Disorder
Charcot-Marie tooth disease

Clinical Characteristics

General description (for patients):

CMT disease consists of a group of disorders with a progressive loss of sensory and motor function, primarily in the arms and legs.  Children may seem floppy at birth and may be late in starting to walk and in other motor milestones.  It is usually painless.  By late in the first decade, many patients have noticeable difficulty walking and weakness in the arms and hands.  Loss of sensation in the extremities and wasting of hand and arm muscle become apparent.  The full expression of symptoms may take decades.  Eventually changes in neck and shoulder muscles become evident and hearing and visual impairments sometimes occur.  Secondary skeletal malformations such scoliosis (curvature of the spine) and foot deformities often occur late.  Some patients have tremors, speech impairment, and problems chewing and swallowing. Pregnancy and emotional stress can exacerbate the symptoms.

Medical description (for healthcare providers):

Charcot-Marie-Tooth disease consists of a group of hereditary motor and sensory neuropathies that can cause progressive deformities and loss of function.  The group can be divided into axonal and demyelinating forms.  Numerous mutations in genes essential to nerve function leads to impaired nerve conduction and/or demyelination primarily in the extremities early.  The onset of symptoms may occur in childhood when motor milestones are delayed.  The progressive loss of nerve function eventually leads to difficulties in walking, weakness in the upper extremities, atrophy of skeletal muscles in the limbs, and gradual loss of sensation.  Secondary changes such as hammer toe, pes cavus, and kyphoscoliosis are common.  Eventually shoulder and neck muscle weakness occurs as well as speech impairment, with swallowing and chewing difficulties.  Clinical diagnosis is based on family history and characteristic findings on physical examination, while EMG/NCV testing and sural nerve biopsies can be diagnostically useful.

Genetics:

Both autosomal dominant and recessive patterns of inheritance have been observed.  A presumed recessive mutation has been found in three sibs of a consanguineous Amish family in Geauga County, OH.  No sensory deficits or vocal cord paresis was noted in these patients.  The homozygous mutation (c.692C>T) was found in exon 5 of the GDAP1 gene located on chromosome 8 (8q13.1-21.3).  A previous report in the pre-genomic era described a presumed recessive form of CMT also in an Amish population.  Other genes associated with CMT include, DNM2, EGR2, FGD4, GARS, GJB1, HSPB1, FIG4, KIF1B, LITAF, LMNA, MFN2, MPZ, MTMR2, NDRG1, NEFL, PRX, RAB7A, SBF2,  SH3TC2, and YARS .

Management:

No cure is available but selected treatments can help manage the symptoms.  Exercises to strengthen muscles of the hand as well as heel cord exercises may help.  Orthopedic surgery can be performed for hip dysplasia and foot deformities.  Acetaminophen (paracetamol) or nonsteroidal anti-inflammatory agents for musculoskeletal pain as well as tricyclic antidepressants, carbamazepine or gabafpentin may be helpful in managing neuropathic pain.  Drugs such as vincristine, taxol, cisplatin, isoniazid, and nitrofurantoin that are known to cause nerve damage should be avoided. Weight management can be useful as well.

Physical therapy to strengthen muscles

Prognosis:

Charcot-Marie-Tooth disease is slowly progressive.  Some parts of the body may become numb, and pain can range from mild to severe.  Eventually the disease leads to disability.

Specialists and specialty centers:

Neurologist

References:

Xin, B., Puffenberger, E., Nye, L., Wiznitzer, M., and Wang, H.:  A novel mutation in the GDAP1 gene is associated with autosomal recessive Charcot-Marie-Tooth disease in an Amish family.  Clin. Genet. 74: 274-278, 2008.  PubMed ID: 18492089. 

Jani-Acsadi, A., Krajewski, K., and Shy, M.E.: Charcot-Marie-Tooth neuropathies: diagnosis and management. Semin. Neurol. 28:185-94, 2008.  PubMed ID: 18351520

Kabzinska, D., Hausmanowa-Petrusewicz, I., and Kochanski, A.: Charcot-Marie-Tooth disorders with an autosomal recessive mode of inheritance.  Clin. Neuropathol. 27(1): 1-12, 2008.  PubMed ID: 18257469

Beighton, P.H.: Recessvely inherited Charcot-Marie-Tooth syndrome in identical twins.  Birth Defects Orig. Art. Ser. VII(2): 105, 1971.  PubMed ID: 5173114

Resources:

Charcot-Marie-Tooth Association