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Neuropathies
(Klein, 2007).
– Insidious onset and indolent course over years to
decades.
(Bassam, 2014; Berger et al., 2002; Kamholz et al., 2000; Lupski, 1998; Scherer, 2006).
– Major advances -molecular basis of inherited
neuropathies.
(Bassam, 2014; Berger et al., 2002; Kamholz et al., 2000; Lupski, 1998; Scherer, 2006).
Clues to diagnosis
History-
– Frequent childhood ankle sprains and toe-
catching falls
– Foot drop
– High arches and hammer toes
– Inverted champagne bottle appearance of the legs
– Recurrent painless foot ulcers
– Thickened nerves in hypertrophic demyelinating
varieties
– Refractory response to the treatment of acquired
disease
– Major sensory loss without positive sensory
symptoms (e.G., Paresthesia, burning, or
lancinating pain).
Neurophysiology
Lewis RA, Sumner AJ. The electrodiagnostic distinctions between chronic familial and acquired demyelinative neuropathies. Neurology. 1982; 32:592–596. [PubMed:
6283420]
Gutierrez A, England JD, Sumner AJ, Ferer S, Warner LE, Lupski JR, et al. Unusual electrophysiological findings in X-linked dominant Charcot–Marie–Tooth disease.
Muscle Nerve. 2000; 23:182–188. [PubMed: 10639608]
– Inheritence may be AD,AR and X linked.
– Can be divided into 3 groups:
(1) Isolated neuropathy involving PNS exclusively
(2) Multisystem neuropathy involving both CNS and
PNS
(3) Neuropathy with multiorgan involvement
affecting nonneurologic organs such as skin,
kidney, heart, and liver
Neuropathy with isolated
nerve involvement
– Hereditary motor and sensory neuropathy (HMSN,
or Charcot– Marie–Tooth)
– Leukodystrophy
– Peroxisomal
– Lipoprotein deficiency
– Porphyrias
– Mitochondrial defects
Miscellaneous
– Neurofibromatosis type 1
– Neurofibromatosis type 2
– Others
Charcot–Marie–Tooth
Disease(HMSN) and Related
Disorders
Charcot–Marie–Tooth
Disease (Hereditary Motor
and Sensory Neuropathy)
– First described in 1886 by Charcot and Marie in
Paris and Tooth in London (Charcot and Marie,
1886; Tooth, 1886).
2. Chromosomal locus
3. Causative genes
A, CMT 1,HNPP,CMTX, DSS,CMT4-inherited disorders of myelin. CMT2 is a primary axonal disorder.
B, Point mutations of these genes (connexin-32 [Cx32], myelin protein zero [MPZ, P0], PMP22, EGR2,
periaxin) result in CMTX, CMT1B, CMT1A, DSS, and CMT4. Mutations of the LITAF gene result in
CMT1C.
C, Point mutations of the KIF1B and NFL genes and specific MPZ missense mutations result in CMT2.
Charcot–Marie–Tooth
Disease Type 1
– Foot deformities
1. Pes cavus and hammer toes ≈3/4 of adult pt.
2. Mild kyphosis ≈ 10%
3. Palpably enlarged hypertrophic peripheral
nerves ≈ 1/4
CMT-1…
A, Semi-thin transverse section of sural nerve showing numerous onion bulbs. (Toluidine blue; bar =
20 μm.) B, Electron micrograph of an onion bulb formation; two small myelinated fibers are
surrounded by multiple layers of Schwann cell processes.
CMT-1…
– 20% -asymptomatic.
CMT-2
– Less-common presentations
1. transient positionally induced sensory symptoms,
2. progressive mononeuropathy,
3. chronic sensory polyneuropathy,
4. CMT phenotype with pes cavus
5. diffuse chronic sensorimotor neuropathy
resembling CIDP
CMT1A.
PMP22 duplication
Normal
PMP22 sequencing
If normal