Nemaline myopathy (nemaline myopathy) - Genes ACTA1, NEB, TNNT1, TPM2, TPM3, CFL2, KBTBD13, KLHL40, KLHL41 and LMOD3
The nemalínicas myopathies are a group of congenital neuromuscular disorders characterized by the presence of numerous rod - shaped structures, called nemalíticos bodies. Usually it manifests itself from birth, but there is also late cases in which it manifests itself in adulthood. Gravity shows a variable range from very severe forms that can be fatal in the early stages of life, slowly progressing forms allowing a relatively normal life.
Nemaline myopathy the divided into six types. In decreasing order of severity, the types are: myopathy nemaline severe congenital, nemaline Amish myopathy, congenital myopathy nemaline intermediate nemaline typical congenital myopathy, myopathy nemaline start in childhood and adult nemaline myopathy. Rates differ by age of onset and severity of symptoms; however, there is overlap between the different types. Severe congenital type is the most dangerous and most people with this type do not survive beyond infancy due to respiratory failure. The Amish type affects only the Amish population of Pennsylvania and is usually fatal in early childhood. The most common type of nemaline myopathy, typical congenital, is characterized by muscle weakness and feeding problems that begin in childhood. Most of these people do not have serious breathing problems and can walk unassisted. People with the kind of childhood onset muscle weakness usually develop in adolescence. Adult - onset type is the mildest of all types. Generally, people with this type develop muscle weakness between 20 and 50 of age.
Symptoms of all presentations nemaline myopathy is always generalized proximal muscle weakness or sometimes accompanied by delayed motor and facial affectation development (long, expressionless face, upper lip V - shaped inverted and palate ogival). Congenital hypotonia, respiratory weakness and swallowing difficulties are common among early forms. Forms of later start first symptom usually manifest as a disorder of the march. Respiratory infections are relatively common and are the main problem of affected individuals in the neonatal period, which can be fatal.
This may be due to mutations in at least ten genes identified. However, most cases of nemaline myopathy with a known genetic cause are due to mutations in one of two NEB or ACTA1 genes. The NEB genetic mutations account for about 50% of all cases, while mutations in the gene ACTA1 represent 15 to 25% of all cases. Mutations in other genes associated with nemaline myopathy each represent only a small percentage of cases. Some individuals with nemaline myopathy have identified a genetic mutation. The genetic cause of the disease is unknown in these individuals.
These genes encode proteins that play important roles in skeletal muscles. Within skeletal muscle cells, these proteins are found in the sarcomere, necessary for muscle contraction. Many of the proteins associated with myopathy nemaline interact inside the sarcomere to facilitate muscle contraction. When skeletal muscle cells of people with nemaline myopathy stained and viewed under a microscope, these cells usually appear abnormal and contain similar structures called rods nemaline bodies. Mutations in any of the genes associated with nemaline myopathy lead to the disruption of proteins in skeletal muscle sarcomeres. Cluttered proteins can not interact normally, disrupting muscle contraction. Muscle contraction in poor condition causes muscle weakness and other characteristics of nemaline myopathy.
The nebulin gene, NEB, located on the long arm of chromosome 2 (2q22), is responsible for most cases of congenital myopathy. The nebulin is a protein that is expressed only in skeletal muscle thin filaments and covering about 3-4% of the total myofibrillar protein. This gene 250kb and consists of between 180-200 exons as several exons of the central part of the gene and the 3'region is differentially expressed according isoform is therefore subject to various processes alternative splicing (cutting and sealing) have been identified 60 mutations in the NEB gene in people with nemaline myopathy. Although the complex process of expressing the variants of nebulin is unknown, it is known that most mutations described so far alter the expression of the mutant protein. This translates into a deficit or a modification of the specific variants of nebulin, which may explain the phenotypic diversity among individuals with nemaline myopathy due to genetic alterations in gene NEB. The enormous size of the NEB gene difficult and expensive full study. However, in most cases, the NEB gene is mutated by a deletion which includes exon 55 and parts of the introns flanking (54 and 55). When nemaline myopathy is due to mutations in the gene NEB, signs and symptoms often manifest at birth or early childhood.
The ACTA1 gene, located on the long arm of chromosome 1 (1q42.13), encodes a protein called ?-actin skeleton. Actin proteins are important for cell movement and muscle contraction. These proteins also help maintain the cytoskeleton. The protein encoded by the gene ACTA1, plays an important role in skeletal muscles. Inside the skeletal muscle cells, it is an essential component of the sarcomeres. They have identified more than 140 mutations in the gene ACTA1 in people with nemaline myopathy. Some of these mutations alter the structure or function of skeletal ?-actin, causing protein is grouped into aggregates. These aggregates interfere with the normal functioning of muscle cells. Other genetic mutations encoding ACTA1 inhibit any ?-actin skeletal muscle, weakening the ability of muscle cells to contract. When nemaline myopathy is due to mutations in the gene ACTA1, severity and the age of onset of symptoms vary widely.
The family of four genes encoding proteins tropomyosin (TPM 1-4) generate over 40 isoforms thereof. Between 2-5% of nemaline myopathy cases are caused by mutations in the gene TPM3, located on the long arm of chromosome 1 (1q21.2) and encoding the ?-tropomyosin or slow tropomyosin (type I ), specific skeletal muscle fibers. Mutations found so far in this gene are located in exons 1a, 4, 5, 9a and 9b which are either exons encoding specific isoforms muscle or exons encoding both specific isoforms of muscle and non - muscle isoforms. Therefore, for analysis of gene TPM3 they should be included in the study, if not find the above altered, 2b, 3, 6b, 7 and 8 exons (in which not yet been recorded anomalies). Conversely you can discard those that do not encode any muscle isoform: 1b, 6a, 9c and 9d.
Nemaline myopathy the generally 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. Less often, this process is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. Most cases are due to new mutations in the gene and occur in people with no history of disease in your family.
Tests in IVAMI: in IVAMI perform the detection of mutations associated with nemaline myopathy, by complete PCR amplification of the exons of ACTA1, NEB, TNNT1, TPM2, TPM3, CFL2, KBTBD13, KLHL40, KLHL41 and LMOD3 genes, respectively and subsequent sequencing. It is recommended to begin the study of the region where most gene mutations NEB (intron-exon 54 55-intron 55) and 6 exons comprising the ACTA1 gene is located. If not found any change in these regions is suggested, if so raises the client, continue by exons gene TPM3 that most likely have to find mutations: 1a, 4, 5, 9a and 9b. It also offers the possibility, if so required, sequencing the remaining exons of TPM3 gene encoding muscle isoforms (2b, 3, 6b, 7 and 8) and TNNT1, TPM2, CFL2, KBTBD13, KLHL40 genes, KLHL41 and LMOD3.
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).