Anemia, Hemolytic, Acquired Autoimmune

The autoimmune hemolytic anemias are rare disorders characterized by the premature destruction (hemolysis) of red blood cells at a rate faster than they can be replaced. Acquired hemolytic anemias are non-genetic in origin. Idiopathic acquired autoimmune diseases occur when the body’s natural defenses against invading organisms (e.g., lymphocytes, antibodies) destroy its own healthy tissues for no known reason. Normally, the red blood cells (erythrocytes) have a life span of approximately 120 days before being removed by the spleen. The severity of this type of anemia is determined by the life span of the red blood cell and by the rate at which these cells are replaced by the bone marrow.

Generally symptoms of acquired autoimmune hemolytic anemia resemble those of other anemias and may include fatigue, pale color, rapid heartbeat, shortness of breath, dark urine, chills, and backache. In severe cases, yellow skin color (jaundice) may be present and the spleen may be enlarged.

Hemolytic anemia may be caused by any one or more of several kinds of disorders. For example, contributing factors may include:

When acquired autoimmune hemolytic anemia occurs from unknown causes, it affects twice as many women as men, specifically women under 50 years old. Cold antibody hemolytic anemia most commonly affects elderly persons, and warm antibody hemolytic anemia can affect anyone at any age.

Symptoms of the following disorder can be similar to those of Acquired Autoimmune Hemolytic Anemia. Comparison may be useful for a differential diagnosis:

Paroxysmal Nocturnal Hemoglobinuria is a disorder characterized by a decrease of red blood cells (anemia) caused by a defect in the membrane of the red blood cells. The major symptom is the presence of blood in the urine (hemoglobinuria) which occurs chiefly at night due to the breakdown of red blood cells. Other symptoms may include paleness, severe abdominal or back pain, yellowing of the skin (jaundice) and enlargement of the spleen and liver. (For more information on this disorder, choose Paroxysmal Nocturnal Hemoglobinuria as your search term in the Rare Disease Database.)


Anemia, Pernicious

*This condition is no longer considered rare

Symptoms of pernicious anemia may include fatigue, shortness of breath, rapid heart rate, jaundice or pallor, tingling and numbness of hands and feet, loss of appetite, diarrhea, unsteadiness when walking, bleeding gums, impaired sense of smell, and confusion.

Pernicious anemia is thought to be an autoimmune disease.  Autoimmune disorders are caused when the body’s natural defenses (e.g., antibodies) against foreign or invading organisms begin to attack healthy tissue for unknown reasons.  Pernicious anemia is sometimes seen in association with certain autoimmune endocrine diseases, such as type 1 diabetes, hypoparathyroidism, Addison’s disease, and Graves’ disease.

Slightly more women than men are affected by pernicious anemia.  The adult form is the most common, and diagnosis typically takes place at around 60 years of age.

The diagnosis of pernicious anemia may be confirmed by a thorough clinical evaluation, including a detailed patient history and specialized laboratory tests. During a Schilling test, the intestines' ability to absorb vitamin B12 is measured. The vitamin is labeled with radioactive cobalt and is ingested by mouth. X-ray studies can then determine if the body is properly absorbing this vitamin.


Anencephaly

Pregnancies affected by anencephaly show high levels of a specific fetal protein (called alpha fetoprotein) in tests done on the mother’s blood or on amniotic fluid.  The presence of excess fluid in the amniotic sac that contains the fetus (polyhydramnios) may be noted during an ultrasound.

Not all of the causes of anencephaly are understood.  Anencephaly can be a multifactorial condition meaning that multiple genes are involved interacting with environmental agents and chance events to cause the condition.  Anencephaly can also be a feature of some chromosomal disorders such as trisomy 18 which are usually sporadic and not familial (inherited).

Many fetuses with anencephaly are stillborn or are spontaneously aborted, but more females are born with anencephaly than males.

The following birth defects can be similar to those of anencephaly. Comparing these terms may help you understand the difference between the diagnoses.


Angelman Syndrome

Angelman syndrome is associated with a broad spectrum of possible symptoms. The specific symptoms of Angelman syndrome vary from person to person. Individuals with Angelman syndrome will not have all of the symptoms discussed below. For example, some individuals with Angelman syndrome may have seizures, others may not. Most may be unable to speak while in a few there is some limited speech.

Deficiency of the E3 ubiquitin protein ligase (UBE3A) gene expression causes Angelman syndrome. The gene is located in chromosome region 15 (15q11-q13).

Angelman syndrome affects males and females in equal numbers. The prevalence of Angelman syndrome is estimated to be approximately 1 in 12,000-20,000 people in the general population. However, many cases may go undiagnosed making it difficult to determine the disorder’s prevalence in the general population.

Symptoms of the following disorders can be similar to those of Angelman syndrome. Comparisons may be useful for a differential diagnosis.

A diagnosis of Angelman syndrome may be made based upon a detailed patient history, a thorough clinical evaluation and identification of characteristic findings. About 80% of cases can be confirmed through a variety of specialized blood tests such as DNA methylation (detects, but does not discriminate between chromosome deletion, imprinting center defect and paternal uniparental disomy). Fluorescent in situ hybridization (FISH) or, most commonly, microarray chromosome analysis can detect the characteristic deletion (seen in 70% of cases) of chromosome 15q11-q13 in cells of the body. Mutation analysis of the Angelman gene, UBE3A, can detect about 10% of individuals with Angelman syndrome who have negative DNA methylation studies.  Mutation analysis of UBE3A can be either ordered specifically as a single test but, more often now, UBE3A mutations are identified by use of a whole exome sequencing panel that includes a group of many genes known to cause intellectual deficiency or when one performs a complete whole exome sequencing test (e.g., a screening test on approximately 20,000 genes).


Angioimmunoblastic T-cell lymphoma

血管免疫母细胞性T细胞淋巴瘤

Angioimmunoblastic T-cell lymphoma (AITL) is a rare form of non-Hodgkin lymphoma, which is a group of related malignancies (cancers) that affect the lymphatic system (lymphomas). Lymphomas are cancer of white blood cells (lymphocytes) and can be divided depending on the type of cells, B-lymphocytes (B-cells) or T-lymphocytes (T-cells), AITL is a T-cell lymphoma. The lymphatic system functions as part of the immune system and helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream.

The specific symptoms and physical findings may vary from one person to another, depending upon the extent and region(s) of involvement and other factors. The progression is often aggressive, but spontaneous remission has occurred in some people. All organ systems can potentially be affected. Researchers believe that many of the symptoms associated with AITL result from dysfunction of the immune system rather than from complications relating to tumor growth or spread.

The exact, underlying cause of AITL is unknown. It is believed that a dysfunctional immune system response to an unknown antigen ultimately leads to the development of the disorder. An antigen is any substance that causes the immune system to produce antibodies. The process through which a dysfunctional or abnormal immune system response ultimately progresses to lymphoma is not fully understood.

