NORD gratefully acknowledges Nens van Alfen, MD, PhD, Department of Neurology, Radboud University Medical Center, The Netherlands, for assistance in the preparation of this report.
Hereditary neuralgic amyotrophy (HNA) is a rare genetic disorder characterized by recurrent episodes of severe pain in the shoulder and arm. In most cases, pain may persist for a few hours to a few weeks and is followed by wasting and weakness of the muscles (amyotrophy) in the affected areas. Additional symptoms including distinct facial features and skeletal abnormalities may also be present. HNA involves the brachial plexus, the interweaving network of nerves that extend from the spine through the neck, into each armpit and down the arms. These nerves control movements and sensations in the shoulders, arms, elbows, wrists and hands. They also control the opening and closing of small blood vessels in the skin, as in response to outside temperature. The number and frequency of episodes can vary greatly from one person to another. Approximately, 75% of affected individuals will have recurrent episodes. The severity of the disorder can also vary greatly due, in part, to the specific nerves involved. HNA may result in residual pain even between episodes and some individuals may develop significant disability to the shoulder and affected areas. In some cases, HNA is caused by mutations or duplications in the SEPT9 gene. The disorder is inherited in an autosomal dominant manner.
The hallmark finding is the abrupt onset of pain in one or both of the shoulders. The right side of the body is affected more often than the left, but both shoulders are affected in approximately one-third of cases. When both shoulders are affected, symptoms are usually worse on one side.
In the classic type, onset may be rapid in some cases, while in others pain onset is gradual and subtle (insidious), followed by a rapid increase in both intensity and severity. Pain has been described as sharp, aching, burning or stabbing. Pain may also affect the neck and the arm, and hand on the same side as the affected shoulder.
Onset is usually in the second or third decade of life. However, children as young as one year old have experienced recurrent episodes of HNA. Recurrent episodes may involve the same peripheral nerves that were originally affected, completely different peripheral nerves, or a mix of the same and different peripheral nerves. The frequency of symptomatic episodes usually decreases as affected individuals grow older.
Pain at onset is often continuous, severe, and worse during the evening or at night. Pain can potentially be excruciating and debilitating and typically lasts for 1-3 weeks. This initial period may be known as the acute phase. Eventually, affected individuals enter a period where the continuous pain lessens and there may be no pain when the affect shoulder and/or arm are not being used (i.e. at rest). However, specific movements may aggravate the condition, causing sharp, stabbing intense pain that persists for a few hours before lessening. This occurs because previously damaged nerves remain abnormally sensitive (hypersensitive). Eventually, affected individuals develop a chronic pain that can persist for a year or longer, sometimes known as the chronic phase.
Eventually, anywhere from a day to a few weeks after the onset of the disorder, a progressive weakness of muscles in the affected shoulder and arm occurs. The severity of muscle weakness can vary greatly, ranging from mild weakness that may be barely noticeable to, in rare cases, almost complete paralysis of the affect muscles. In individuals with HNA, muscle weakness results from damage to the nerves that serve the muscles in the shoulders and arms. The degree of weakness is related to the number of nerves affected. In addition to weakness, the affected muscles may progressively shrink and thin (atrophy) due to lack of use. Muscle weakness may go unnoticed at first, until atrophy and wasting of the affected muscles progresses and is easy to observe, or when the person affected notices he or she can’t use the arm as well as before, especially in overhead activities.
Additional symptoms that can occur in HNA include absent or reduced reflexes and sensory deficits in the affected areas such as the loss of sensation or numbness (hypoesthesia), a sensation of tickling, prickling, or burning on the skin of the affected areas (paresthesia), or an abnormally unpleasant or painful sensation to a light touch (dysesthesia).
Because nerve damage in HNA can affect blood vessels additional symptoms may develop including affected skin, particularly on the hands, becoming reddened, purplish or spotted. Swelling due to fluid retention (edema) may also occur. The skin, hair and nails may grow quickly than normal. Certain areas of the body particularly the hands and forearms may no longer be able to respond properly to outside temperature. Excessive sweating may occur or affected individuals may feel abnormally cold in the affected areas.
