Última actualización:
May 29, 2020
Años publicados: 2014, 2017, 2020
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.
Summary
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 at least one recurrent episode. 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 many individuals develop persistent pain due to altered posture and movement, and overuse of the affected shoulder and arm. Some patients have an inherited predisposition to developing HNA that is associated with changes (mutations) or duplications in the SEPT9 gene. The trait for developing NA symptoms is inherited in an autosomal dominant manner.
The hallmark finding is the abrupt onset of pain in one or both of the shoulders and/or arms. The right side of the body is affected more often than the left, but both shoulders are affected in approximately one-third of patients. When both shoulders are affected, symptoms are usually worse on one side.
In the classic type, onset may be rapid in some patients, 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. If patients rate the severity of their pain at onset on a scale from 0 (no pain) to 10 (most severe pain ever), they usually score a 7 or higher. 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.
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 on average; although in some patients it may be longer. 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, around 2/3 of all affected individuals develop a chronic, more muscle ache type pain that can persist indefinitely. This is sometimes known as the chronic phase of HNA.
Eventually, anywhere from a day to a few weeks after the onset of the disorder, a progressive weakness of several 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 some affected 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 nerve fibers affected in a nerve. In addition to weakness, the affected muscles may progressively shrink and thin (atrophy) due to lack of use. Muscle weakness may go unnoticed, unless atrophy and wasting of the affected muscles are severe and easy to observe, or when the person affected notices he or she can’t use the arm as well as before, especially during reaching or 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). These symptoms mainly occur when nerves that supply the forearm and hand are involved.
Because nerve damage in HNA can affect blood vessel constriction, 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. Just as the sensory symptoms, these so-called autonomic nerve symptoms occur mainly occur in the forearms and hands.
Additional complications can develop in some affected individuals. The position of the shoulders, arms, wrists, and hands can shift slightly because of atrophy and weakness of affected muscles. The most common finding is a combination of an abnormally moving shoulder blade, a decreased ability to extend the arm behind the back and some weakness in bending the tip of the thumb. The weakness and limitations of movement find their origin in the so-called serratus anterior muscle. This muscle is responsible for holding the shoulder blade close to the chest when someone is upright or trying to lift the arm. The nerve to this muscle is affected in around 70% of people with HNA. Weakness of the serratus anterior leads to loss of contact of the shoulder blade with the chest. As a result, the shoulder blade will protrude backwards during movement of the arm. This is called a winged scapula, or scapula alata. This can leave an affected individual at risk of secondary shoulder joint impingement or subluxation. Secondary impingement is a painful condition that occurs when the shoulder’s tendons are compressed or trapped during shoulder movements. Because the shoulder blade also forms the socket of the shoulder joint, it needs to rotate during movement of the arm to hold the socket and the upper arm bone neatly together without impinging tendons in the joint. If weakness causes this rotation to fail, the shoulder joint tendons will often become irritated as they are constantly impinged during movement of the arm. Subluxation refers to partial dislocation of the shoulder joint, which occurs when the muscle that supports the weight of the arm in the joint socket (the deltoid muscle) is too weak. Fortunately the arm will not completely luxate as a rule, because this type of weakness of this deltoid muscle automatically means people cannot lift their arm higher than elbow height, and hence cannot luxate the 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 patients, nerves outside of the brachial plexus may be involved such as the nerves of the lumbosacral plexus (the nerves to the leg and foot), the phrenic nerve that supplies the main muscle for inspiration, or rarely the recurrent laryngeal nerve that supplies half of the vocal cords. 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 and in trouble sleeping well. 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.
Many individuals recover some strength and functionality of the shoulder or other affected areas. Numerous reports in the medical literature state that most individuals will regain up to 70%-90% of their original strength within two years. However, strength recovery does not automatically mean recovery of function in HNA. Recent studies indicate that recovery may take more than two years in some people, and may even take up to 3-4 years for phrenic nerve recovery. Many people will experience residual, chronic pain and complications such as impaired movement of the shoulder and/or affected joints. It is now known that these residual complaints have no relation with the strength of individual muscles anymore. There are two reasons that pain and fatigue may persist. The first reason is a loss of endurance, i.e. the ability to keep up a certain position or movement with a previously affected muscle. Decreased endurance is the price our body has to pay for how nerves are healed. It is the main reason why patients with (hereditary) NA can often not go back to a full day of work or home duties. The second reason is the changed, adaptive, posture and movement pattern that occurs after nerves have been damaged around the shoulder. These new movements that were initially less or lost causes every movement to cost more energy than the “normal” movement did, and can lead to significant fatigue. The pattern is also mechanically less healthy for your body and can lead to secondary injury to the shoulder joint and tendons. The resulting imbalance between one’s physical possibilities and what is required of someone in his or her daily life and work often leads to chronic pain and fatigue.