The incidence of AITL in the general population is unknown. It is estimated to account for 1-2 percent of all people with non-Hodgkin lymphoma. Some reports state the AITL occurs slightly more often in men than women, but others state the ratio is 1:1. Most people develop AITL in their 60s and 70s. The disorder can occur in younger adults and, although rarely, has also been reported in children.

Symptoms of the following disorders can be similar to those of AITL. Comparisons may be useful for a differential diagnosis.

A diagnosis of AITL is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a biopsy of an affected lymph node or other affected areas such as the skin or bone marrow.

The diagnosis and therapeutic management of AITL may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other healthcare professionals.


无虹膜症-小脑共济失调-智力障碍综合征

Aniridia Cerebellar Ataxia Mental Deficiency

Aniridia, cerebellar ataxia, and mental deficiency, also known as Gillespie syndrome, is an extremely rare inherited disorder that is characterized by the absence, in whole (aniridia) or in part (partial aniridia), of the colored portion (iris) of the eye; impaired coordination of voluntary movements due to underdevelopment (hypoplasia) of the brain’s cerebellum (cerebellar ataxia); and mental retardation. The condition usually affects both eyes (bilateral) but a few cases have been reported in which only one eye is affected. Some individuals with this syndrome also exhibit a delay in the acquisition of skills requiring coordination of muscular and mental activity (psychomotor retardation). ACAMD is thought to be inherited as an autosomal recessive genetic trait and is extremely rare, with only 20 to 30 cases reported in the medical literature.

Aniridia-cerebellar ataxia-mental deficiency, also known as Gillespie syndrome, is an extremely rare inherited disorder that is characterized by malformations of the eye, neuromuscular abnormalities, developmental delays, and/or mental retardation.  Some affected individuals may also exhibit additional physical abnormalities.

The disorder aniridia, cerebellar ataxia and mental deficiency is thought to be inherited as an autosomal recessive genetic trait, but researchers have not yet been able to establish the mode of inheritance conclusively.  The genetics of the disorder are not well understood at this time.

Aniridia, cerebellar ataxia and mental deficiency is an extremely rare inherited disorder that appears to affect females more than males, although the sample size is very low.  Only about 20 or 30 cases have been reported in the medical literature.  One report suggests that people with this syndrome make up about 2% of all patients with aniridia.

Marinesco-Sjogren Syndrome is a rare inherited disorder that is characterized by impaired coordination of voluntary movement due to underdevelopment (hypoplasia) of the cerebellum (cerebellar ataxia), clouding of the lens of both eyes (bilateral cataracts), involuntary movements of the eyes (nystagmus), difficulty speaking due to an impaired ability to control the muscles enabling speech (dysarthria), and/or mild mental retardation.  Many affected individuals exhibit additional physical abnormalities.  Marinesco-Sjogren Syndrome is inherited as an autosomal recessive genetic trait.  (For more information on this disorder, choose Marinesco-Sjogren as your search term in the Rare Disease Database.)

The diagnosis of aniridia, cerebellar ataxia and mental deficiency may be made at birth if the newborn (neonate) presents with partial absence of the iris in association with hypotonia. Although partial aniridia may be obvious at birth, the other symptoms may not become apparent until later in the child's development. Therefore, the disorder usually is not diagnosed until early childhood, based upon a thorough clinical evaluation, a detailed patient history, specialized laboratory tests, and advanced imaging techniques.


Anthra

Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. It is usually a disease of wild and domestic animals, including cattle, sheep, and goats. However, human infection, while rare, does occur. Human infection usually results from contact with infected animals or their products. However, anthrax has become of interest because of the possibility that a nation or terrorist group might attempt to use it as a weapon of warfare or terrorism. There are three types of anthrax: cutaneous (through the skin), gastrointestinal, and inhalational.

Symptoms usually appear within seven days of exposure, although in some cases the incubation period has been significantly longer than this.

Anthrax is primarily a disease of animals, specifically herbivores such as cattle, goats, and sheep. They contract the disease after coming into contact with B. anthracis spores, which are present in the soil around the world. The rare cases when humans are infected typically occur when people come into contact through their occupations with infected animals or when people eat undercooked meat or other products from infected animals. Its occurrence is most likely in developing countries, although animal products imported from those countries may pose a risk.

Anthrax is most common in developing countries. It can be found globally, although the regions of the world with the greatest incidence of agricultural anthrax are South and Central America, Southern and Eastern Europe, Asia, Africa, the Caribbean, and the Middle East.

Influenza is a common infectious viral disease with symptoms that may appear similar to inhalational anthrax. However, anthrax does not cause runny nose, which is a typical symptom of the common cold and influenza. Also, patients with anthrax appear to have abnormal X-rays, while those with flu and other viruses do not.

Cutaneous anthrax may be diagnosed by the characteristic signs, such as the raised area on the skin and detection of the presence of the anthrax bacilli in the area of the lesion. A history of exposure to livestock or other possible animal sources also is important. Gastrointestinal anthrax is more difficult to diagnose. In the first, mild phase of inhalational anthrax, symptoms resemble a common cold or upper respiratory infection. With the sudden onset of the more severe symptoms of the second phase, radiographic examination of the chest may show characteristic changes.


Antiphospholipid syndrome

欧洲非罕见：抗磷脂综合征

Antiphospholipid syndrome (APS) is a rare autoimmune disorder characterized by recurring blood clots (thromboses). Blood clots can form in any blood vessel of the body. The specific symptoms and severity of APS vary greatly from person to person depending upon the exact location of a blood clot and the organ system affected. APS may occur as an isolated disorder (primary antiphospholipid syndrome) or may occur along with another autoimmune disorder such as systemic lupus erythematosus (secondary antiphospholipid syndrome).

The specific symptoms associated with antiphospholipid syndrome are related to the presence and location of blood clots. Blood clots can form in any blood vessel of the body. Clots are twice as likely to form in vessels that carry blood to the heart (veins) as in vessels that carry blood away from the heart (arteries). Any organ system of the body can become involved. The lower limbs, lungs and brain are affected most often. APS also causes significant complications during pregnancy.

Antiphospholipid syndrome is an autoimmune disorder of unknown cause. Autoimmune disorders are caused when the body natural defenses (antibodies, lymphocytes, etc.) against invading organisms attack perfectly healthy tissue. Researchers believe that multiple factors including genetic and environmental factors play a role in the development of APS. In rare cases, APS has run in families suggesting that a genetic predisposition to developing the disorder may exist.

APS affects males and females, but a large percentage of primary APS patients are women with recurrent pregnancy loss. Some estimates suggest that 1 in 5 cases of recurrent miscarriages or deep vein thromboses are due to APS. As many as one-third of cases of stroke in people under 50 years of age may be due to APS. Secondary APS occurs mainly in lupus, and about 90% of lupus patients are female.