Additional complications can develop in some cases. The position of the shoulders, arms, wrists, and hands can shift slightly because of atrophy and weakness of affected muscles. This can leave an affected individual at risk of secondary impingement or subluxation. Secondary impingement is a painful condition that occurs when the shoulder’s tendons are compressed or trapped during shoulder movements. Subluxation refers to partial dislocation of the shoulder joint. Affected individuals may also be at risk of developing contractures, in which abnormal shortening of muscles or tendons leads to deformity or rigidity of an affected joint. Contracture of the shoulder, also known as adhesive capsulitis, can result in pain and limitation of normal range of movement of the joint.
In some cases, nerves outside of the brachial plexus may be involved such as the nerves of the lumbosacral plexus, the phrenic nerve, or the recurrent laryngeal nerve. Involvement of the nerves in the lower portion of the back (lumbosacral plexus) can cause pain, hypoesthesia, and paresthesia in the legs. The phrenic nerve sends signals between the brain and the diaphragm, the muscle that separates the lungs from the abdomen. Involvement of the phrenic nerve can result in a significant shortness of breath, especially when lying down or bending over. Involvement of the recurrent laryngeal nerve can result in weakness and partial paralysis of the vocal cords and, consequently, hoarseness and soft speech (hypophonia). In extremely rare cases, facial or other cranial nerves may be affected.
Some individuals may recover strength and functional levels of the shoulder or affected areas. Numerous reports in the medical literature state that most individuals will regain up to 70%-90% of their original strength and functional levels within two years. However, recent studies indicate that this can take more than two years in some people, while other people will experience residual, chronic pain and complications such as impaired movement of the shoulder and/or affected joints. In severe cases, affected individuals can be left with significant disability that can impact their ability to work and perform common tasks.
In certain individuals, HNA can also be associated with specific features or physical findings. Some affected individuals with develop distinctive facial features including deep-set eyes that are set abnormally close together (hypotelorism), skin folds that cover the inner corner of the eyes (epicanthal folds), an abnormally narrow distance between the eyelids (narrow palpebral fissures), a long bridge of the nose, a narrow, small mouth (microstomia), low-set ears, and wide-set teeth. Hypotelorism can be striking in some cases. Affected individuals may also display features that appear dissimilar from one side of the face to the other (facial asymmetry). Distinctive facial features usually become less pronounced with age. In these cases, additional physical findings can be present including partial webbing or fusion of the fingers or toes (partial syndactyly), hammer toes, fused bones in the forearms, and excess skin folds on the neck, a groove or gap in the roof of the mouth (cleft palate), and a cleft or split in the fleshy flap of tissue (uvula) that hangs in the back of the throat (bifid uvula). Short stature has also occurred in these individuals.
Some cases of hereditary neuralgic amyotrophy are caused by mutations or duplications in the SEPT9 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Although SEPT9 mutations have been shown to cause HNA, these mutations have only been found in approximately 55% of cases. Therefore, it is likely that additional, as-yet-unidentified genes may also cause or contribute to HNA (genetic heterogeneity).
Investigators have determined that the SEPT9 gene is located on the long arm (q) of chromosome 17 (17q25.3). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “”hromosome 17q25.3″ refers to band 25.3 on the long arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The SEPT9 gene creates (encodes) a protein known as septin 9, which is part of a group of proteins known as septins. Septins are involved in the formation and maintenance of the framework of a cell (cytoskeleton) and plays a role in cell division. Mutations in this gene lead to low levels of function septin 9. The exact, underlying manner in which SEPT9 mutations cause HNA is not fully understood. It is possible that mutations in the SEPT9 gene convey a genetic susceptibility to brachial plexus injury. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental or immunologic factors.
HNA episodes may occur spontaneously, but may also be preceded a “triggering” event that activates the body’s immune system. A recent viral illness is the most common ‘triggering’ factor associated with the development of HNA. Additional factors that have been known to trigger HNA episodes are recent immunization, surgery on the brachial plexus, unaccustomed strenuous exercise, minor trauma, bacterial infection, parasitic infection, anesthesia, rheumatologic diseases such as connective tissue disorders, and autoimmune disorders such as lupus, temporal arteritis, or polyarteritis nodosa. In women, childbirth can trigger HNA. In some cases, no triggering event or underlying factor can be identified.
