Myasthenia Gravis

Disease Overview

Myasthenia gravis is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. Although the disorder usually becomes apparent during adulthood, symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia), or may become more generalized (generalized myasthenia gravis), involving multiple muscle groups.

Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis); weakness of eye muscles, resulting in double vision (diplopia); and excessive muscle fatigue following activity. Additional features commonly include weakness of facial muscles; impaired speech (dysarthria); difficulties chewing and swallowing (dysphagia); and weakness of the upper arms and legs (proximal limb weakness). In addition, in about 10% of affected individuals may develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis).

Myasthenia gravis results from an abnormal immune reaction in which the body’s natural immune defenses (i.e., antibodies) inappropriately attack and gradually injure certain receptors in muscles that receive nerve impulses (antibody-mediated autoimmune response).

Treatments include medications such as anticholinesterase drugs, immunosuppressive drugs and efgartigimod (Vyvgart), a procedure such as plasmapheresis, antibody infusions and a surgery for removal of the thymus.

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Synonyms

• MG

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Subdivisions

• generalized myasthenia gravis
• ocular myasthenia gravis
• transient neonatal myasthenia gravis

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Signs & Symptoms

Symptoms may be variable, with disease involvement potentially localized to certain muscles or affecting multiple muscles. In some affected individuals, the disease process may be limited to certain eye muscles, which is often described as “ocular myasthenia.” In those with more generalized disease or “generalized myasthenia gravis,” affected muscles may include those of the eyes, face, jaw and throat region, arm and leg muscles, and muscles involved in breathing (respiratory muscles). The disorder often begins with weakness of muscles controlling the eyes, resulting in drooping of the upper eyelids (ptosis), double vision (diplopia) or both.

Signs and symptoms may include:

• Variable muscle involvement:
  • Some people have localized involvement, affecting only certain muscles
  • In others, the disease can affect multiple muscle groups
• Ocular myasthenia (localized to eye muscles):
  • Disease limited to the muscles controlling the eyes
• Generalized myasthenia gravis:
  • Muscles affected may include:
    • Eyes, causing drooping of the upper eyelids (ptosis), double vision (diplopia)
    • Face, jaw and throat weakness that may cause:
      • Difficulty speaking (dysarthria), where the voice may sound weak, hoarse or nasal
      • Trouble chewing and swallowing (dysphagia) that can lead to choking, coughing or inhaling food or liquids (aspiration)
    • Arm and leg weakness and easy fatigue
    • Respiratory muscles which may affect breathing
• Myasthenic crisis:
  • Occurs in approximately 10% of patients
  • Sudden, severe weakness of the jaw, throat (oropharyngeal) or respiratory muscles
  • Can require respiratory support
  • Triggers for sudden worsening may include:
    • Infections, severe stress, surgery, changes in prednisone dosage

• MuSK antibodies: Some people with MuSK antibodies may experience muscle atrophy, especially in the face and tongue muscles.

The progression of the disease can be very variable and muscle weakness may vary from hour to hour, day to day, or over weeks and months. Weakness tends to worsen with repeated muscle use and improves with rest.

There are periods of remissions and exacerbations, especially common during the early years of the disease. Symptoms can temporarily improve (remission) or worsen (exacerbation). Factors that may trigger short-term worsening include infections, excessive physical activity, menstruation and childbirth.

Transient Neonatal Myasthenia Gravis 

• Infants of mothers with myasthenia gravis:
  • May develop a temporary form of the disorder, starting around 48 hours after birth
• Symptoms in newborns may include:
  • Generalized muscle weakness and low muscle tone (hypotonia)
  • Difficulty with sucking or swallowing
  • Weak cry
  • Breathing problems (respiratory insufficiency)
  • Reduced spontaneous movement
  • Symptoms may last days to weeks, after which the baby’s muscle strength returns to normal

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Causes

Most individuals with myasthenia gravis (MG) have no family history of MG and the disorder appears to occur spontaneously (sporadically) for unknown reasons. However, upwards of 5 percent of patients may have family members with MG or other autoimmune disorders. Individuals with MG have an increased frequency of certain genetically determined “human leukocyte antigens” (HLAs), suggesting that genetic predisposition may play some role. (HLAs are proteins that play an important role in the body’s immune system; they influence the outcome of transplantation and appear to affect an individual’s predisposition to certain diseases.) Other autoimmune diseases also appear to occur with increased frequency in individuals with MG, including thyroid disorders and systemic lupus erythematosus. These observations suggest that there is some genetic predisposition to MG which requires a trigger from the environment to cause the disease.