Symptoms of the following disorders can be similar to those of antiphospholipid syndrome. Comparisons may be useful for a differential diagnosis.

A diagnosis of antiphospholipid syndrome is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic physical findings (at least one blood clot or clinical finding), and a variety of tests including simple blood tests.


Antisynthetase syndrome

Antisynthetase syndrome is a rare, chronic disorder that can affect multiple systems of the body. The disorder is immune-mediated, which means there is inflammation resulting from abnormal functioning of the immune system and the presence of specific autoantibodies that target specific proteins in the body. The symptoms and severity of the disorder can vary greatly among affected individuals. Common symptoms include inflammation of the muscles (myositis), inflammation of several joints (polyarthritis), interstitial lung disease and thickening and cracking (fissuring) and discoloration of the skin of the fingers, called mechanic’s hands). Some individuals develop pain and numbness or a prickly feeling in the fingers and toes in response to cold (Raynaud phenomenon). During a Raynaud episode, the fingers or toes may turn white or blue.

The signs and symptoms can vary greatly from one person to another. Every person is unique and how the disorder will affect them can be very different. Symptoms can develop rapidly. Affected individuals will usually not have all of the symptoms discussed below. For example, some affected individuals will have little muscle involvement, but prominent signs of lung disease. Muscle disease, interstitial lung disease and arthritis are generally considered the three main symptoms of this disorder (the classic triad), but they may not develop at the same time.

The exact cause of antisynthetase syndrome is not fully understood. Affected individuals have autoantibodies. Antibodies are part of the immune system; they are specialized proteins that target foreign or invading organisms. Autoantibodies are antibodies that mistakenly attack healthy tissue. In antisynthetase syndrome, affected individuals have autoantibodies that target certain enzymes in the body called aminoacyl-tRNA synthetases. Enzymes are specialized proteins that help to bring about specific biochemical reactions in the body and aminoacyl-tRNA synthetases help to regulate the production of other proteins and are important for the overall health and function of the body. Researches do not know why these autoantibodies target aminoacyl-tRNA synthetases. Not every person who develops these autoantibodies will go on to develop symptoms of antisynthetase syndrome.

Antisynthetase syndrome is a rare disorder that affects females twice as often as males. Age of onset can range from the late teens to the elderly, with a mean average of the 50s. The exact incidence or prevalence of the disorder is unknown. Because rare disorders often go undiagnosed or misdiagnosed, determining the true frequency of antisynthetase syndrome in the general population is difficult.

Symptoms of the following disorders can be similar to those of antisynthetase syndrome. Comparisons may be useful for a differential diagnosis.

A diagnosis of antisynthetase syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and tests that confirm the presence of autoantibodies against the one of the aminoacyl-tRNA synthetase enzymes.


Antithrombin Deficiency

遗传性抗凝血酶缺乏所致遗传性易栓症

Antithrombin deficiency is a blood disorder characterized by the tendency to form clots in the veins (thrombosis). An inherited tendency to thrombosis is known as thrombophilia. Antithrombin is a substance in the blood that limits the blood’s ability to clot (coagulation) and the primary inhibitor of thrombin, which is required for the development of blood clots; it also is the primary inhibitor of two clotting factors, factor Xa and factor IXa, that are required for the generation of thrombin. In people with congenital antithrombin deficiency, there is a reduced amount of this substance in the blood due to a genetic abnormality. Antithrombin deficiency may also be acquired; in such cases, the disorder may be reversible with resoluton/improvement in the disease process responsible for the deficiency.

People with antithrombin deficiency are at risk of developing a blood clot (thrombus) within a vein (thrombosis). The first episode of thrombosis typically occurs before the age of 40 years. A thrombus is a clump of blood cells (i.e., platelets, clotting factors, fibrin, etc.) that may become attached (adhere) to the interior wall of a blood vessel, usually a deep vein in the leg. This may be brought on by surgery, pregnancy, childbirth, trauma, or use of oral contraceptives. About 40 percent of people with antithrombin deficiency develop a thrombus that pulls away from the wall of a vein in the legs or pelvis (deep vein thrombosis or DVT) and travels through the blood stream to the lungs (pulmonary embolism or PE). Pulmonary emboli are dangerous and hence DVT and PE must be treated quickly. Thrombi also occur the superficial veins in the legs (superficial thrombophlebitis). Thrombi may also occur in the veins in the abdomen (mesenteric, portal, hepatic or splenic veins) or around the brain (sinus veins). Clots in the arteries of the heart may lead to heart attack (myocardial infarction) and clots in the arteries of the brain to stroke. However, arterial clots are rare in antithrombin deficiency.

Antithrombin deficiency may be inherited or acquired. Inherited AT deficiency increases the risk of blood clots; acquired AT deficiency often does not. Acquired AT deficiency is the consequence of some other disorder, usually involving the liver, kidneys, or treatment of certain types of blood disorders, e.g., leukemias with a drug called L-asparaginase. Low antithrombin levels may also be temporarily associated with some other conditions such as heparin therapy, disseminated intravascular coagulation usually due to a severe infection of the blood stream, severe trauma, severe burns or the presence of acute blood clots.

Antithrombin deficiency is a rare disorder that affects males and females in equal numbers. Type I antithrombin deficiency is the most common subtype and is thought to occur in about one in every 3,000 to 5,000 people in the United States and is not limited to any particular ethnic group. It is estimated that approximately 1 percent of people who have venous thrombosis and embolism have congenital antithrombin deficiency. The acquired form of antithrombin deficiency is more prevalent than the congenital form of the disorder.

Symptoms of the following disorders can be similar to those of antithrombin deficiency. Comparisons may be useful for a differential diagnosis:

Antiphospholipid syndrome (APLS) is an autoimmune disorder characterized by blood clots in the veins or arteries.  Clots in arteries may break away from the walls of the blood vessels and result in stroke. Women with this disorder can experience a high rate of miscarriages. Other symptoms may include inflammation and thickening of the valves of the heart, migraine headaches, and skin rashes. (For more information on this disorder, choose Antiphospholipid as your search term in the Rare Disease Database.)


Amniotic band syndrome

Antley-Bixler syndrome is a rare genetic disorder that can cause structural changes of the skull, bones of the face and other skeletal abnormalities. The disorder is typically associated with premature closure of joints (cranial sutures) between particular bones of the skull (craniosynostosis). Many affected infants and children also may have a prominent forehead, underdeveloped midfacial regions (midfacial hypoplasia), protruding eyes (proptosis), and low-set ears.

Antley-Bixler syndrome is typically characterized by structural changes of the skull, bones of the face and other skeletal abnormalities. In most affected infants, there is premature closure of the joints (sutures) between different portions of the skull (craniosynostosis) Additional craniofacial abnormalities may include a large, prominent forehead (frontal bossing), underdeveloped middle regions of the face (midfacial hypoplasia); a large nose with a low nasal bridge; protruding eyes (proptosis); and low-set, malformed (dysplastic) ears.

