Congenital myopathies

Congenital myopathy is a term for any muscle disorder present at birth. This defect of either the brain, stimulating nerve, or muscle causes weakness throughout the skeletal muscle. Congenital myopathies account for one of the top neuromuscular disorders in the world today, comprising approximately 6 in 100,000 live births every year. Congenital myopathies can broadly be defined as follows:
 * An obvious abnormality in the skeletal muscle on the cellular level; observable via electron or light microscope
 * Originates in the myofibrae, affecting the sarcolemma, or skeletal muscle cell membrane.
 * Symptoms of muscle weakness and hypotonia
 * Is a congenital disorder, meaning it occurs during development and symptoms present themselves at birth or in early life.
 * Is a genetic disorder.

Impairments in Embryological Development
Skeletal muscle develops from the myotome and dermamyotome derivatives. Since there is such variation between different types of congenital myopathies, the processes of disease onset is also quite varied. Below is a brief explanation for some of the major groupings of congenital myopathies.

Myopathies with Protein Accumulation
Development of congenital myopathies with protein accumulation is one of the best understood, as the most understood congenital myopathy, nemaline myopathy (see below) falls into this category. Typically, the development error in this category occurs with the genes coding for the thin filaments of the sarcomere and the genes coding for the proteins responsible for replacing thin filaments. Currently, this is how scientists believe protein accumulation begins. Since the proteins involved in building and turnover of the sarcomere no longer function, sarcomere components build up within the cell, slowing contraction and causing weakness of the skeletal muscles.

Myopathies with Cores
Myopathies with cores, such as multicore and central core myopathies discussed below, are due to mutation in the genes that code for involved in calcium regulation. Calcium is a major component in excitation-contraction coupling, which is the basic process of muscle contraction. This error causes malfunctioning of the sarcoplasmic recticulum, which releases calcium, and the calcium regulatory gates within the muscle. Malfunctions in both of these areas can lead to lower levels of calcium within the muscle, causing the muscle weakness.

Myopathies with Central Nuclei
Myopathies with central nuclei, such as myotubular myopathy, involves an error in the gene involved in vesicle movement throughout the cell. This creates problems in vesicles reaching the plasma membrane with the cellular components necessary to fuse myoblast, a major step in the formation of the skeletal muscle. This creates structural problems throughout the skeletal muscle and in the Z line of the sarcomere, creating the weakness in the muscle.

Myopathies with Fiber Size Variation
Myopathies with varying fiber size, such as congenital fiber type disproportion, occurs when type 1 fibers, the slow twitch fibers involved in sustaining activity, are smaller than type 2 fibers, the fast twitch fibers involved in quick activity. Since smaller type 1 fibers is not associated with nemaline myopathy, the most common type of congenital myopathy, it has not been studied in as great detail as many of the others. However, the smaller type 1 fibers explains why patients typically can participate in activities for shorter periods of time, but struggle with extended activity.

Types
The conditions included under the term "congenital myopathy" can vary. One source includes nemaline myopathy, myotubular myopathy, central core myopathy, congenital fiber type disproportion, and multicore myopathy. The term can also be used more broadly, to describe conditions present from birth.

Nemaline myopathy
Nemaline myopathy is skeletal muscle weakness typically in the face, neck, and limb regions. Approximately 1 in 50,000 people are affected by this disorder. Today, at least six gene mutations are known to cause nemaline myopathy. All the genes are involved in protein production of the sacromere, the main unit of muscle contraction within skeletal muscle. Histologically, protein accumulation can be seen within cells of affected skeletal muscles. Nemaline myopathy is an autosomal recessive genetic disorder, meaning mutated copies must be inherited from both parents for the disease to onset.

Myotubular myopathy
Myotubular myopathy, also known as centeronuclear myopathy, is recognized by pain during exercise and difficulty walking. People affected by this disease typically are wheel-chair-bound by middle adulthood, have weakness in the muscles involved in eye movement, nerve function disorders, and some form of intellectual disability. Myotubular myopathy is very rare, with less than 50 families currently affected. Genetically, myotubular myopathy can have two causes: autosomal dominant and autosomal recessive. When caused by a mutation in the DNM2 gene, the disorder is autosomal dominant, meaning it can be passed on by one mutated gene. When the mutation takes place in the BIN1 gene, the disease is instead autosomal recessive, and both genes must be mutated for the disease to be inherited. Autosomal recessive oset is most common.

Central core myopathy
Central core myopathy is mild weakness in skeletal muscle that persists throughout life but typically does not worsen with time. People with central core disease typically have poor reactions to surgeries and some medications, which require the use of muscle relaxants. Central core myopathy is believed to be more prevalent than currently reported, as it is hard to recognize and often misdiagnosed in early childhood. Central core myopathy has been found to strongly relate to malignant hyperthermia, which strongly increases metabolic activities in the body to leading to potential circulatory system collapse. Mutations typically appear in the RYR1 gene.

Congenital fiber type disproportion
Congenital fiber type disproportion affects skeletal muscle, typically causing weakness in the shoulders, upper arms, thighs, and hips. Skeletal muscle is made up of two kinds of fiber, type 1 and type 2. In congenital fiber type disproportion, type 1 fibers are not only smaller but often more abundant than type 2 fibers. This leads to affected individuals being able to maintain an active lifestyle, though they usually have lower levels of stamina. Severity with this disease varies greatly, but people typically present symptoms by the age of one. Individuals do not usually worsen with time, and cases have even been reported of improvements.

Multicore myopathy
Multicore myopathy, also referred to as minicore myopathy, is associated with small areas of decreased oxidative activities, resulting in areas that appear in this histology as “cores”. These appear through microscopy very similar to central core, however the cores are typically smaller in multicore myopathy. As with congenital fiber type disproportion, patients have a greater number of type 1 fibers. Overall, approximately half of diagnosed individuals report no progression of muscle weakness, while half report a very slow progression.

Cylindrical spiral myopathy
Cylindrical spiral myopathy is very rare with only 17 individual cases described as of 2013. The majority of cases are sporadic. It characterized by the presence of cylindrical spirals(CS), which are peculiar lamellar structures consisting of concentric membranous whorls found at electron microscopy analysis of muscle biopsies. These structures are composed of a spiraling double-laminated membrane, which sometimes merge or intermingle with glycogen or tubular structures resembling T-tubules or tubular aggregates. Cylindrical spirals were first described in 1979.

Phenotypes are quite variable, and manifestations can include weakness (at times facioscapular), abnormal gait, scoliosis, myotonia, cramps, and scoliosis.

Diagnosis
There are a variety of tests physicians can run to determine if a person is inflicted with one of the myopathy types. Tests can be run to check creatine kinase levels in the blood, or electromyography can be run to check the electrical activity of the muscle. However, diagnosis heavily relies on muscle pathology, where physician view the muscle on the cellular level. Diagnosis usually relies on this method, as creatine kinase levels and electromyography can come back normal even in inflicted patients. Since congenital myopathy does occur during the development of the embryo, there have also been some advancements in prenatal screenings for the disease.

Treatment
Currently, there are no treatments for any of the congenital myopathies types. However, depending on the severity, there are different therapies available to help alleviate any pain and aid patients in performing varying activities. For example, many congenital myopathy patients are involved in physical or occupational therapy in an attempt to strengthen their skeletal muscles. In certain cases, orthopedic surgery may be an option, especially with myopathies affected the pectoral and pelvic girdles. Survival is typically determined by the level of respiratory muscle insufficiency.