Charcot-Marie-Tooth disease – PMP22, MPZ, MFN2, GJB1 genes. Other genes: DYNC1H1, EGR2, FGD4, FIG4, GARS, GDAP1, GNB4, HARS, HINT1, HK1, HSPB1, HSPB3, HSPB8, IGHMBP2, INF2, JPH1, KARS, KIF1B, KIF5A, LITAF. LMNA, LRSAM1, MARS, MCM3AP, MED25, MME, MORC2, MPV17, MT-ATP6, MTMR2, NAGLU, NDRG1, NEFH, NEFL, PDK3, PLEKHG5, PRPS1, PRX, PTRH2, RAB7A, SBF1, SBF2, SCO2, SETX, SGPL1, SH3TC2, SIGMAR1, SLC25A46, SPG11, SPTLC1, SURF1, TRIM2, TRPV4, VCP, WARS, YARS, Chromosome 17.
Charcot-Marie-Tooth disease (CMT), or hereditary Charcot-Marie-Tooth neuropathy, is a heterogeneous clinical and genetic group of hereditary peripheral neuropathies, comprising several types and subtypes, and affecting the peripheral nerves, giving place to problems of mobility and sensitivity in feet, legs and hands. Usually this disease becomes apparent in adolescence or at the beginning of adulthood, but it can also begin in the extreme ages of life, without affecting life expectancy.
This disease is characterized by symmetric distal muscular weakness, with atrophy, bilateral cavus foot and decreased deep tendon reflexes. The manifestations are of gradual progression, and usually begin with muscular weakness in the feet, which can cause their bowing or the curling of the fingers (hammer toes). These alterations can hinder the flexion of the foot and the action of walking, with the consequent risk of damaging the ankles by taking high steps. As this disease progresses, the lower leg muscles weaken, and the mobility of the hands is also disturbed, causing difficulty in writing, buttoning or turning the door handles. At the same time, due to the alteration of the sensitive conduction, the affected people present sensations of pain and burning in the feet and legs, or decrease in the sensitivity to touch and temperature. In some cases hearing and vision loss occurs.
Several types of Charcot-Marie-Tooth (CMT) diseases have been described, depending on their signs and symptoms, the type of abnormalities that alter nerve function, and the genetic cause and type of inheritance. In addition, in each type, several subtypes can be distinguished according to the altered gene.
The genes involved in the development of this disease encode proteins that are involved in the function of the peripheral nerves in the feet, legs and hands. It is likely that the genetic mutations that lead to the development of CMT affect the axons, which are responsible for transmitting the nerve impulse, or affect the cells that produce myelin, a substance that involves the axons. In most cases, longer nerves that transmit impulses to the body's appendages are more likely to be affected. As a consequence, peripheral nerve cells slowly lose the ability to stimulate the muscles of the feet, legs and, finally, the hands, and to transmit sensory signals from these appendages to the brain. Different mutations within a single gene can cause signs and symptoms of different severity or lead to different types of the disease.
Type 1 (CMT1): abnormalities in myelin, a substance that covers and protects nerve cells, and slows the transmission of nerve impulses. Between 70 and 80 percent of individuals with CMT1 have mutations that affect the PMP22 gene. Most of these cases occur when there is an additional copy of the gene, resulting from a small duplication of genetic material on chromosome 17. Another 10 to 12 percent of individuals with CMT1 have mutations in the MPZ gene. Subtype 1A (PMP22 gene); subtype 1B (MPZ gene); subtype 1C (LITAF gene); subtype 1D (EGR2 gene); subtype 1F (NEFL gene); subtype 1E (PMP22 gene).
- Type 2 (CMT2): abnormalities in the fiber or axon, which extends from the cell body and transmits the impulses. These abnormalities reduce the strength of the nerve impulse. The most common cause of CMT2 is mutations in the MFN2 gene, which accounts for approximately 20 percent of cases. Subtype 2A (MFN2, KIF1B gene); subtype 2B (RAB7 A gene); subtype 2B1 (LMNA gene); subtype 2C (TRPV4 gene); 2D subtype (BSCL2 and GARS genes); subtype 2E (NEFL gene); subtype 2F (HSPB1 gene); subtype 2I (MPZ gene); subtype 2J (MPZ gene); subtype 2K (GDAP1 gene); subtype 2L (HSPB8 gene).
- Type 3 (CMT3): currently corresponds to Dejerine-Sottas disease (DS), equivalent to a Charcot-Marie-Tooth disease with hypertrophic neuropathy, with early childhood onset (PMP22, MPZ, EGR2, PRX genes).
- Type 4 (CMT4): affects both neuronal axon and myelin, and is distinguished from the other types by its inheritance pattern. Subtype 4A (GDAP1 gene), subtype 4B1 (MTMR2 gene); subtype 4B2 (SBF2 gene); subtype 4C (SH3TC2 gene); subtype 4D (NDRG1 gene); subtype 4E (EGR2 gene); subtype 4F (PRX gene); subtype 4H (FGD4 gene); subtype 4J (FIG4 gene).
- Type X (CMTX): mutation on the X chromosome. Approximately 90 percent of people with CMTX have mutations in the GJB1 gene. Subtype X1 (GJB1 gene); subtype X5 - Rosenberg-Chutorian syndrome - currently not considered a form of Charcot-Marie-Tooth disease (PRPS1 gene); subtypes X2, X3 and X4 (without knowing exactly the genes involved).
Charcot-Marie-Tooth disease can be inherited in an autosomal dominant or recessive manner, depending on the type of clinical presentation. An autosomal dominant inheritance pattern means that one copy of the altered gene in each cell is sufficient for the disease to be expressed. An autosomal recessive pattern means that both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.
Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with different types of Charcot-Marie-Tooth disease, by means of the complete PCR amplification of the exons of the genes involved in each of them, and their subsequent sequencing.
Recommended samples non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).