Antley-Bixler syndrome can be caused by mutations in two different genes. ABS1 is associated with mutations in the POR gene and is inherited in an autosomal recessive pattern. This means that a person will have ABS1 when he or she inherits two non-working copies of the POR gene, one from each parent. If an individual receives one working copy of the gene and one not working copy of the gene, the person will be a carrier for the syndrome but will not show symptoms. When both parents are carriers for the syndrome, there is a 25 percent chance the child will have ABS1. Additionally, there is fifty percent chance their child will be carriers of the condition (just like their parents) and a twenty-five percent chance that their child will receive both working copies of the gene. The risk is the same for each pregnancy.

This condition has been described in over 30 patients to date. The estimated prevalence for the condition is less than 1 in 1,000,000.

Symptoms of the following disorders can be similar to those of Antley-Bixler syndrome. Comparisons may be useful for a differential diagnosis:

Primary craniosynostosis is a rare disorder of the skull. It occurs when there is an early closure of the bones (sutures) in the skull resulting in an abnormally shaped head. The severity of the symptoms and shape of the skull depend on which skull bones close early. In this condition, the head may be larger than normal due to accumulation of fluid (hydrocephaly) in the skull. (For more information on this disorder, choose primary craniosynostosis as your search term in the Rare Disease Database.)


严重智力障碍和进行性痉挛性截瘫

Severe intellectual disability and progressive spastic paraplegia

AP-4-Associated Hereditary Spastic Paraplegia (AP-4-HSP)

Most children with AP-4-associated HSP have:

AP-4-associated HSP are inherited in an autosomal recessive manner. The four genes that encode subunits of the AP-4 complex are AP4B1, AP4E1, AP4M1, and AP4S1.

AP-4-associated HSP affects males and females of many ethnic groups from around the world. The prevalence of AP-4-HSP is unknown. AP-4-HSP is likely under-recognized since the symptoms (phenotypic spectrum) largely overlap with that of cerebral palsy and, in the absence of genetic testing, patients may be misdiagnosed as having cerebral palsy.

Many of the initial clinical manifestations of AP-4-associated HSP are nonspecific and may resemble other disorders characterized by spasticity, developmental delay / intellectual disability and seizures. Patients may be misdiagnosed as having cerebral palsy.

The diagnosis of AP-4-associated HSP is based on clinical characteristics and testing that may include a brain MRI showing characteristic features such as a thin corpus callosum, wide lateral ventricles and changes in the white matter. A definitive diagnosis is reached by genetic testing.


Apert syndrome

Apert syndrome is characterized by craniosynostosis, the premature closure of the fibrous joints (sutures) between certain bones in the skull. In individuals without craniosynostosis, sutures allow an infant’s head to grow and expand. Eventually, these bones fuse together to form the skull. For people with craniosynostosis, the brain is still growing after these sutures prematurely close. The pressure of brain growth can cause various bones of the skull and face to change shape during development. Depending on which sutures prematurely close, the severity can vary. In most affected individuals, there is premature closure of the sutures between the bones forming the forehead and the upper sides of the skull. This tends to cause the head to appear pointed at the top (acrocephaly) from birth. In addition, the back portion of the skull may appear flattened, with a high and broad forehead. There can be a large, late-closing soft spot on the skull. Individuals may also have hydrocephalus, in which cerebrospinal fluid abnormally accumulates in the cavities of the brain. This can cause pressure on the brain.

Apert syndrome is caused by a change (mutation) in the fibroblast growth factor receptor-2 (FGFR2) gene. This gene plays a critical role in skeletal development. Genes provide instructions for creating proteins that play distinct roles in our body. When a mutation of a gene occurs, the protein product may not work as it should. In Apert syndrome, mutations in FGFR2 result in these receptors not properly communicating with fibroblast growth factors. This affects the formation of normal sutures in the brain and can obstruct the development of many other structures in the body. This improper formation is what causes the malformations seen in Apert syndrome.

Apert syndrome is estimated to occur in about one in 65,000 births. Males and females seem to have Apert syndrome in relatively equal numbers. Over 300 cases have been reported since the disorder was originally described in 1894 and 1906. Asian individuals have been reported to have the highest incidence of Apert syndrome.

Symptoms of the following disorders may be similar to those of Apert syndrome. Comparisons may be useful for a differential diagnosis.

A diagnosis of Apert syndrome is most often made at birth or during infancy. An individual is diagnosed through clinical evaluation and a variety of specialized tests. Physical features like facial anomalies or syndactyly would be identified. Skeletal abnormalities and congenital heart defects may be detected using imaging, like a computed tomography (CT) scan or an MRI. Hearing impairment may be detected during a newborn screening hearing test. Individuals may also have testing for mutations in the FGFR2 gene, which can provide a genetic diagnosis of Apert syndrome.


Adrenocortical carcinoma

Aplasia Cutis Congenita is a rare disorder with a complicated pattern of inheritance. Babies are born with the absence of certain layer(s) of skin, most often on the scalp, but also on the trunk, and/or arms and legs. The affected area is typically covered with a thin, transparent membrane. The skull and/or underlying areas may be visible and be abnormally developed. Aplasia Cutis Congenita may be the primary disorder or it may occur in association with other underlying disorders.

Individuals born with Aplasia Cutis Congenita lack skin (and therefore hair), in localized areas of the body, usually, but not always, on the scalp (70 percent of cases). In some cases, the trunk, arms, and/or legs may also be involved.  Sometimes, the underlying bone may be missing as well as the skin. The affected area(s) are usually replaced with a thin transparent membrane.  In some cases, these affected structures and other organs may be seen through the transparent membrane.

Aplasia Cutis Congenita is a rare disorder that may be inherited as an autosomal dominant or autosomal recessive trait.  Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

Aplasia Cutis Congenita is a very rare disorder that affects males and females in equal numbers.  At least five hundred cases have been reported in the medical literature.  Absence of skin is obvious at birth (congenital).

Aplasia Cutis Congenita may be one of the symptoms of the following disorders.

Diagnosis of Aplasia Cutis Congenita is generally obvious at birth through the characteristic absence of skin affecting the scalp, trunk, arms, and/or legs.


Apnea, Infantile

Apnea is a term used to describe the temporary absence of spontaneous breathing. Infantile apnea occurs in children under the age of one year. Apnea may occur because of neurological impairment of the respiratory rhythm or obstruction of air flow through the air passages. The symptoms of infantile apnea include the stoppage of breathing during sleep, an abnormal bluish discoloration to the skin (cyanosis) and sometimes an unusually slow heartbeat (bradycardia). Infantile apnea may be related to some cases of sudden infant death syndrome. Episodes of apnea may decrease with age. However, several forms of adult sleep apnea also exist.

