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Charcot-Marie-Tooth Disease

 

History and genetics – Described in 1886 by two French professors Jean-Martn Charcot and his student Pierre Marie and later by Dr. Howard Tooth of London. Also called peroneal  muscular atrophy because of early involvement of the peroneal muscle that dorsiflexes the foot. For a time, a classification system by Dyck and Lambert (the hereditary motor and sensory neuropathies – HMSN) was used to classify the different hereditary neuropathies. Identification of genetic causes for an increasing number of neuropathies has made this system less useful.  In general, CMT1, affecting approximately 80% of CMT patients, is a demyelinating form and CMT2 (affecting at least 20% of CMT patients) is neuronal, involving the nerve fiber rather than the myelin coating. Both types are autosomal dominant. CMT is fairly common affecting 36 out of every 100,000 individuals in the United States. CMT is now known to have multiple genetic causes. During the last decade, 18 genes and 11 additional loci harboring candidate genes have been associated with Charcot-Marie-Tooth disease (CMT) and related peripheral neuropathies.

Some genetic abnormalities are listed below;

 

CMT 1A                     

Autosomal dominant with duplication of a 1.5 Mb (megabase = 1 million nucleotides)  region on the short  arm of Chromosome 17(p11.2-p12) containing the PMP22(peripheral myelin protein 22) gene. This occurs in 70-90% of patients with clinical disease

Point mutation in PMP22 gene

CMT1B                      

Rare and is associated with point mutations in the myelin protein zero(MP0 or MPZ) gene. MPZ is a major protein of compact peripheral nervous system myelin.

Hereditary neuropathy with                                              Deletion on chromosome 17

Liability to pressure palsy (HNPP)                                (same region  as  duplication in CMT1A )

CMTX                                                 X linked dominant(CMTX1) and X-linked recessive(CMTX2) forms of   CMT occur due to an abnormality in the connexin 32 gene at Xq13.1 This gene encodes a gap junction protein of peripheral myelin protein.

CMT4B                                               Point mutations of MTMR2 gene, encoding myotubularin-related Protein-2

CMT 2A                                  Gene abnormality on chromosome 1 encoding for the mitofusion 2 (MFN2) protein that controls behavior of 

                                                mitochondria. Large clusters are formed that fail to travel down the axon causing synapses to fail.

CMT 2E                                  Point mutations in neurofilament light (NF-L) gene

  Genetic testing is available for a number of different CMT types. It is also known that the pathologies of the different types overlap due to the close interaction of Schwann cells (that produce myelin) and the axons. There is evidence for abnormal communication between Schwann cells and axons in CMT.

Clinical Features - CMT1 is associated with loss of reflexes, hypertrophy of nerves, and slow NCV measures. CMT2 has normal reflexes, no nerve enlargement and no or only mildly affected NCV studies. Both may have weakness, abnormalities of gait(steppage gait), foot deformities, loss of balance, pes cavus, hammer toes, leg atrophy, intrinsic hand muscle atrophy, leg cramps, functional loss of use of hands, hand tremors, stocking pin prick loss(rare) and vibratory loss.

 

Treatment

Pain

Medications can be used including antidepressants such as the tricyclics such as  amitryptiline, desipramine or nortriptyline or newer antidepressants such as Remeron or Cymbalta. Anticonvulsants can be used including Neurontin or Lyrica

Mind – body techniques including meditation, using a mantra or focussing on one’s breath; guided imagery placing oneself in tranquil settings and contacting “inner guides”; deep breathing by inhaling deeply for 4 seconds then exhaling over 4 seconds(relaxing muscles and lowering blood pressure); progressive muscle relaxation using tension for 5 seconds followed by relaxation starting with your fists and moving to the rest of your muscle groups.

Acupuncture; may help pain and improve functional level. Acupuncture increases the flow of chi, the life-force, by placing needles in points along lines called meridians that course over the body.

Use of supplements to improve function and provide neuroprotection

Creatine - Creatine is a nitrogenous organic acid that naturally occurs in vertebrates and helps to supply energy to muscle cells.It  keeps the ATP/ADP ratio high which ensures that the free energy of ATP (the main energy molecule of the body) remains high and minimizes the loss of adenosine nucleotides (components of DNA), which would cause cellular dysfunction. Although the use of creatine in CMT has shown “mixed results”, the most recent study revealed changes in muscle fiber composition and improved strength in CMT patients when combined with resistance training (1,2). Dosage is 2-5 gms/day in three divided dosages.

 Co-enzyme Q10 - Coenzyme Q10(CoQ10) is a fat soluble quinone, created from tyrosine, occurring in the mitochondria of all cells. It is a cofactor in the electron transport chain that generates ATP. It also recycles vitamin E. It’s level is reduced by HMG-CoA reductase inhibitors (such as Lipitor or Pravachol) and susceptibility to deficiency is greatest in the most metabolically active cells including the heart, gingiva, immune system and gastric mucosa. Inadequate nutritional intake, a genetic or acquired defect in synthesis, increased tissue needs or advancing age can lead to inadequate tissue levels.  Several studies have shown a positive benefit of CoQ10 in neuromuscular disorders including CMT disease (3,4). Dosage should be at least 100mg/day (3,4).