The SEPT9 mutations associated with HNA are inherited an autosomal dominant manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
HNA is a rare disorder that affects males and females in equal numbers. The exact incidence or prevalence is unknown. Approximately 300 affected families have been reported in the medical literature. However, because cases often go misdiagnosed or undiagnosed, determining the true frequency of HNA in the general population is difficult.
A diagnosis of HNA is based upon identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. A variety of specialized tests can help rule out other diagnoses.
Clinical Testing and Workup
Certain tests such as nerve conduction studies or electromyography can be used to assess the health of muscles and the nerves that control muscles. Nerve conduction studies determine the ability of specific nerves in the peripheral nervous system to relay nerve impulses to the brain. During a nerve conduction study, electrodes are placed over specific nerves such as those of the shoulders and arms. The electrodes stimulate the nerves and record the conduction of the signal. This test can help to pinpoint the site of disease or injury to the nerve.
During an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control that muscle.
A specialized imaging technique known as magnetic resonance imaging (MRI) can help to obtain a diagnosis of HNA. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI can help to exclude other potential cause of shoulder pain, demonstrate atrophy of affected muscles, and detect signal changes caused by lack of nerve supply (denervation).
A traditional x-ray (radiograph) of the shoulder may be ordered to rule out specific conditions that can damage the shoulder.
The treatment of HNA is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Most patients primarily need a team consisting of a (pediatric) neurologist, physiatrist, physical therapist and occupational therapist. In case of phrenic nerve palsy a specialized pulmonologist and sometimes home nighttime ventilation is needed. Recurrent laryngeal nerve palsy may require the help of a speech therapist. For HNA patients with rare and special features of craniofacial abnormalities, the help of specialized dentists or maxillofacial surgeons may be warranted.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with HNA. Genetic counseling may be of benefit for affected individuals and their families.
An episode may resolve on its own without treatment and only require support measures such as various pain management strategies including pain medications (analgesics). Specific pain medications used to treat HNA include opiates and non-steroidal anti-inflammatory drugs (NSAIDs), which are usually used in combination. Some physicians have recommended using oral corticosteroids such as prednisone, which has led to a decreased duration of pain and accelerated the healing process in some cases. However, corticosteroids have proven ineffective for many individuals and are potentially associated with adverse side effects.
After the acute phase, different medications known as co-analgesics may be administered. Such medications include gabapentin, carbamazepine, and amitryptiline and they specifically treat nerve pain. Their effect, however, is usually limited.
Physical and rehabilitation therapy are also used to treat individuals with HNA in order to preserve muscle strength and range of motion of affected joints. Specific techniques include scapular coordination training using kinetic control strategies and occupational therapy to increase self-management and energy conservation strategies. In severe cases, active and passive range of motion exercises may to help to prevent muscle atrophy and contractures. In most cases, muscle strengthening exercises cannot be used during the acute phase of the disorder because they worsen pain and because strength training is generally ineffective in muscles below that cannot reach 75% of their maximum contraction strength (i.e. MRC grade 4).
Other techniques used to treat individuals with HNA include the application of heat or cold or transcutaneous electrical nerve stimulation (TENS), a procedure during which electrical impulses a sent through the skin to help to control pain by altering or blocking nerve transmissions. The effect is usually limited.
Specific symptoms associated with HNA are treated by standard protocols. For example, cleft palate may require surgical repair from an experienced craniofacial team.
The prognosis for HNA varies greatly. Some individuals fully recover their strength and functional level in the shoulder and other affected areas. According to the older medical literature, most affected individuals will recover up to 90% of their original strength and functional level. However, more recent medical articles suggest that residual complications are more common than previously believed. Many individuals experience repeated episodes, which increases the risk of long-term complications or disability. Some affected individuals experience residual persistent pain and decreased endurance or exercise intolerance in the affected shoulder. There have been cases reported in which affected individuals experience significant disability that can impact quality of life by making basic household tasks or work extremely difficult. For example, some individuals may have difficulty reaching or lifting. Other people may have difficulty with repetitive tasks that involve the shoulder or arm. Some individuals may develop a winged scapula, a condition in which the shoulder blade (scapula) protrudes or sticks out abnormally from the back.
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