The symptoms of infantile apnea include the temporary cessation of breathing; an abnormal bluish discoloration of the skin, lips, and mouth (cyanosis), and/or an unusually slow heartbeat (bradycardia).  Serious apnea is defined as the cessation of breathing during sleep for longer than 10 to 15 seconds.

The exact cause of infantile apnea is not known.  It may occur as the result of a combination of environmental and developmental factors (multifactoral). In extremely rare cases, central infantile apnea may be familial and affect more family members than would otherwise be expected.

Infantile apnea affects males and females in equal numbers and occurs in children less than 1 year old.  Infants who are born prematurely tend to experience episodes of apnea (apnea of prematurity).

Symptoms of the following disorders can be similar to those of infantile apnea.  Comparisons may be useful for a differential diagnosis:

Sudden infant death syndrome (SIDS) is the sudden death of any infant or young child that is unexpected, based on their medical history and for which no adequate cause for death can be found.  Infants are not breathing during a time when they are presumed to be sleeping.  The exact relationship between sudden infant death syndrome and infantile apnea is not clear.  (For more information on this disorder, choose sudden infant death as your search term in the Rare Disease Database.)

To help prevent the potentially severe complications of infantile apnea, home apnea and cardiac monitors can alert a parent or caregiver to an episode of symptoms. These devices should be purchased only under the advice of a physician who is knowledgeable about the safety and effectiveness of apnea and cardiac monitors. Treatment may sometimes include the administration of drugs that stimulate the respiratory system (i.e., theophylline or caffeine). Parents and caregivers should be knowledgeable in lifesaving techniques such as cardiopulmonary resuscitation (CPR). In some infants, overheating should be avoided to possibly help reduce the frequency of apneic episodes. The infant should sleep in a supine position, unless he/she has obstructive sleep apnea or gastroesophageal reflux.


Arachnoid Cysts

Arachnoid cysts are fluid-filled sacs that occur on the arachnoid membrane that covers the brain (intracranial) and the spinal cord (spinal). There are three membranes covering these parts of the central nervous system: the dura mater, arachnoid, and pia mater. Arachnoid cysts appear on the arachnoid membrane, and they may also expand into the space between the pia mater and arachnoid membranes (subarachnoid space). The most common locations for intracranial arachnoid cysts are the middle fossa (near the temporal lobe), the suprasellar region (near the third ventricle) and the posterior fossa, which contains the cerebellum, pons, and medulla oblongata.

In most cases, arachnoid cysts are present at birth (congenital), but usually do not cause any symptoms (asymptomatic) throughout an individual’s life. Less often, arachnoid cysts may develop because of head injury, the presence of a tumor, infection or surgery on the brain

The exact cause of arachnoid cysts is not known. Researchers believe that most cases of arachnoid cysts are developmental malformations that arise from the unexplained splitting or tearing of the arachnoid membrane. According to the medical literature, cases of arachnoid cysts have run in families (familial cases) suggesting that a genetic predisposition may play a role in the development of arachnoid cysts in some individuals.

Arachnoid cysts affect males more often than females. These cysts may occur at any age and have been found in all races and geographic locations. They are the most common type of intracranial cyst. Because many cases of arachnoid cysts have no symptoms, it is difficult to determine the true frequency of this disorder in the general population.

Symptoms of the following disorders can be similar to those of arachnoid cysts. Comparisons may be useful for a differential diagnosis:

Brain tumors are growths in the brain that can be either cancerous (malignant) or noncancerous (benign). The symptoms of malignant and benign brain tumors are similar, and depend on the type of tumor and its location. Symptoms may include recurrent headache, seizures, emotional instability, nausea, and/or facial pain or numbness. There are many different types of brain tumors. (For more information on these disorders, choose Brain Tumor as your search term in the Rare Disease Database).


Argininemia

Symptoms associated with arginase-1 deficiency differ from those associated with other disorders of the urea cycle. Most infants with arginase-1 deficiency do not exhibit any symptoms during the first few months to a year of life. Infants with arginase-1 deficiency infrequently experience severe hyperammonemia or hyperammonemic coma, which are characteristic of the other urea cycle disorders.

Arginase-1 deficiency is inherited as an autosomal recessive genetic disorder and is caused by changes (mutations or pathogenic variants) in the ARG1 gene. Mutations in the ARG1 gene result in production of an abnormal arginase enzyme.

Arginase-1 deficiency has been estimated to occur in approximately 1 in 300,000-1,000,000 births.

Symptoms of the following disorders may be similar to those of arginase-1 deficiency. Comparisons may be useful for a differential diagnosis:

The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures and/or coma. The liver may be abnormally enlarged (hepatomegaly). In some patients, life-threatening complications may result. In addition to arginase-1 deficiency, the other urea cycle disorders are: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinate synthetase deficiency (citrullinemia); argininosuccinate lyase (ASL) deficiency; ornithine transcarbamylase (OTC) deficiency; and N-acetylglutamate synthetase (NAGS) deficiency. (For more information about these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)


Arginine vasopressin deficiency

AVP-D symptoms may develop abruptly or more gradually over time and may occur at any age. Typically, individuals experience excessive urination (polyuria), even at night (nocturia), and as a result, excessive thirst (polydipsia). Some individuals with AVP-D lack thirst (adipsia) and are thus more vulnerable to dehydration from untreated AVP-D, and also hyponatremia from possible inadvertent excess fluid and synthetic AVP. The severity and progression of AVP-D varies from person to person. Some individuals may have a severe form of the disorder (complete AVP-D) with little or no AVP activity. Others may have a milder form of the disorder (partial AVP-D) with residual AVP activity.

AVP-D is caused by partial or complete deficiency of the antidiuretic hormone, AVP. This deficiency usually results from damage to the hypothalamus or pituitary gland, often from a tumor (or surgical resection of that tumor) affecting these regions. In extremely rare cases, AVP deficiency is caused by a gene change (variant) that is inherited in an autosomal dominant or autosomal recessive pattern. In a minority of individuals, no specific cause can be identified (idiopathic AVP-D). There is speculation that there may be an autoimmune contribution. Finally, some medications, including a subset of anesthetic medications used in the intensive care unit, and novel anti-tumor therapies such as immune check-point inhibitors, can also cause AVP-D.

AVP-D can occur at any age and affects males and females in equal numbers. Onset is more common between the ages of 10 and 20 years. The inherited form of AVP-D is extremely rare. When considering all forms, AVP-D is estimated to occur in 1 out of every 25,000 individuals.

Symptoms of the following disorders can be similar to those of AVP-D. Comparisons may be useful for a differential diagnosis.

