mytonia congenita: a muscle channelopathy

characterized by muscle stiffness and an inability of the muscle to quickly relax after voluntary contraction. although myotonia can affect any skeletal muscles, including muscles of the face and tongue, it occurs most often in the legs. myotonia causes muscle stiffness (a myotonic disorder should be considered in the differential diagnosis of a patient complaining of muscle stiffness) that can interfere with movement. in some people the stiffness is very mild, while in other cases it may be severe enough to interfere with walking, running, and other activities of daily life. these muscle problems are particularly noticeable during movement following a period of rest. many affected individuals find that repeated movements can temporarily alleviate their muscle stiffness, a phenomenon known as the warm-up effect. the presence of muscle hypertrophy should be sought on examination and may be a clue to a chloride channel myotonia. the presence of muscle hypertrophy should be sought on examination and may be a clue to a myotonia congenita. the age of onset is usually in infancy and early childhood but onset may be as late as the third or fourth decade of life. mutations in the clcn1 gene cause myotonia congenita. mc is inherited both in an autosomal recessive manner (becker disease) and in an autosomal dominant manner (thomsen disease). distinguishing between ad and ar myotonia congenita depends mainly upon the family history, as the same mutations can occur in both ar myotonia congenita and ad myotonia congenita. the clcn1 gene encodes the voltage-gated chloride channel. this channel is composed of a dimer of two subunits that form an hourglass shape two pores are gated by a common slow gate, and two individual fast gates. clcn1 is necessary in order to stabilize the high resting membrane potential of skeletal muscle. dysfunction of this channel as a result of genetic mutation, causes partial depolarization of the membrane and allows a hyperexcitable state to exist, resulting in myotonia. it is postulated that permanent excitability gives rise to constant mild muscle activity, resulting in muscle hypertrophy. the majority of the more than 80 different clcn1 mutations cause ar myotonia congenita. approximately fifteen mutations have been reported to result in ad myotonia congenita. approximately ten mutations have been associated with both ar and ad myotonia congenita, making a clear distinction between the two modes of inheritance difficult. the majority of the dominant mutations can be associated with reduced penetrance. family members heterozygous for the same mutation may exhibit variable phenotypes ranging from absence of myotonia to severe myotonia. sequence analysis detects the majority of mutations (>95%) that cause both ar and ad myotonia congenita. until now all the ten families suspected to mc that we have seen in iran ,based on pedigree had becker type mc. probabaly this pattern of inheritance is because of high incidence of consanguineous marriage in iran. we formerly checked only the exons 2,5,8 and 15 of the clcn1 gene in our lab. we now have set up all the 23 clcn1 gene exons.we have decided to start to find common mutations of the clcni gene in iranian population. the differential diagnosis of myotonia congenita includes other disorders in which myotonia is a prominent finding. myotonia congenita can usually be distinguished from these disorders based on the following: • factors that provoke or alleviate myotonia • presence or absence of extramuscular manifestations • findings on electrodiagnostic testing