Environmental modifiers of Charcot-Marie-Tooth phenotype: Diabetes Mellitus, pregnancy and abnormalities of the immune response

• Grant number: 12/14803-5
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2013
• End date: May 31, 2015
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Wilson Marques Junior
• Grantee: Wilson Marques Junior
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Charcot-Marie-Tooth disease (CMT) is the most frequente hereditary motor and sensory neuropathy. The subtype CMT1A results from duplication of the PMP22 gene, localized at the 17p11.2-p12 region, accounting for approximately 50% of the CMT patients and 75% of the demyelinating CMT. Disease onset is usually in the first or second decade, being the classical clinical manifestations weakness and atrophy of the anterior aspect of the legs, sensory loss, areflexia and skeletal abnormalities, mainly pes cavus and hammer toes. This disease is usually situated in the benigne side in the spectrum of the neuropathies. There is however considerable clinical variability. In some patients the disease is extremelly mild while in others it is extremely severe resulting in wheelchair restriction and even respiratory insufficiency. This variability has been atributed to modifiers factors, either genetic or environmemntal.Diabetes mellitus and pregnancy have been suggested to be environmental factors that may change the clinical expression of the PMP22 duplication. A third factor would be an associated abnormal immunological response. Sporadic case reports have shown that patients with CMT and DM may develop a more severe neuropathy in both motor and sensory functions. A retrospective study however sugested that the association of CMT and DM would result in a more severe motor involvement with no repercussion in the sensory manifestations. Larger studies are necessary to better define this question, as DM and CMT are frequent diseases and their association is not so uncommon. There are some descriptions reporting the installation of a neuropathy in previously health pregnant women. Interestingly, in some patients the neuropathy occured again in the following pregnancies. In at least one paper the same phenomenon appeared in other family members, suggesting an hereditary tendency to the development of a neuropathy in the curse of a pregnancy. Additionally, worsening of the CMT status with pregnancy has been occasionally reported in patients with CMT1A and CMT1C. The importance of this topic increased after the description that the activation of the nuclear receptor of the progesterone was associated with an increase in the production of the PMP22 protein. It was proposed that the increased progesterone leves in pregnancy would increase the production of the PMP22 protein, possibly agravating the the deleterious effect of the excess of this protein at the Schwann cells membrane of patients with CMT1A. An experimental investigation demonstrated that onapristone, a progesterone antagonist, could compensate at least partially these effects, but a restrospective clinical investigation did not find any change in CMT1A status in pregnancy. Finally, it has been known since last century that some CMT neuropathies may improved with immunossupressive treatments. It seems that specific mutations may be particularly prone for this response that most of the times is transitory. Aditionally, it seems that some patients may have a concomitance of CMT with an inflammatory neuropathy, mainly a chronic inflammatory demyelinating polineuropathy (CIDP) with a good response to treatment. Although these isolated reports are all very important, no study has been conducted to evaluate if patients with CIDP carry on mutations in those genes associated to a demyelinating CMT that would behaviour like facilitators to the developemement of an acquired neuropathy. By other side, it is possible that some patients diagnosed as having CIDP have in fact a non-uniforme demyelinating neuropathy that was misdiagnosed as an inflammatory neuropathy. These patients should not receive immunossupressive or immunomodulating treatment. In conclusion, DM, pregnancy and abnormalities in the immune response are three possible modifier factors of CMT phenotype whose real role have still to be defined (AU)