A diagnosis of AVP-D may be suspected based upon presentation with characteristic symptoms, specifically excessive thirst and excessive urination. A thorough clinical evaluation, a detailed patient history and a variety of specialized tests may be used to confirm a diagnosis. Physicians may take blood and urine samples to determine the concentration of salts and sugar within those samples. The degree of overall concentration of blood or urine is known as osmolality. Individuals with untreated AVP-D tend to have a high osmolality in the blood and a low osmolality in the urine. The urine osmolality may be approximated by the urine specific gravity, which is low in AVP-D. Often, paired blood and urine samples after the longest usual interval without drinking are sufficient to make the diagnosis of disordered AVP activity (AVP-D or AVP-R). For safety reasons, i.e., to avoid clinically significant dehydration, fluid deprivation beyond the longest usual interval is not recommended in the outpatient setting.


Argininosuccinic aciduria

The severity and specific symptoms of argininosuccinic aciduria varies from one person to another. A severe form of the disorder, which is characterized by a complete or near complete lack of the ASL enzyme, occurs shortly after birth (neonatal period). A milder form of the disorder, which is characterized by partial lack of the ASL enzyme, affects some individuals later during infancy or childhood or even adulthood (late-onset form).

Argininosuccinic aciduria is caused by changes (pathogenic variants or mutations) in the ASL 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 protein, this can affect many organ systems of the body.

Argininosuccinic aciduria is a rare disorder that affects fewer than a thousand people in the United States. It is estimated to affect anywhere between approximately one in 70,000 to 1 in 218,000 live births. Males and females are affected in equal numbers. Onset of symptoms usually occurs at birth but may not be noticeable for days or weeks. In some children, onset of symptoms may not occur until later during infancy or childhood.

Symptoms of the following disorders may be similar to those of argininosuccinic aciduria. Comparisons may be useful for a differential diagnosis:

Urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures and/or coma. The liver may be abnormally enlarged (hepatomegaly). In some people, life-threatening complications may result. In addition to argininosuccinic aciduria, the other urea cycle disorders are: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinate synthetase deficiency (citrullinemia); ornithine transcarbamylase (OTC) deficiency; arginase deficiency and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)


芳香族L-氨基酸脱羧酶缺乏症

Aromatic L-amino acid decarboxylase deficiency

Aromatic L-Amino Acid Decarboxylase Deficiency

aromatic amino acid decarboxylase deficiency

AADC deficiency is a disorder that manifests early in life. The symptoms can begin during the neonatal period or when the child is a few months old. There is a wide range of possible symptoms and the severity of the disease varies among affected individuals. The two most common symptoms are hypotonia in the trunk and oculogyric crises. These crises are characterized by abnormal rotation of the eyeballs and gaze deviation, uncontrolled movements of the head and neck, muscle spasms, agitation, and irritability. They can last several hours and tend to recur every 2 to 5 days. Other movement disorders can be present such as decreased movements (hypokinesia), increased muscle tone (hypertonia) in the limbs, sustained muscle contraction and abnormal postures (dystonia), involuntary writhing movements (athetosis), involuntary and irregular movements of the hands and feet (chorea), and tremors.

AADC deficiency is caused by mutations (changes) in a gene called DDC (which stands for DOPA decarboxylase, another name for AADC). An abnormal DDC gene leads to production of a dysfunctional AADC enzyme that cannot accomplish its normal functions. Enzymes are a type of protein widely present in the body and their role is to facilitate and accelerate (catalyze) chemical reactions that have to take place in order for the body to function correctly. AADC catalyzes chemical reactions responsible for the formation (synthesis) of molecules called neurotransmitters that are essential for proper communication between neurons of the nervous system. The neurotransmitters affected by AADC deficiency are epinephrine and norepinephrine (products of dopamine and involved in the control of the sympathetic nervous system, the fight or flight branch of the autonomic nervous system), dopamine (involved in motor control, reward, and motivation), and serotonin (involved in sleep, memory, appetite, and mood). Serotonin is also required for the synthesis of melatonin, which is primarily involved in the regulation of the sleep-wake cycle. Deficiency of those neurotransmitters is responsible for the manifestations of AADC deficiency.

AADC deficiency is an extremely rare disorder; fewer than 150 patients have been reported in the literature. Half of these cases are in Asian individuals, and a fifth are in individuals with Taiwanese ancestry. Males and females seem to be equally affected.  AADC deficiency is probably underdiagnosed. The estimated prevalence in the U.S. based on cerebrospinal fluid (CSF) analysis and genetic testing is roughly 1-3:100,000 live newborns.

The symptoms seen in AADC deficiency can be seen in numerous other disorders. Some have a very similar clinical presentation and are mostly differentiated with laboratory testing and medical imaging. Below is a list of some conditions that can present similarly to AADC deficiency, with an emphasis on neurometabolic disorders.

AADC deficiency is a very rare and complex disease with features that overlap with many other disorders (see above). A complete clinical evaluation and a high index of suspicion are required to make the diagnosis. The evaluation of a child with neurodevelopmental delay starts with a perinatal and developmental history and a complete physical examination. Although many tests, such as a complete blood count, measurement of electrolyte levels, and magnetic resonance imaging of the brain are usually performed in the diagnostic workup of a child presenting with neurodevelopmental delay, the laboratory diagnosis of AADC deficiency is centered about four specific tests:


Arterial tortuosity syndrome

Researchers have been able to establish a clear syndrome with characteristic or core symptoms, but much about ATS is not fully understood. It has been difficult to determine a complete picture of associated symptoms and prognosis because of the small number of identified patients, the lack of large clinical studies and the possibility of other genes influencing the disorder.

Arterial tortuosity syndrome is caused by variants in the SLC2A10 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 protein, this can affect many organ systems of the body, including the brain.

Arterial tortuosity syndrome affects males and females in equal numbers. Approximately 100 cases have been reported in the medical literature. The exact incidence and prevalence are unknown. The male to female ratio is 1:1. Because affected individuals may go undiagnosed or misdiagnosed, determining the true frequency of arterial tortuosity syndrome in the general population is difficult.

Symptoms of the following disorders can be similar to those of arterial tortuosity syndrome. Comparisons may be useful for a differential diagnosis.

A diagnosis of ATS is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The diagnosis can be confirmed with molecular genetic testing for variants in the SLC2A10 gene.


Arteriovenous Malformation

Arteriovenous malformation (AVM) is a vascular lesion that is a tangle of vessels of varying sizes in which there is one or more direct connections between the arterial and venous circulations. In the lesion there is no capillary bed, which is part of normal tissue. Brain AVMs are often presumed to be congenital, but there is no direct evidence that they form in utero. The distribution of age at detection for brain AVMs is normally-distributed with the mean age in the mid-30’s. Although a small number of AVMs manifest themselves at or shortly after birth, most of them present later in life, and just as likely, form and progress during the later years of life. The lack of capillaries allows blood traveling through the abnormal fistulous connections to flow rapidly. The low resistance of the direct A-V connections, termed fistulas, results in very high flow rates in the vessels leading to and within the AVM. These high flow rates can lower the pressure in the arteries leading to the AVM and to surrounding relatively normal brain tissue. Further, because of the direct A-V connections, the pressure in the arteries, even if somewhat reduced, are transmitted to the veins draining the AVM and surrounding brain, which normally operate at very low pressures. AVM can occur in many different parts of the body, but those located in the central nervous system (brain and spinal cord) can cause problems that affect the brain like other forms of stroke.

