mitofusin 2 gene (MFN2) account for a substantial proportion of other genetically-definable CMT. 2,3 Some 15% of demyelinating CMT and 70% of axonal CMT await genetic clarification. Other hereditary neuropathies include the hereditary sensory and autonomic neuropathies, the familial amyloid polyneuropathies, and multisystem disorders (e.g., lipid storage diseases and inherited ataxias) that have peripheral neuropathy as a major or minor component.…”