Myasthenia gravis is caused by an abnormal immune reaction (antibody-mediated autoimmune response) in which the body’s immune defenses (i.e., antibodies) inappropriately attack certain proteins in muscles that receive nerve impulses. The areas of contact between nerve endings and skeletal muscle fibers are known as neuromuscular junctions. Nerve endings release a chemical (the neurotransmitter acetylcholine) that transmits impulses to muscle fibers, ultimately resulting in their contraction. However, in individuals with myasthenia gravis, antibodies are inappropriately directed against sites (receptors) on the surface of certain muscle cells that bind with the neurotransmitter acetylcholine (acetylcholine receptors). (These antibodies are known as “anti-acetylcholine receptor antibodies [anti-AChR].)

The abnormal autoimmune response results in a decreased number of acetylcholine receptors, causing failed nerve transmission at certain neuromuscular junctions and associated deficiency or weakness of muscle contractions. Some patients with anti-AChR have antibodies that attack another protein called the muscle specific kinase protein (MuSK). These anti-MuSK antibodies also lead to a decrease in the number of acetylcholine receptors. Recently, antibodies to LRP-4 (lipoprotein receptor protein 4) were identified in patients without antibodies to MuSK or AChR. In five to eight percent of patients an antibody in the blood cannot be identified but patients have other tests consistent with myasthenia gravis.

The specific cause of abnormal autoimmune responses in patients with myasthenia gravis is unknown. However, researchers suggest that the thymus has some role in this process. According to reports in the medical literature, up to approximately 75% of individuals with myasthenia gravis have distinctive abnormalities of the thymus. In most patients, there are increased numbers of cells in the thymus (hyperplasia). In addition, in about 10% of affected individuals, the thymus contains a tumor (thymoma) that is typically noncancerous (benign). However, some thymomas may be malignant. Researchers suggest that the thymus of MG patients does not appropriately eliminate cells that produce antibodies that attack body tissues.

Antibodies are produced that react against acetylcholine receptors, triggering the abnormal autoimmune response within the thymus. A lymphoid tissue organ located behind the breastbone, the thymus, plays an important role in the immune system beginning during early fetal development until puberty. It is important in the maturation of certain specialized white blood cells (T lymphocytes) that have several functions, including assisting in the recognition of certain foreign proteins (antigens) or binding to cells invaded by microorganisms and destroying them. The abnormalities that lead to production of anti-MuSK antibodies is poorly understood and appears not to involve the thymus.

Some infants born to mothers with myasthenia gravis may develop temporary muscle weakness and associated findings (i.e., transient neonatal myasthenia gravis). This condition results from the passage of anti-acetylcholine receptor antibodies through the placenta to the unborn child during pregnancy.

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Affected populations

Myasthenia gravis has a prevalence of approximately 14-40 per 100,000 individuals in the United States. Reports indicate that the frequency of the disorder has appeared to increase over the last several decades. This may be because of better identification of patients, but also autoimmune disorders in general are increasing in frequency across the world.

Myasthenia gravis more frequently affects females than males. Associated symptoms may become apparent at any age; however, symptom onset most commonly peaks in females during their 20s or 30s and in males in their 50s or 60s.

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Disorders with Similar Symptoms

Symptoms of the following disorders may be similar to those of myasthenia gravis (MG). Comparisons may be useful for a differential diagnosis:

Lambert-Eaton myasthenic syndrome is also known as Eaton-Lambert syndrome. It is a rare autoimmune disorder of adulthood in which antibodies abnormally attack certain proteins on the surface of nerve endings that regulate calcium levels (calcium channels), resulting in inadequate release of acetylcholine. It is characterized by muscle weakness and fatigue, particularly of the hip and thigh muscles. Additional symptoms and findings may include absence of certain reduced reflex responses and dysfunction of involuntary functions (autonomic symptoms), such as dryness of the mouth, constipation, impotence and/or other abnormalities. Cancer, particularly certain types of lung cancer, is frequently associated with the disease.