Symptoms of AVM occur only after a highly variable amount of damage to the brain or spinal cord has occurred: this ranges from minor symptoms such as headache to devastating rupture with hemorrhagic stroke. A small percentage of AVMs are detected incidentally during investigation of unrelated medical problems and are completely asymptomatic. AVMs cause damage to the brain or spinal cord by several mechanisms: directly reducing oxygen to neurological tissues through (a) a change in vascular pressures; (b) compression of adjacent neural tissue by the abnormal vascular structures of the AVM; (c) bleeding (hemorrhage) into surrounding tissues. Bleeding has several adverse effects including exerting pressure on adjacent neural tissue and also by leaving toxic blood products in contact with neural tissue.

AVM are often attributed to result from an error in embryonic or fetal development, but there is no direct evidence of this assertion. No environmental risk factors have been identified for neurological AVM. AVM does not usually run in families, but somewhere on the order of 5% of AVMs may be due to autosomal dominant inheritance of a genetic mutation, most commonly hereditary hemorrhagic telangiectasia or the capillary malformation-AVM syndrome. AVM can rarely be associated with certain syndromes such as Wyburn-Mason syndrome.

AVM affects males and females in equal numbers. There does not appear to be an increased risk for particular ethnic and racial groups. The best estimates for new detection of an AVM are 1 per 100,000 population per year (about 3000 new cases detected per year in the U.S.) The population prevalence is about 10 per 100,000, i.e., there are probably about 30,000 individuals in the U.S. who harbor an AVM or have had an AVM that was treated. They occur throughout life, but the peak onset of symptoms is 35-40 years of age.

Symptoms of the following disorders can be similar to those of arteriovenous malformation. Comparisons may be useful for a differential diagnosis:

A variety of imaging studies are used to diagnose AVM. Noninvasive imaging technologies that are used to diagnose AVM are computed axial tomography (CT) and magnetic resonance imaging (MRI). CT is particularly useful in identifying a hemorrhage but can identify only large AVM. MRI is necessary for the initial diagnosis of AVM. Magnetic resonance angiography (MRA) can be used to determine the pattern and speed of blood flow through AVM but can miss small lesions.


Arteritis, Takayasu

Takayasu arteritis is a rare disorder characterized by the progressive inflammation of one or more of the larger arteries leading from the heart. The main artery of the heart (aorta) and the pulmonary (lung) artery, among others, may be affected. When this disorder causes progressive inflammation of many arteries, it is known as polyarteritis. One of the consequences of polyarteritis is the reduction of blood flow to any of several organs and/or arms and legs. Arteries in the head and arms may be affected, and this can result in the loss of the major pulse points in the body. Some people with Takayasu arteritis have irregular narrowing of portions of the large arteries (segmental stenosis) and abnormal backward flow of blood from the aorta into the left ventricle of the heart (aortic regurgitation). Other patients may have symptoms of ballooning and weakening (aneurysm) of the wall of a major vessel.

About half of the patients with Takayasu arteritis display a general feeling of weakness (malaise).  In addition, patients may complain of muscle aches (myalgias), and joint pain (arthralgias).  Progressive obstructive arterial disease and narrowing of the arteries (stenosis) may follow the initial phase of the disease.  When the aorta and the major arteries in the neck (carotid arteries) are affected by Takayasu arteritis, the patient usually experiences lightheadedness, dizziness, and brief moments of unconsciousness (syncope). These symptoms are the result of a  decrease in blood supply to the brain (cerebral ischemia).  The pulses that are normally found in the neck and on the temples (carotid and superficial temporal pulses) may be absent. Most often, progression of the arteritis is slow so that there is sufficient time to develop adequate alternate circulation (collateral or secondary circulation).

The exact cause of Takayasu arteritis is not known.  Certain laboratory findings, such as elevated levels of globulins and the presence in serum of unusual antibodies, suggest a defect in the immune system and a possible autoimmune association.  Autoimmune disorders are caused when the body’s natural defenses (e.g., antibodies) against foreign or invading organisms begin to attack healthy tissue for unknown reasons.

Takayasu arteritis is a rare disorder that affects more females than males. Approximately 80 to 90 percent of the cases affect females.  This disorder is common in Japan, and occurs throughout the Orient.  Takayasu arteritis has been reported in India and South America.  The symptoms of this disorder typically begin between 15 and 35 years of age although it can affect children as well.  It is estimated that between 2 and 3 new cases per million are recorded in the USA population per year.

Symptoms of the following disorders can be similar to those of Takayasu arteritis.  Comparisons may be useful for a differential diagnosis:

Giant cell arteritis is a generalized vascular disorder characterized by inflammation of the arteries resulting from the accumulation of granular tissue.  This causes abnormal changes in the walls of the arteries. Inflammation is generally confined to the different branches of the aortic arch, particularly the temporal arteries.  Symptoms may begin suddenly or there may be a gradual onset of low-grade fever, joint stiffness, and weakness.  In some cases people may have a sore throat, cough, and/or hoarseness.  Involvement of the temporal arteries may result in headache, throbbing or stabbing sensation in the temples, and scalp tenderness.  (For more information on this disorder, choose giant cell arteritis as your search term in the Rare Disease Database.)


Arthritis, Infectious

Infectious arthritis is an inflammation of one or more joints that occurs as a result of infection by bacteria, viruses or, less frequently, fungi or parasites. The symptoms of Infectious arthritis depend upon which agent has caused the infection but symptoms often include fever, chills, general weakness, and headaches, followed by inflammation and painful swelling of one or more joints of the body.

The symptoms of infectious arthritis depend upon which agent has caused the infection.  The symptoms usually include fever (which may be quite high), chills, general weakness and headaches, followed by inflammation of one or more joints.  The affected joint or joints often become very painful, swollen, slightly red and stiff within a few hours or days.  Rapid onset of symptoms may indicate that a bacterium is the cause.  In a few people, however, the infection develops slowly, over a period of months or even years.  This slower developing infection is more often the result of a viral or fungal infection than a bacterial one.

Any disease-causing microbe may infect a joint.  Bacteria are most often responsible, typically producing an acute arthritic attack.  In young children the most common bacteria are staphylococci, haemophilus influenzae, and gram- negative bacilli.  Older children and adults are most commonly infected with gonococci, staphylococci, streptococci or pneumococci.  Acute infectious arthritis at any age may be associated with rubella, mumps or hepatitis B infections.  Fungi and fungi-like bacteria such as mycobacterium tuberculosis, etc may cause chronic infectious arthritis.  People with rheumatoid arthritis and chronically inflamed joints are particularly susceptible to infectious arthritis.

