About Neuromuscular Disorders > Learn More
OverviewNeuromuscular disorder is a broad term that encompasses many different syndromes and diseases that either directly or indirectly impairs the function of the skeletal muscles, the muscles that move the limbs and trunk. This can be through problems with the muscle structure itself (pathology) or problems found in the signal that is sent to the muscle, such as through a nerve. When problems arise in the muscle itself this often occurs in the muscle cell membrane. This cell membrane forms the scaffolding necessary to maintain the stability of the muscle membrane (outer structure of the cell), and is called the sarcolemma. The sarcolemma is made of many different proteins, which form this structure. Alterations in the sarcolemma structure are often a result of change in the genetic instructions found within a person's cells. These genetic changes are called gene mutations. Gene mutations can be the result of a new mutation (spontaneous mutation) or inherited, having been passed through generations in a family (inherited).
The text of this section is a brief overview of the different neuromuscular diseases and the information provided here may not be applicable to you or your child. Please consult your healthcare provider for more information.
Congenital Muscular Dystrophy (CMD)The term Congenital Muscular Dystrophy (CMD) refers to a group of genetic disorders that share the onset of muscle weakness in infancy or childhood. The disease commonly presents at birth as a "floppy baby" meaning a baby with poor muscle tone. CMD can be either syndromic or nonsyndromic. Syndromic CMD includes a group of diseases referred to as muscle-eye-brain diseases. The nonsyndromic forms of CMD include merosin-deficient CMD, which accounts for approximately 50% of CMD. Merosin is one of the proteins which forms the sarcolemma or scaffolding of the muscle membrane. The majority of CMD is inherited in an autosomal recessive manner but there have been cases of dominant inheritance and CMD that is caused by a spontaneous mutation. It is a group of rare diseases and about one in 125,000 people have a form of CMD.
Please visit the websites Cure CMD, Congenital muscular dystrophies or Muscular Dystrophy Association for more information on Congenital Muscular Dystrophy.
DystrophinopathiesThe dystrophinopathies include a spectrum of muscle disease causes by a mutation in the DMD or dystrophin gene, which encodes a protein called dystrophin. The mild end of the dystrophinopathy spectrum includes individuals with some muscle cramping and elevated creatine kinase (CK) levels. CK is an enzyme found within the muscle that is released when muscle damage occurs. The severe end of the spectrum includes progressive muscle diseases that are classified as Becker and Duchenne muscular dystrophy. Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) primarily affect skeletal and cardiac muscles.
Duchenne Muscular Dystrophy (DMD)DMD is characterized by lack of, or near lack of, functional dystrophin caused by a dystrophin gene mutation.
The dystrophin gene is found on the X chromosome. Normally, every person has 23 pairs of chromosomes. Chromosomes 1 through 22 are numbered and the last pair (23rd pair) are the sex chromosomes which are labeled X and Y. Every person inherits one chromosome in each pair from their mother and one from their father. Therefore, girls have two copies of the X chromosome (one from their mother and one from their father) and boys have one copy of the X chromosome (from their mother) and a copy of the Y chromosome (from their father).
There are thousands of genes within the packaging called chromosomes, and each gene provides the body with specific instructions. Everyone has changes in their genetic code. In some cases the change disrupts a gene and causes a genetic disease, such as DMD. In other cases the genetic change simply contributes to individual characteristics such as green eyes (versus brown eyes). It is impossible to know what changes are contained in one's genes, and it is also impossible to control which of these changes will be passed on to one's children.
DMD is inherited in an X-linked recessive manner. X-linked refers to a change on the X chromosome and recessive means that a person only appears to show symptoms of the disease if they have no working copies of the gene. As mentioned earlier, males have only one copy of the X chromosome and one copy of the Y chromosome (which means that males have only one copy of the dystrophin gene) whereas females have two copies of the X chromosome (which means they have two copies of the dystrophin gene). If a male has a change in the dystrophin gene that prevents the gene's ability to give correct instructions to make dystrophin, he may not produce any dystrophin protein. Alternately, since females have two copies of this gene, if one copy does not work, they have a second back up copy that is producing the full amount of the dystrophin protein; this is why we see males affected with DMD but seldom see affected females. In very rare instances females can be affected and these individuals can be referred to as 'DMD manifesting carriers'. DMD manifesting carriers can be the result of something called skewed X-inactivation. The majority of females that carry a DMD mutation are considered 'asymptomatic carriers.'
