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Nemaline myopathy (also called rod myopathy or nemaline rod myopathy) is a congenital, hereditary neuromuscular disorder that causes muscle weakness, generally nonprogressive, of varying severity.

"Myopathy" means "muscle disease," and a biopsy of muscle from a person with nemaline myopathy shows abnormal thread-like rods, called nemaline bodies, in the muscle cells. People with nemaline myopathy (or NM) usually experience delayed motor development and weakness in the arm, leg, trunk, throat, and face muscles.

The disorder is often clinically categorized into several groups, including mild (typical), intermediate, severe, and adult-onset; however, these distinctions are somewhat ambiguous, as the categories frequently overlap. Respiratory problems are a primary concern for people with all forms of NM, and though in some severe cases they may threaten life expectancy, aggressive and proactive care allows most individuals to survive and lead active lives.

Nemaline myopathy is one of forty neuromuscular diseases covered by the Muscular Dystrophy Association.

Causes

Nemaline myopathy is a clinically and genetically heterogeneous disorder. Both autosomal dominant and autosomal recessive forms occur. Nemaline Myopathy is caused by mutations in one of many different genes. Genes make proteins that allow muscle cells to work. In muscle cells, proteins are found in structures called sarcomeres. Sarcomeres allow muscle cells to contract or tense up. Patients with nemaline myopathy have abnormal sarcomeres. The sarcomeres contain abnormal structures called nemaline bodies. Nemaline bodies are rod shaped structures, and this results in the many names for nemaline myopathy.

The two most common gene mutations causing nemaline myopathy are mutations on NEB or ACTA1. Mutations of the NEB gene usually result in symptoms present at birth or beginning in early childhood. This mutation results in about 50% of affected nemaline myopathy patients. Mutations of the ACTA1 gene the onset age and range of symptoms varies. This mutation results in about 15 to 25 percent of nemaline myopathy patients. The reason this is lower is because mutations in the ACTA1 gene would usually not be passed down from parents, this mutation happens spontaneously in the egg or sperm.

The most common cases of nemaline myopathy are inherited in a pattern of autosomal recessive. This means that a patient must be homozygous recessive in a gene that causes nemaline myopathy. In very few cases, nemaline myopathy can be caused by a pattern of autosomal dominance. The risk of all cases of nemaline myopathy is the same in males and females.

Mechanism

Diseases in the nemaline myopathy group come about from the presence of rod-like structures running parallel to the sarcomeres in skeletal muscle fibers. The presence of these rods in muscle cells makes it more difficult for the muscles to contract. Normally, muscle cells contract by different fibers slide past one another. The structures in the muscle cells created by these fibers are called sarcomeres. All of the different gene mutations leading to NM that have been found so far are in genes that encode different aspects of the sarcomeres. In normal muscle cells, the different kinds of fibers in the sarcomeres are distributed evenly. Evidence suggests that some kind of NM affect the arrangement of these fibers, causing the muscles to be unable to contract as efficiently.

Nemaline myopathy is usually genetic and shows traits in the affected individual from birth or an early age. However, there are some cases of symptoms of NM not showing up until adulthood. These cases are usually not genetic. Of the genes that have been linked to nemaline myopathy, most are also involved in encoding proteins in the sarcomeres in the muscle cells. Respiratory muscles are often more affected than other skeletal muscle groups. Cardiac muscles usually function normally in those affected by nemaline myopathy.

The different genes whose mutations lead to the different kinds of nemaline myopathies affect the cells and the person’s body differently. The first kind of nemaline myopathy identified is due to the slow α-tropomyosin gene TPM3 and varies from case to case with its severity. In this kind of nemaline myopathy, affected people are weaker and see greater weakness in their lower limbs than their upper limbs.

A kind of nemaline myopathy caused by a mutation in the nebulin gene, NEB, also has a large range of severity. All identified cases where nemaline myopathy is caused by a mutation in this gene have been recessive. Patients with this kind of NM are more affected in the muscles in their head, rather than their proximal muscles at the core of their body. Consequently, patients with this genetic mutation often cannot lift their heads. There have been cases with evidence that people this kind of NM may have higher intellect.