Patients with ocular myasthenia may be confused with having a stroke in the brainstem or within nerves that control eye movements. Patients with Graves’ disease that involves the muscles that move the eyes may also be misdiagnosed with MG. However, MG and Graves’ disease may occur simultaneously in a patient.

Congenital myasthenia, or congenital myasthenic syndromes (CMS) are genetic disorders caused by changes (variants) in genes involved in nerve-muscle communication. CMS are present from birth or early childhood and are not treated with immunosuppressive medications. CMS tend to be more stable or slowly progressive compared to MG. Both conditions affect the neuromuscular junction, but their causes, onset and treatments differ significantly.

Symptoms may include:

• Feeding difficulties

• Episodes of reduced breathing (apnea)

• Slow growth and weight gain

• Muscle weakness and fatigue

• Paralysis or weakness of the eye muscles (ophthalmoplegia)

Additional disorders may also be characterized by certain symptoms and findings similar to those associated with the different forms of myasthenia gravis. Such disorders are typically associated with characteristic features that may help to differentiate them from MG.

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Diagnosis

Myasthenia gravis is diagnosed based upon a thorough clinical evaluation, detection of characteristic symptoms and physical findings, a detailed patient history and a variety of specialized tests. The diagnosis is suspected based on a characteristic distribution of muscle weakness and fatigue, without impairment other of neurologic function. Diagnostic studies include the intravenous injection of a drug that rapidly inhibits the action of an enzyme involved in breaking down acetylcholine, allowing the neurotransmitter to repeatedly interact with available acetylcholine receptors (edrophonium or Tensilon test). In those with the disorder, anticholinesterase testing of weak muscle groups temporarily restores muscle strength. The drugs edrophonium or neostigmine may be used during such testing. The ice pack test involves placing a cold pack across the eyes for 10 minutes and then determining if eye lid droop has significantly improved. The rest test involves a patient closing their eyelids for 30 minutes and again assessment for improved lid position or eye movement is made. For all these tests there can be “false negatives” in which a patient with disease does not show improvement with the testing.

Specialized blood studies are also conducted to detect the presence of antibodies to the acetylcholine receptor or muscle specific kinase. Acetylcholine receptor antibodies may be detected in up to 90 percent of affected individuals with generalized disease and up to 50 percent of those with the ocular form. Muscle specific kinase antibodies are found in about 3-6 percent of patients and LRP-4 antibodies even more rarely.

Additional diagnostic studies may include electromyography (EMG), a test that records electrical activity in skeletal muscles. A specialized test usually performed only at academic medical centers called a single fiber exam is highly sensitive for detecting the abnormalities of MG. In addition, advanced imaging techniques may be conducted to help detect tumors of the thymus. Such studies may include computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the mediastinum, which is the space between the lungs that contains the thymus and several other bodily structures. During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves create detailed cross-sectional images of certain organs and tissues.

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Standard Therapies

Treatment

Myasthenia gravis is a chronic condition that affects muscle strength, but with the right treatments, most people can manage their symptoms and live a normal life. While there’s no known cure for myasthenia gravis, there are several treatments available to help reduce muscle weakness and improve quality of life.

Common treatments for myasthenia gravis include:

• Anticholinesterase medications: These medications, like pyridostigmine (Mestinon), help improve muscle strength by slowing the breakdown of acetylcholine, a chemical that helps muscles contract. By improving communication between nerves and muscles, these drugs can reduce muscle weakness.
• Thymectomy (surgical removal of the thymus gland): Some people with myasthenia gravis may benefit from a thymectomy, which involves removing the thymus gland. Studies show that this surgery can reduce symptoms by rebalancing the immune system, potentially leading to less reliance on immunosuppressive drugs and improving muscle strength. Around 50% of patients experience long-term remission after this procedure.
  • Thymectomy is generally recommended for individuals with generalized myasthenia gravis between the ages of 18 and 65 who have acetylcholine receptor antibodies.
  • Thymectomy is not typically advised for people with ocular myasthenia unless a thymoma (a tumor in the thymus gland) is present.
  • Surgery is not helpful for congenital myasthenia, which does not involve the immune system.