When a female has a genetic change in one copy of the dystrophin gene, she is called a carrier of DMD. Carrier females typically do not show any features of the condition; however, some carriers may experience heart problems in adulthood. Women often do not know that one copy of the dystrophin gene is not working properly. It is important to note that not all mothers of boys with DMD are carriers. The change in the dystrophin gene can be passed through a family as described above or can be caused by a new sporadic change in the egg cell that created that child; this is called a de novo change.
The first symptoms of DMD usually occur in early childhood. The most common presentation in the first 2 years of life manifests as delayed independent walking. By 3-4 years of age most boys with DMD show difficulty climbing stairs or rising from a seated position on the floor. Enlargement of the calf muscles (described as pseudohypertrophy) is common. Cognitive processing difficulties, including learning disability and neurobehavioral problems, are found in about 30% of boys with DMD. DMD is suspected when boys exhibit symptoms of motor delay and pelvic girdle weakness. A simple blood test measuring a muscle enzyme called creatine kinase (CK) should be the first laboratory test performed. In DMD boys, CK is invariably elevated many times the normal values. A suspected clinical diagnosis can sometime be confirmed by ordering genetic testing and/or a muscle biopsy. These tests are described elsewhere.
DMD occurs in 1/3,500 to 1/5,600 live male births. Two-thirds of cases of DMD result from young men inheriting a defective X-chromosome from their mothers. One-third of cases arise from spontaneous mutation, sometimes called gonadal mosaicism.
Both the Muscular Dystrophy Association and the National Institutes of Health have more information on Duchenne Muscular Dystrophy.
Becker Muscular Dystrophy (BMD)Becker Muscular Dystrophy (BMD) is caused by a mutation in the dystrophin gene, the same gene that causes DMD and codes for the production of dystrophin, located on the X-chromosome. BMD represents a clinical picture very similar to DMD. However, unlike DMD where dystrophin protein is usually absent from muscle, males afflicted with BMD are able to manufacture dystrophin protein, but it often has smaller size or decreased abundance. Although the quantity and/or quality of dystrophin may be abnormal, the protein can be partially functional. Therefore, the clinical course of BMD can be milder than that seen in DMD, but much more variable. Individuals with BMD can have a waddling gait, difficulty climbing stairs, and enlarged calf muscles. However, symptoms occur later and the disease progresses much more slowly. Generally, the age of the patient when disease symptoms begin to show predicts how severe the disease will be.
BMD occurs in about 1/18,450 live male births thus is rarer than DMD. BMD is typically an inherited disease and new (or spontaneous) mutations are typically rare.
For more information on Becker Muscular Dystrophy, please visit the National Institutes of Health or the Muscular Dystrophy Association. For more information about Dystrophinopathies visit the GeneReviews Website.
Facioscapulohumeral Muscular Dystrophy (FSHD)FSHD, also known as Landouzy-Dejerine, is caused by a missing piece of genetic material from a region of DNA located on the end of chromosome 4, called the D4Z4. FSHD is a disorder characterized by muscle weakness and wasting (atrophy). FSHD is named for the areas of the body that are affected most often: the face (facio-), around the shoulders (scapulo-) and upper arms (humeral). Typically the signs and symptoms of FHSD usually appear in late adolescence but the onset of symptoms can vary. The clinical signs of the disorder can vary significantly between individuals, even between affected members of the same family.
The genetic material which is deleted in FSHD, found at D4Z4 region of the chromosome is a segment of repeated DNA, typically containing 11 to more than 100 repeat DNA segments. In FSHD one of the chromosome 4 D4Z4 segments only contains between 1 and 10 repeats. This genetic mutation in inherited in an autosomal dominant manner, meaning that the disease may be inherited through either the father or the mother and only one changed copy of the gene is needed to cause disease. It also may occur without a family history, as a result of a new (de novo) D4Z4 deletion on one copy of chromosome 4.
About 1/20,000 people have FSHD.
Please see The FSH Society and Facioscapulohumeral dystrophy for more information about FSHD.
Limb Girdle Muscular Dystrophy (LGMD)The term Limb Girdle Muscular Dystrophy (LGMD) represents a family of genetic muscle disorders that produce weakness and muscle wasting restricted to the limbs. The pattern of weakness tends to be more proximal than distal. There is variability both between individuals and between subtypes of LGMD. At least 21 distinct forms of LGMD have been identified over the past 20 years. LGMD is categorized by mode of genetic inheritance. Autosomal dominant forms of LGMD require that a person inherit only one copy of a gene containing a disease-causing mutation from either mother or father to show clinical symptoms of the disease. Seven forms of LGMD result from autosomal dominant gene mutations. The autosomal recessive LGMD disorders account for 14 forms of distinct LGMD. To show clinical symptoms of an autosomal recessive disorder, a person needs two copies of an altered gene: one from mother and one from father. Tremendous progress has been made in understanding the underlying genetic basis of LGMD. For most of the 21 diseases, the altered gene has been defined and the defective or missing proteins have been identified. The LGMDs present a very diverse spectrum of clinical symptoms. The age of onset varies from early childhood to adulthood and both males and females may be affected.