A third kind of nemaline myopathy in the skeletal muscle α-actin gene ACTA1 is due to a recessive null mutation. These patients do not always show the typical nemaline bodies in their muscle cells. The only abnormality they show is an abnormal distribution of muscle fibers.

There are several other identified kinds of mutations that lead to nemaline myopathies. One affects slow skeletal muscles, one leads to the formation of both nemaline bodies and other abnormal, core-like, structures forming in the patient’s muscles.

Physical characteristics and effects

Physical expression of nemaline myopathy varies greatly, but weakness is usually concentrated in the proximal muscles, particularly respiratory, bulbar and trunk muscles. People with severe NM are usually obviously affected at birth, while those with intermediate or mild NM may initially appear unaffected. Babies with NM are frequently observed to be "floppy" and hypotonic. Children born with NM often gain strength as they grow, though the effect of muscle weakness on body features may become more evident with time. Adults with NM typically have a very slender physique.

Signs and symptoms

Signs depend from person to person. Young children and babies lack movement and have a difficult time eating and breathing. For young ones, this would be the earliest symptoms if they were not physically visible before. Visible signs include potentially swollen face in disproportional areas, for example. Other examples in newborns would be a difficulty in moving and swaying in a way that would be considered normal behavior for babies. Other symptoms include feeble muscles in the neck and upper rib cage area. In adults, the most common symptom is a respiratory problem. Other symptoms in adults could range from mild to severe speech impediments and in elderly, it is not uncommon to be diagnosed with scoliosis in relations to nemaline myopathy.

As babies that have NM develop and become of age when they should start walking, many take longer than average due to the lack of muscle, or just muscle fatigue.

Since facial muscles are involved in NM takeover, elongated faces and a lower mandible are often observed in people with NM. People affected by NM usually will begin to feel muscle exhaustion between ages 20-50. Because NM only becomes worse, even with treatment, people who show early signs of NM only become weaker faster as opposed to a teenager who is just now showing symptoms, for example. Gastroesophageal reflux, although not common, is associated with NM. Heart abnormalities can occur as a result of NM, but the likelihood of that happening are not high.

Diagnosis

• Electromyography or (EMG). This procedure determines if nerve or muscle cells are damaged. Since a common symptom of Nemaline Myopathy is muscle weakness this allows doctors to determine where and why the weakness is occurring.

• MRI of the Musculoskeletal System. MRI uses a magnetic field to take pictures of body structures and allows physicians to determine if a patient has a certain disease.

• Needle biopsy A needle biopsy allows a physician to test specific cells in the body. These cells are sent to a laboratory to undergo testing and can further determine why muscle weakness throughout the body could be occurring. This testing can confirm that muscle cells contain rod like structures.

Mobility and orthopedics

Most children with mild NM eventually walk independently, although often at a later age than their peers. Some use wheelchairs or other devices, such as walkers or braces, to enhance their mobility. Individuals with severe NM generally have limited limb movement and use wheelchairs full-time.

Because of weakness in the trunk muscles, people with NM are prone to scoliosis, which usually develops in childhood and worsens during puberty. Many individuals with NM undergo spinal fusion surgery to straighten and stabilize their backs. Osteoporosis is also common in NM.

Although patients early on often have mobility in their joints that is past the normal range, as they age, joint deformities and scoliosis usually occur. If the person with nemaline myopathy keeps an eye on his or her joints early on, the problems with them can be detected when they begin and their progression can be delayed. Treatment of joint problems ranges from stretching exercises with physical therapy to surgical introduction of braces. The benefits of exercise in people with nemaline myopathy are still being studied, however, researchers have seen improvements in muscle function from low-intensity exercise. Vigorous exercise and the use of heavy weights should be avoided.

