Disorders In Depth
AR-CMT2: Autosomal Recessive Axonal Neuropathy (or CMT2B1-5)
These are all rare disorders; most have been found just a few families. The term, “severe, early-onset axonal neuropathy” (SEOAN), describes well the individuals with AR-CMT2C/CMT2B3, AR-CMT2D/CMT2B4, and AR-CMT2E/CMT2B5.
AR-CMT2A/CMT2B1 (OMIM 605588)
Recessive mutations of LMNA cause AR-CMT2A/CMT2B1. LMNA encodes a component of the nuclear envelope, and dominant LMNA mutations are associated with a variety of syndromes.
Most affected individuals are from north Africa, where the Arg298Cys mutation is common (Tazir et al., 2004). For this mutation, the clinical age of onset typically ranges from 12 to 24 years. Progression can be strikingly rapid: forearm muscles may be affected within months after onset, and pelvic girdle weakness with 4 years. Some patients, however, do not progress to have proximal limb involvement. Electrophysiological studies are fully consistent with an axonal neuropathy affecting myelinated motor and sensory axons.
AR-CMT2B/CMT2B2 (OMIM 605589)
Recessive mutations in MED25 cause AR-CMT2B/CMT2B2 (Leal et al., 2009). MED25 is a subunit of the human activator-recruited co-factor, whose role in neuron biology remains to be determined.
Affected individuals had clinical onset between 28 and 42 years, and developed weakness and atrophy in the distal muscles of the arms and legs, as well as distal sensory loss. Sensory nerve responses were typically absent, and motor conductions showed variable degrees of slowing.
AR-CMT2C/CMT2B3 (no OMIM)
Recessive mutations in GDAP1 cause AR-CMT2C/CMT2B3, although this has yet to be officially recognized in OMIM (and given a number). GDAP1 is a protein that is localized to the outer membrane of mitochondria, and is required for normal fission (Niemann et al., 2005).
Although some recessive GDAP1 mutations cause milder phenotypes, individuals with AR-CMT2C/CMT2B3 have an early onset (typically by age 2), progressive neuropathy that results in severe proximal and distal weakness, and may cause inability to walk and vocal cord paresis (Bouhouche et al., 2007). Sensory nerve responses are absent, and motor nerve responses show variable degrees of slowing. Other GDAP1 mutations cause dominant axonal CMT (CMT2K). Whether other recessive GDAP1 mutations truly cause a primary, demyelinating neuropathy (CMT4A) needs to be clarified.
AR-CMT2D/CMT2B4 (no OMIM)
Recessive mutations in MFN2 cause AR-CMT2C/CMT2B4 (Nicholson et al., 2008), although this has yet to be officially recognized in OMIM (and given a number). MFN2 is a protein that is localized to the outer membrane of mitochondria, and is required for normal fusion (see section on CMT2A2).
The clinical onset is by age 3, and the neuropathy progresses to cause profound distal weakness, atrophy, and sensory loss. Sensory responses are absent and motor responses are minimally slowed.
AR-CMT2E/CMT2B5 (no OMIM)
Recessive mutations in NEFL cause CMT2B5 (Yum et al., 2009), although this has yet to be officially recognized in OMIM (and given a number). NEFL encodes the light subunit, one of three subunits that comprise neurofilaments, which are the predominant cytoskeletal element in axons.
The neuropathy can be clinically detected before age 2, with hypotonia and delayed motor milestones. Weakness and sensory loss progress through childhood, leading to severe distal and even proximal weakness and sensory loss. The sensory nerve responses disappear during childhood, and the motor and sensory responses are slowed well into the demyelinating range (~20 m/s). Nerve biopsies show no large myelinated axons, and axons lack neurofilaments. Based on the analysis of mice and quail that have recessive Nefl mutations, the likely basis of slowed conduction is that the myelinated axons fail to enlarge normally during development; it is not a true demyelinating neuropathy.
Giant Axonal Neuropathy (OMIM )
Recessive mutations in Gigaxonin (GAN) cause giant axonal neuropathy (Bomont et al., 2000). Gigaxonin is required for the ubiquitination and degradation of microtubule-associated protein 1B light chain (Yang et al., 2007).
Originally patients with Giant Axonal Neuropathy were described as having a childhood onset of an axonal neuropathy, with assoicated upper motor neuron and cerebellar findings, and kinky hair. Some patients, however, have a much milder disease, with few clinical CNS findings, so this disorder is discussed here. Electrophysiology demonstrates distal axonal loss, and nerve biopsies reveal the characteristic finding of enlarged axons containing large bundles of neurofilaments (Yang et al., 2007).
Bomont P, Cavalier L, Blondeau F, Hamida CB, Belal S, Tazir M, Demir E, Topaloglu H, Korinthenberg R, Tuysuz B, Landrieu P, Hentati F, Koenig M (2000) The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy. Nat Genet 26:370-374.
Bouhouche A, Birouk N, Azzedine H, Benomar A, Durosier G, Ente D, Muriel MP, Ruberg M, Slassi I, Yahyaoui M, Dubourg O, Ouazzani R, Le Guern E (2007) Autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2): phenotype-genotype correlations in 13 Moroccan families. Brain 130:1062-1075.
Leal A, Huehne K, Bauer F, Sticht H, Berger P, Suter U, Morera B, Del Valle G, Lupski JR, Ekici A, Pasutto F, Endele S, Barrantes R, Berghoff C, Berghoff M, Neundorfer B, Heuss D, Dorn T, Young P, Santolin L, Uhlmann T, Meisterernst M, Sereda M, Meyer zu Horste G, Nave KA, Ries A, Rautenstrauss B (2009) Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models. Neurogenetics 10:275-287.
Nicholson GA, Magdelaine C, Zhu D, Grew S, Ryan MM, Sturtz F, Vallat JM, Ouvrier RA (2008) Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations. Neurology 70:1678-1681.
Niemann A, Ruegg M, LaPadula V, Schenone A, Suter U (2005) Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease. J Cell Biol 170:1067-1078.
Tazir M, Azzedine H, Assami S, Sindou P, Nouioua S, Zemmouri R, Hamadouche T, Chaouch M, Feingold J, Vallat JM, Le Guern E, Grid D (2004) Phenotypic variability in autosomal recessive axonal Charcot-Marie-Tooth disease due to the R298C mutation in lamin A/C. Brain 127:154-163.
Yang Y, Allen E, Ding J, Wang W (2007) Giant axonal neuropathy. Cell Mol Life Sci 64:601-609.
Yum SW, Zhang J-x, Mo K, Li J, Scherer SS (2009) A novel recessive NEFL mutation causes a severe, early-onset axonal neuropathy. Ann Neurol 66:759-770.