In a small subset of individuals, HNA can also be associated with specific features or physical findings. Some affected individuals have 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. However, on an individual level, there is no sure tell-sign that someone has hereditary NA versus the non-hereditary variant, unless there are other people affected in the same family.
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 affected individuals in the North Americas, and in only < 5% of the families from Europe. Therefore, it is likely that additional, as-yet-unidentified genes may also cause or contribute to HNA (genetic heterogeneity). 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 or predispose for HNA is not 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.
The exact disease mechanism in HNA is not known, but it is thought to be complex and depending on multiple factors. An interplay between environmental factors (such as infections and other immune system activators) and mechanical factors (repetitive or strenuous motor tasks that stretch the nerves) placed upon a genetic predisposition, is assumed to be the cause of HNA episodes. Such episodes may occur seemingly spontaneously, but may also be preceded a “triggering” event that activates the body’s immune system. This can be any event that triggers the immune system. A recent viral illness is the most common ‘triggering’ factor associated with the development of HNA. Recently, is has become known that the hepatitis E virus is often a trigger of NA. It often affects middle-aged males, and overall the episodes seem to be more severe, with bilateral arm involvement and involvement of the phrenic nerve for breathing being quite common. Hepatitis E does not affect the prognosis and requires no specific treatment unless the patient already has a severe liver illness. Additional factors that have been known to trigger HNA episodes are recent immunization, surgery, unaccustomed strenuous exercise, minor trauma, bacterial infection, parasitic infection, anesthesia,. In women, childbirth can trigger HNA. However, in many cases, no triggering event or underlying factor can be identified.
The SEPT9 mutations associated with HNA are inherited an autosomal dominant manner. 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. The risk is the same for males and females.
HNA is a rare disorder that affects males a little more often than females. The exact incidence or prevalence is unknown, but can be extrapolated from the incidence of sporadic, non-familial NA which is about 1 in 1000 per year and the fact that in a large group of 1300+ NA patients approximately 1 in 10 people had a family history for the disorder. This combined suggests that HNA occurs in about 1 in 10.000 people in the population.
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
The most characteristic features of HNA are the very severe acute-onset pain in one or both shoulder girdles and arm, followed by patchy muscle weakness in the upper extremity. A thorough clinical examination will confirm that the symptoms do not match the distribution of for example a cervical root compression syndrome, and weakness and atrophy tell there is more going on than just a shoulder joint problem. Other than the typical clinical features, there are no tests that are specific for the diagnosis of HNA. 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, but is often non-informative when it comes to nerves affected in HNA.
During an electromyography (EMG), 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. Needle EMG can be helpful to detect affected nerves in HNA. But as not all 50 muscles of the arm are routinely examined, the test can also be falsely negative sometimes, when muscle are examined that are not clinically involved.
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).
Nerve ultrasound is a recently developed, non-invasive and painless technique that can look at the shoulder and arm nerves with much detail, and can see inflamed parts of the nerves in certain areas. Affected nerves can be seen in about 70% of HNA patients. This can confirm the diagnosis of HNA. Ultrasound can also help detect diaphragm weakness. However, currently not many centers offer ultrasound of the brachial plexus nerves and diaphragm.
A traditional x-ray (radiograph) of the shoulder may be ordered to rule out specific conditions that can damage the shoulder.
Treatment
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.
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, especially if they can be started early (i.e. within the first 1-2 weeks) However, corticosteroids have proven ineffective for many individuals and are potentially associated with adverse side effects. In some patients, intravenous immunoglobulin (IVIG) seems to be effective in the acute phase. This treatment, however, is very expensive and not well researched yet.
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 patients, 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). In a pilot study, a specific rehabilitation approach that focused on scapular coordination, energy distribution strategies and self-management, was found helpful to improve functioning and performance satisfaction in daily life.
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. Occasionally 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. This is because the decreased muscle endurance and altered movement patterns do not tend to go away by themselves. Many individuals experience repeated episodes, which increases the risk of long-term complications or disability. Most affected individuals experience residual persistent pain and decreased endurance or exercise intolerance in the affected shoulder. Affected individuals often 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.
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov .All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
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Naito KS, Fukushima K, Suzuki S, et al. Intravenous immunoglobulin (IVIg) with methylprednisolone pulse therapy for motor impairment of neuralgic amyotrophy: clinical observations in 10 cases. Intern Med. 2012;51:1493-1500. https://www.ncbi.nlm.nih.gov/pubmed/22728480
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van Alfen N, Huisman WJ, Overeem S, van Engelen BG, Zwarts MJ.Sensory nerve conduction studies in neuralgic amyotrophy. Am J Phys Med Rehabil. 2009 Nov;88(11):941-6. doi: 10.1097/PHM.0b013e3181a5b980
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INTERNET
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McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:162100; Last Update:07/09/2016. Available at: https://omim.org/entry/162100 Accessed May 21, 2020.
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