Respiratory involvement

Attention to respiratory issues is critical to the health of all people with NM. Infants with severe NM frequently experience respiratory distress at or soon after birth. Many are ventilated via tracheostomy, and with proper breathing assistance they may attain good health. Though respiratory compromise may not be immediately apparent in people with intermediate or mild NM, it nearly always exists to some extent. As in many neuromuscular disorders, hypoventilation can begin insidiously, and it may cause serious health problems if not remedied by the use of noninvasive mechanical devices to assist breathing, particularly at night.

Communication and eating

Bulbar (throat) muscle weakness is a main feature of nemaline myopathy. Most individuals with severe NM are unable to swallow and receive their nutrition through feeding tubes. Most people with intermediate and mild NM take some or all of their nutrition orally. Bulbar muscle impairment may also lead to difficulty with communication. People with NM often have hypernasal speech as a result of poor closure of the velopharyngeal port (between the soft palate and the back of the throat). Communicative skills may be enhanced through speech therapy, oral prosthetic devices, surgery, and augmentative communication devices. Individuals with NM are usually highly sociable and intelligent, with a great desire to communicate.

Treatment

Nemaline myopathy is a very rare disease that only affects 1 out of 50,000 on average, although recent studies show that this number is even smaller. At present, Nemaline myopathy does not have a cure. There are a number of treatments to minimize the symptoms of the disease. The treatments and procedures to help patients with nemaline myopathy vary depending on the severity of the disease.

As people with NM grow and develop throughout their lives, it is important for them to see a variety of doctors regularly, including a neurologist, physical therapist, and others, such as speech therapists and psychologists, to help both the patient and family adjust to everyday life.

Prevention

Nemaline myopathy is a very rare disease that only effects 1 out of 50,000 on average, although recent studies show that this number is even smaller. NM is inherited from abnormal recessive genes of the parent, or by a new mutation of certain genes to one of the abnormal recessive genes from one of the parents. There is no true prevention for nemaline myopathy, but there are a few possible treatments to look at, although none are guaranteed to fully recover a person back to complete health. Like signs and symptoms, therapies vary from person to person depending on the magnitude of their discomfort. A few possible remedies could be the use of a stabilizer, such as a brace. Other means include moderate stretching and moderate exercise to help target muscles maintain maximum health.

Outcome

Although it is possible, and common, that you may never recover fully, many people live healthy active lives even with moderate to severe cases of nemaline myopathy. For those who don’t recover full, there is a good chance your symptoms actually become worse as you get older. Muscle loss increases with age naturally, but it is expatiated even more with NM.

Society and culture/ Nemaline community

In 1999, the first non-medical webpage on nemaline myopathy was launched, and in October 2004, the first Nemaline Myopathy Convention was held in Toronto, Canada. A second convention took place in the summer of 2007 in Edinburgh, Scotland. In March 2006, Niki Shisler released a book, Fragile, in which she recounted her experiences surrounding the birth of twin sons with severe NM. Men and females are both effected by Nemaline Myopathy. Many members of a certain Amish population displayed symptoms from a young age. Symptoms included tremors and contractions which eventually went away soon after birth, but they all developed respiratory deficiency that is life threatening. There is no known reason as to why this specific population were favored for NM. As mentioned earlier, the rare occurrence of this disease is 1 in 50,000 people. But in the Amish community, it is 1 in 500 people. Again, the reason is unclear at this time.

History

"Rod myopathy" was first identified by Douglas Reye, an Australian physician, in 1958. However, Reye's results were never published because another doctor dismissed his finding of rods in the muscle tissue as an artifact of the biopsy. Forty years later, Reye's "rod myopathy" patient was confirmed to have nemaline myopathy. Another group of Australian researchers has since published an article recognizing Reye for his work.

"Nemaline myopathy" was first named in a published paper in 1963 by North American researchers Cohen and Shy. Today, laboratories performing research on NM are located in the United States (Boston), Finland, and Australia. Shy and his team discovered rod- like structures in muscle fibers of patients with muscle weakness by performing muscle biopsies on multiple patients.

Current research

Research today on NM seeks to better understand the molecular effects the gene mutations have on both muscle cells and the rest of the body. Research is also being done to observe any connections NM has to other diseases and health complications.