Disorders In Depth
Because motor conduction velocities are a traditional means to classify CMT patients, Davis et al. (Davis et al., 1977) proposed the term “dominant-intermediate” for patients with dominantly inherited CMT and median motor conduction velocities between 25-45 m/s, which likely included some CMT1X kindreds. Kennerson et al. (Kennerson et al., 2001) adopted this term to accommodate families in which there is uncertainty regarding whether the neuropathy is primarily axonal or demyelinating because affected members have “intermediate” conduction velocities (25-54 m/s in their index family). Note that CMT1X (which is clearly a demyelinating neuropathy in animal models) fits this description, is not usually classified as a DI-CMT. Many families with CMT1B could also be classified as DI-CMT, but this is usually not done, as the wide range of phenotypes caused by dominant MPZ mutations is well described. Similarly, some families with CMT2E, CMT2N, and likely others, could be classified as DI-CMT.
A single family defines this entity, which has been mapped to 10q24.1-q25.1 (Verhoeven et al., 2001). The clinical onset of weakness in before 10 years, and median nerve motor conduction velocities range from 25-45 m/s.
DI-CMTB (OMIM 696482)
Some dominant mutations in Dynamin 2 (DNM2)cause DI-CMTB; these are distinct from other dominant mutations that cause centonuclear myopathy. Dynamin 2 is a GTPase that is required for endocytosis and other cellular functions; it is an essential enzyme and is expressed in all cells. How dominant mutations cause a neuropathy is unknown.
In six kindreds, the age of onset varied from 2-51 years (Claeys et al., 2009). Patients showed progressive, distal weakness and sensory loss that is typical of CMT; in some kindred progression was marked and patients became wheelchair-dependent. Median motor conduction velocities range from 25 m/s to normal (>50 m/s); sensory responses were relatively preserved. Sural nerve biopsies show loss of myelinated axons and clusters of regenerated axons. Teased fibers from one kindred showed shortened myelin internodes; this would be expected to decrease conduction velocity. Two families had associated neutropenia and one family had unusual cataracts.
DI-CMTC (OMIM 608323)
Dominant mutations in Tyrosyl-tRNA Synthase (YARS) cause DI-CMTC. YARS catalyzes the aminoacylation of tyrosine to its tRNA. It is an essential enzyme and is expressed in all cells. How dominant mutations cause a neuropathy is unknown.
Two families have been described (Jordanova et al., 2003). In one, the onset is in the first to second decades, with the progressive development of weakness and sensory loss in distal extremites. The median motor response ranged between 30-40 m/s. Sural nerve biopsies showed aged-related loss of myelinated axons and clusters of regenerated axons. In the other, the onset was between 7 and 59 years, with weakness confined to the distal legs; the median motor velocity ranged from 33 m/s to normal.
Claeys KG, Zuchner S, Kennerson M, Berciano J, Garcia A, Verhoeven K, Storey E, Merory JR, Bienfait HME, Lammens M, Nelis E, Baets J, DeVriendt E, Berneman ZN, DeVeuster I, Vance JM, Nicholson G, Timmerman V, DeJonghe P (2009) Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. Brain 132:1741-1752.
Davis DJF, Bradley WG, Madrid R (1977) The peroneal muscular atrophy syndrome - clinical, genetic, electrophysiological and nerve biopsy studies. 1. Clinical, genetic, and electrophysiological findings and classification. J Génét Hum 26:311-349.
Jordanova A, Thomas FP, Guergue-ltcheva V, Tourney I, Gondim FAA, Ishpekova B, De Vriendt E, Jacobs A, Litvinenko I, Ivanova N, Buzhov B, De Jonghe P, Kremensky I, Timmerman V (2003) Dominant intermediate Charcot-Marie-Tooth type C maps to chromosome 1p34-p35. Amer J Hum Genet 73:1423-1430.
Kennerson ML, Zhu D, Gardner RJM, Storey E, Merory J, Robertson SP, Nicholson GA (2001) Dominant intermediate Charcot-Marie-Tooth neuropathy maps to chromosome 19p12-p13.2. Amer J Hum Genet 69:883-888.
Verhoeven K, Villanova M, Rossi A, Malandrini A, De Jonghe P, Timmerman V (2001) Localization of the gene for the intermediate form of Charcot-Marie-Tooth to chromosome 10q24.1-q25.1. Amer J Hum Genet 69:889-894.