Charcot-Marie-Tooth 2L, disease ... (Charcot-Marie-Tooth disease type 2L -CMT2L-) - Gen HSPB8
The disease called Charcot-Marie-Tooth (CMT) is a heterogeneous group of inherited peripheral neuropathies clinical and genetic group, with various types and subtypes that affect the peripheral nerves, and lead to problems of mobility and sensitivity, which affecting feet, legs and hands. This disease becomes apparent, usually in adolescence or early adulthood, but can start at the extreme ages of life, without affecting life expectancy. These diseases are characterized by manifesting distal symmetrical muscle weakness, atrophy, bilateral pes cavus, and decreased deep tendon reflexes. Demonstrations of gradual onset, usually start with muscle weakness in the feet, which can cause it to bow (pes cavus), or steepening of the fingers (hammertoes). These alterations may hinder flexion standing, walking, and doing giving high passes, with the risk of damaged ankles. Progresses, the lower leg muscles weaken, mobility is impaired hands causing difficulty writing, buttoning buttons, or turn the door handles. At the same time, impaired sensory conduction, have painful sensations, and burning sensation in the feet and legs, or decreased sensitivity to touch and temperature. In some cases hearing and vision loss occurs.
Several types of disease Charcot-Marie-Tooth differ, depending on your signs and symptoms, the type of anomalies that disrupt nerve function, genetic cause, and the type of inheritance. Furthermore, each type, several subtypes may be distinguished according to the altered gene. Example of these are:
- Type 1 (CMT1): abnormal myelin covering and protecting nerve cells. These anomalies slow the transmission of nerve impulses. 1A subtype (PMP22 gene); 1B subtype (MPZ gene); 1C subtype (LITAF gene); 1D subtype (EGR2 gene); 1F subtype (NEFL gene); 1E subtype (PMP22 gene).
- Type 2 (CMT2): anomalies in the fiber or axon, extending from the cell body and transmits the pulse. These abnormalities reduce the strength of nerve impulses. Subtype 2 A (MFN2 gene KIF1B); 2B subtype (RAB7 gene A); subtype 2B1 (LMNA); 2C subtype (TRPV4 gene); 2D subtype (BSCL2 genes and GARS); 2E subtype (NEFL gene); 2F subtype (HSPB1 gene); 2I subtype (MPZ gene); subtype 2J (MPZ gene); subtype 2K (GDAP1 gene); subtype 2L (HSPB8 gene).
- Type 3 (CMT3) currently corresponds to Dejerine-Sottas disease, equivalent to Charcot-Marie-Tooth neuropathy hypertrophic, early childhood - onset (genes PMP22, MPZ, EGR2, PRX).
- Type 4 (CMT4) affects both the neuronal axon and myelin and is distinguished from other types by its pattern of inheritance. 4A subtype (GDAP1 gene), subtype 4B1 (MTMR2 gene); subtype 4B2 (SBF2 gene); 4C subtype (SH3TC2 gene); 4D subtype (NDRG1 gene); 4E subtype (EGR2 gene); 4F subtype (PRX gene); 4H subtype (FGD4 gene); 4J subtype (FIG4 gene).
- Type X (CMTX) mutation on chromosome X. X1 Subtype (GJB1 gene); X5 - syndrome subtype-Chutorian- Rosenberg, currently not considered a form of Charcot-Marie-Tooth (PRPS1 gene) disease; subtypes X2, X3 and X4 (unknown exactly genes involved)
In Charcot-Marie-Tooth 2L mutations have been detected in the HSPB8 gene, located on the long arm of chromosome 12 (12q24.23). This gene encodes the "Heat Shock protein 22 kDa" (Heat Shock Protein Beta-8). This protein is part of the protein family "Heat shock" that protect cells from various adverse conditions such as infections, inflammation, exposure to toxins and exposure to elevated temperatures. Moreover, they would block the signals that induce programmed cell death (apoptosis). It also appears involved in controlling cell movement and stabilize the structures of the cell cytoskeleton, plegarían and stabilize proteins synthesized by cells, and would repair damaged proteins. The protein HSPB8 be found in the cells of our body, being more abundant in nerve and muscle cells. In nerve cells, help to organize the neurofilament network that keeps the diameter of axons, essential for the efficient transmission of nerve impulses. In muscle cells, contribute to proper muscle contraction.
In Charcot-Marie-Tooth 2L, exist changes in one or more amino acids in the protein Heat Shock Protein Beta-8, which alter the protein aggregates causing the appearance of it. A particular mutation in the gene HSPB8 has been identified in more than a dozen people in a large Chinese family with 2L type of Charcot-Marie-Tooth. This gene mutation changes the amino acid lysine for the amino acid asparagine at position 141 (K141N or Lys141Asn). These and other mutations in the gene HSPB8 alter a region of the protein that is critical for proper operation. Although it is unclear how HSPB8 genetic mutations cause the characteristic signs and symptoms of Charcot-Marie-Tooth disease type 2L, it is believed that the mutated protein HSPB8 would interact more intensively with HSPB1 protein (encoded from HSPB1 gene ) forming aggregates. These aggregates interfere with normal function of nerve cells, particularly in the function of their axons.
Charcot-Marie-Tooth (CMT), it can be inherited as an autosomal dominant or autosomal recessive trait depending on the type. Most cases of type 2 disease (CMT2) are inherited in an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient for the disease to be expressed. However, some cases of CMT2 are inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with Charcot-Marie-Tooth disease type 2L (CMT2L), by complete PCR amplification of exons HSPB8 gene, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).