• Immunosuppressive drugs: Medications like prednisone, azathioprine, mycophenolate mofetil and tacrolimus are used to suppress the immune system. By lowering the production of harmful antibodies that attack the neuromuscular junction, these drugs can help improve muscle strength. However, they can cause serious side effects, so regular monitoring by a doctor is essential.
• Complement inhibition: The medication eculizumab (Soliris) is used to treat people with generalized myasthenia gravis who test positive for the anti-acetylcholine receptor (AchR) antibody. Eculizumab blocks certain proteins in the immune system that damage the neuromuscular junction. Though effective, it is expensive and usually reserved for people who haven’t responded to other treatments.
• Efgartigimod (Vyvgart) was approved by the FDA in 2021 for adults with generalized myasthenia gravis who test positive for anti-acetylcholine receptor antibodies. This medication works by reducing the harmful antibodies that cause the disease.
• Plasmapheresis and intravenous immunoglobulin (IVIG): These therapies are often used in severe cases or during a myasthenic crisis, a life-threatening complication where muscle weakness affects breathing. Both treatments provide short-term relief, lasting a few weeks to months.
  • Plasmapheresis, also known as plasma exchange, is a procedure that filters harmful antibodies from the blood providing a short-term reduction in the levels of anti-ACh receptor antibodies
    • Plasmapheresis may be effective as a temporary therapy in those with severe symptoms or to help treat myasthenic crisis
    • Plasmapheresis may be recommended to help improve an affected individual’s condition before a surgical removal of the thymus
  • IVIG gives a temporary boost to the immune system by providing healthy antibodies (immunoglobulins) obtained from thousands of blood donors and by purification of the fluid portion of the blood

Myasthenic crisis is a medical emergency that requires management in an intensive care unit. Treatment may include emergency respiratory assistance (assisted ventilation); temporary cessation of anticholinesterase therapy to exclude excessive dosage as a possible cause, immediate treatment of possible causative infection with appropriate antibiotic medication or other therapy including plasmapheresis, intravenous immunoglobulin, high dose prednisone and possibly other therapies.

Some medications, including certain antibiotics and muscle relaxants, can worsen symptoms. It’s important for people with myasthenia gravis to avoid or use these drugs with caution. Affected people should always check with their doctor before starting new medications.

Gentle, regular exercise may help maintain muscle strength, but it’s important to avoid overexertion. Some people may benefit from assistive devices to help with mobility, and working closely with a physical therapist can ensure exercises are done safely.

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Clinical Trials and Studies

Researchers are constantly looking for new treatments. The Myasthenia Gravis Rare Disease Network MGNet project, for example, is collecting data from people with the condition to improve treatments and, ultimately, find a cure. Clinical trials are ongoing to test new drugs and therapies, which may provide better results with fewer side effects in the future.

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:

Tollfree: (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, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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Resources

RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease.  For more information, visit www.rareconnect.org

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References

TEXTBOOKS
Engel AG. Myasthenia Gravis and Related Disorders. Oxford University Press, Oxford UK, 2012.

Kaminski HJ Kusner LL, Myasthenia Gravis and Related Disorders, New York, NY. 3rd Edition, Humana Press (Springer); 2016.

JOURNAL ARTICLES
Narayanaswami P, Sanders DB, Wolfe G, et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. Nov 3 2020.

Gilhus NE. Myasthenia Gravis. N Engl J Med. Mar 30 2017;376(13):e25.

Melzer N, Ruck T, Fuhr, P, et al. Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society. J Neurol. 2016;263:1473-94.

Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology 2016; 87:419-25.

Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375:511-22.

Cavalcante P, Bernasconi P, Mantegazza R. Autoimmune mechanisms in myasthenia gravis. Curr Opin Neurol 2012;25(5):621-629.

Haines SR, Thurtell MJ. Treatment of ocular myasthenia gravis. Curr Treat Options Neurol 2012;14(1):103-112.

Pevzner A, Schoser B, Peters K, Cosma NC, Karakatsani A, Schalke B, Melms A, Kroger S. Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. J Neurol 2012;259(3):427-435.