LGMD is a rare disorder and the number of people who have LGMD at any one time range from 1/ 14,500 to 1/123,000, depending on the type.
Please visit Muscular Dystrophy Association or Limb-Girdle Muscular Dystrophies for more information on Limb Girdle Muscular Dystrophy.
Myotonic Muscular Dystrophy (DM)There are two known forms of this disease; myotonic dystrophy type 1 (type 1 DM) and myotonic dystrophy type 2 (type 2 DM). Both are caused by abnormal expansions of repeated areas of genes. Type 1 DM is the most common form of muscular dystrophy that begins in adulthood. Type 1 DM is caused by a DNA expansion in the DMPK gene. Type 2 DM is caused by a DNA expansion in the CNBP gene. Both types of DM are inherited in an autosomal dominant manner.
DM is a multi-system disorder that affects the skeletal muscles, as well as smooth muscles (the muscles that control the digestive system) and cardiac muscles of the heart. Symptoms of myotonic dystrophy may include difficulty releasing one's grip (myotonia), weakness of muscles in the hands and feet, difficulty swallowing and abnormal heart rhythm. Non-muscle symptoms may also include learning difficulties, daytime sleepiness, infertility and early cataracts.
The clinical features of type 2 DM tend to be milder than those of type 1. A variation in type 1 DM, which is called congenital DM, can be diagnosed at birth. The symptoms and signs of congenital DM are weak muscle tone (hypotonia), club feet, generalized weakness, breathing problems, developmental delay and intellectual disability.
In type 1 DM, the repeat expansion can enlarge when passed on in each generation, which can lead to earlier onset and increased severity of symptoms with each successive generation. This phenomenon is called anticipation, and is seen more often when the repeat expansion in the DMPK gene is inherited through the mother.
DM affects about 1/8000 people worldwide, with 98% of all cases being type 1 and the remaining 2% being type 2.
Please see Myotonic Dystrophy Foundation and Myotonic Dystrophy for more information on Myotonic Dystrophy.
Spinal Muscular Atrophy (SMA)SMA is a neuromuscular disease characterized by degeneration of motor neurons resulting in progressive muscle atrophy or wasting and weakness. There are four types of SMA that affect children before 1 year of age. These include: 1) SMA type I also called Werdnig-Hoffman disease, a severe form of the disorder that is evident at birth or within the first few months of life; 2) SMA type II which is characterized by muscle weakness that develops in children between ages 6 months to 1 year; 3) an X-linked form that is similar to type I, except children typically are born with joint contractures that make movement more difficult; 4) Distal spinal muscular atrophy type 1 causes a progressive muscle weakness in the hands and feet that eventually spreads to the limbs. There are three other types of SMA that can affect people in early childhood and adulthood. These include: 1) type III (Kugelberg-Welander disease or juvenile type), which is a milder form than types I, II, and X-linked form; 2) SMA type IV and 3) Finkel-type which is typically diagnosed after 30 years of age.
SMA results from loss of the signal that is transmitted to the muscles from the spinal cord (denervation). Normal transmission is from the motor neurons in the spinal cord to muscle traveling along the motor neuron axon. In all forms of SMA either the motor neuron with its axon, or the axon itself is lost. As a result, the muscles used for activities such as walking and sitting up are affected; in the more severe forms, the muscles used for breathing and swallowing are affected as well. The clinical spectrum of SMA ranges from early infant death to normal adult life with only mild weakness. SMA is caused by the absence of, or a mutation in, the Survival Motor Neuron (SMN1) gene, which is critical to the function and survival of motor neurons.
SMA affects about 1/6,000 to 1/10,000 people.
For more information on Spinal Muscular Atrophy, please visit the SMA Foundation or the National Institute of Neurological Disorders and Stroke.
Other Neuromuscular DisordersInformation on some of the most common forms of neuromuscular disorders has been provided here, but there are many others. If you are seeking information on other neuromuscular disorders or muscular dystrophies, the Muscular Dystrophy Association covers all muscular dystrophies and is a good starting point. Your health care provider is the best resource.
If you would like to review some more basic information about genetics and inheritance the National Human Genome Research Institute offers some excellent educational information.