Sri-udomkajorn S, Panichai P, Liumsuwan S. Childhood myasthenia gravis: clinical features and outcomes. J Med Assoc Thai 2011;94 Suppl 3:S152-157.

Zielinski M. Management of myasthenic patients with thymoma. Thorac Surg Clin 2011;21(1):47-57.

INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Myasthenia Gravis. Last Update 08/23/2024. Available at: https://omim.org/entry/254200 Accessed Sept 26, 2024.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Myasthenic Syndrome, Congenital, Associated with Episodic Apnea. Entry No: 254210. Last Updated 07/21/2017. Available at: https://omim.org/entry/254210 Accessed Sept 26, 2024.

Shah A. Myasthenia Gravis. Dec 05, 2023. Medscape Reference. https://emedicine.medscape.com/article/1171206-overview Accessed Sept 26, 2024.

Myasthenia Gravis. National Institute of Neurological Disorders and Stroke. July 19, 2024. https://www.ninds.nih.gov/health-information/disorders/myasthenia-gravis Accessed Sept 26, 2024.

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Programs & Resources

• Assistance Programs
• Patient Organizations
• More Information

RareCare^® Assistance Programs

Myasthenia Gravis Medical Assistance

Accepting Applications

Phone: 860-498-4307 Email: [email protected] Fax: 203-571-3167

Related Rare Diseases: Myasthenia Gravis

Resource(s): MG-PremCopay&Medical Assist-Sept2024

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Myasthenia Gravis Premium Copay Assistance

Accepting Applications

Phone: 860-498-4307 Email: [email protected] Fax: 203-571-3167

Related Rare Diseases: Myasthenia Gravis

Resource(s): MG-PremCopay&Medical Assist-Sept2024

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Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

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Patient Organizations

Myasthenia Gravis Foundation of America, Inc

NORD Member

Email: [email protected]

Related Rare Diseases: Congenital Myasthenic Syndromes, Autoimmune Polyendocrine Syndrome Type II, Lambert-Eaton Myasthenic Syndrome, ...

https://rarediseases.org/organizations/myasthenia-gravis-foundation-of-america-inc/

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Muscular Dystrophy Association

NORD Member

Phone: 800-572-1717 Email: [email protected]

Related Rare Diseases: X-Linked Myopathy with Excessive Autophagy, Walker Warburg Syndrome, GNE Myopathy, ...

https://rarediseases.org/organizations/muscular-dystrophy-association/

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Autoimmune Association

Email: [email protected]

Related Rare Diseases: Warm Autoimmune Hemolytic Anemia, Systemic Scleroderma, Miller Fisher Syndrome, ...

https://rarediseases.org/organizations/autoimmune-association/

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Muscular Dystrophy Canada

Email: [email protected] Fax: 416-488-7523

Related Rare Diseases: Distal Myopathy, Facioscapulohumeral Muscular Dystrophy, Giant Axonal Neuropathy, ...

https://rarediseases.org/organizations/muscular-dystrophy-canada/

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NIH/National Institute of Neurological Disorders and Stroke

Phone: 301-496-5751 Fax: 301-402-2186

Related Rare Diseases: MOG Antibody Disease, Aromatic L-Amino Acid Decarboxylase Deficiency, Miller Fisher Syndrome, ...

https://rarediseases.org/organizations/nih-national-institute-of-neurological-disorders-and-stroke/

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New Horizons Un-Limited, Inc.

Phone: 414-299-0124 Email: [email protected] Fax: 414-347-1977

Related Rare Diseases: MECP2 Duplication Syndrome, Collagen Type VI-Related Disorders, Spinal Muscular Atrophy, ...

https://rarediseases.org/organizations/new-horizons-un-limited-inc/

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European Society for Immunodeficiencies

Email: [email protected]

Related Rare Diseases: Complete DiGeorge Syndrome, CARD9 Deficiency, WHIM Syndrome, ...

https://rarediseases.org/organizations/european-society-for-immunodeficiencies/

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The AIP BIPOC Network

Email: [email protected]

Related Rare Diseases: Cicatricial Alopecia, Alopecia Areata, Autoimmune Hepatitis, ...

https://rarediseases.org/organizations/the-aip-bipoc-network/

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More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).

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Orphanet

Orphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.

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OMIM

Online Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

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