Infectious arthritis can affect people of all ages and both sexes.  About half of all cases involve adults over the age of 60.  The incidence is reported as 2-10 cases per 100,000 of general population.  For patients with immunologic disorders, the incidence increases to about 30-70 cases per 100,000 people.  In gonococcal arthritis, the disorder is found in three times as many women as men.

Rheumatoid Arthritis is a chronic disease characterized by  usually symmetric inflammation of the peripheral joints, which can eventually result in progressive destruction of joints.  Generalized symptoms may also be present.

A thorough history and physical examination are essential for diagnosis. Blood tests as well as tests of the fluid commonly found in the joints are essential for identification of the infecting agent and to confirm diagnosis. Once the infecting agent is known, an appropriate course of treatment may be designed.


Arthrogryposis multiplex congenita

Arthrogryposis is a general or descriptive term for the development of nonprogressive contractures affecting one or more areas of the body prior to birth (congenitally). A contracture is a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint. When congenital contractures occur only in one body area, it is not referred to as arthrogryposis but rather an isolated congenital contracture. The most common form of an isolated congenital contracture is clubfoot. When arthrogryposis affects two or more different areas of the body, it may be referred to as arthrogryposis multiplex congenita (AMC). The most common form of AMC is amyoplasia. Arthrogryposis and arthrogryposis multiplex congenita are sometimes used interchangeably.

The most common universal symptom of AMC is limited or absent movement around small and large joints (contractures). The contractures are present at birth (congenital). The muscles of the affected limbs may be underdeveloped (hypoplastic), resulting in a tube-shaped limb with a soft, doughy feeling. Soft tissue webbing may develop over the affected joints.

The cause of AMC depends on the specific type. For many types, the cause is not fully understood. Arthrogryposis or AMC is not a specific diagnosis, but a physical finding that can be associated with numerous disorders and conditions. AMC is thought to be related to decreased movement in utero, which can have multiple causes. Neurologic and muscle problems may well be the most common causes of decreased fetal movement, but connective tissue disorders, maternal illness and limited space are also common causes. Some cases of AMC occur as part of rare genetic disorders that are inherited. Some cases of AMC are related to multiple factors including genetic and environmental ones (multifactorial inheritance).

The number of males and females affected by AMC is approximately equal. The condition has been reported in individuals of Asian, African and European descent. Isolated congenital contractures affect approximately 1 in 500 individuals in the general population. AMC affects approximately 1 in 3,000 individuals.

A diagnosis of AMC is made based upon identification of characteristic symptoms (e.g., multiple congenital contractures), a detailed patient history and a thorough clinical evaluation. Certain tests may be necessary to determine the underlying cause of AMC including nerve conduction, electromyography and muscle biopsy, which can help diagnose neuropathic or myopathic disorders. A nerve conduction study measures how rapidly nerves carry an electrical impulse. Electromyography is a test that records electrical activity in skeletal voluntary muscles at rest and during muscle contraction. A biopsy is a procedure in which a small amount of affected tissue (e.g., muscle) is removed and studied under a microscopic to detect characteristic changes or findings that can aid in obtaining a diagnosis. Imaging studies of the central nervous system (CNS) and genetic tests including comparative genomic hybridization (CGH) array, microarray, and exome studies may also be useful studies in making a diagnosis. Because variants in many genes can lead to arthrogryposis, whole genome sequencing is often required (preferably in both parents for comparison as well) to make a diagnosis.


关节挛缩-肾功能不全-胆汁淤积综合征

Arthrogryposis Renal Dysfunction Cholestasis Syndrome

Arthrogryposis renal dysfunction cholestasis syndrome (ARC) is a very rare genetic condition. The condition is present at birth, but symptoms may not be noticed until later in a child’s life. The name of the condition describes the symptoms. Arthrogryposis comes from the Greek word for bent describing limbs that are difficult to straighten. Renal dysfunction refers to the kidneys not working. Cholestasis comes from the Greek word for bile referring to a problem with the flow of bile, a substance which normally helps the body digest fats.

ARC type 1 is caused by disease-causing variants in the VPS33B gene. ARC type 2 is caused by disease-causing variants in the VIPAS39 gene.

ARC affects males and females in equal numbers. ARC is very rare, affecting less than 1,000 people worldwide.

The diagnosis of ARC can be made when an infant has symptoms of arthrogryposis (limbs that are difficult to straighten), renal dysfunction (kidneys are not removing acid from the bloodstream) and cholestasis (bile is not flowing normally). When a diagnosis is suspected based on these clinical symptoms, genetic testing can be done to identify disease-causing variants in both copies of the VPS33B gene or the VIPAS39 gene.

The treatment of ARC is directed towards the specific symptoms that are present. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, dermatologists, nephrologists, hepatologists, physical therapists, feeding therapists, dieticians and other health care professionals may be needed for an individual’s treatment and to look for limb, kidney and skin problems and other internal organ problems. Families of children with complex medical needs may benefit from a case worker to navigate the healthcare system. Genetic counseling is recommended for families of individuals with ARC. Other treatments for this disorder are symptomatic and supportive.


Farber disease

ASAH1-related disorders are an extremely rare group of disorders caused by an alteration (mutation) in the ASAH1 gene. Alterations in this gene result in a deficiency of the enzyme acid ceramidase. Enzymes are specialized proteins that act to bring about biochemical reactions in the body. The acid ceramidase enzyme is required to help break down certain fatty substances – called ceramides – in the body. Because the activity of this enzyme is reduced, these fatty substances build up abnormally in the cells and tissues of the body. This can cause a variety of signs and symptoms based on where the fatty substance builds up and how much of it builds up. The most common form of ASAH1-related disorder is called Farber disease, which can present in several different ways. The most common presentation is characterized by the three main symptoms: small bumps beneath the skin (subcutaneous nodules), joint disease, and hoarseness of voice. Some people will have additional symptoms, or different symptoms, that can include heart (cardiac), neurological, or breathing problems. A specific form of ASAH1-related disorder is called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), which is characterized by muscle weakness and degeneration, specifically in the legs, as well as seizures. ASAH1-related disorders can be best thought of as a spectrum of disease that can affect one person very differently from how it affects another person. This is true even for members of the same family. The signs, severity, and age of onset of symptoms can all be very different and can range from mild to severe. ASAH1-related disorders are inherited in an autosomal recessive manner.

ASAH1-related disorders are caused by variations (mutations) in the ASAH1 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, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

ASAH1-related disorders are extremely rare disorders. They affect males and females in equal numbers. Fewer than 200 individuals have been described in the medical literature. However, rare disorders like ASAH1-related disorders often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.

Symptoms of the following disorders can be similar to those of ASAH-1-related disorders. Comparisons may be useful for a differential diagnosis.

A diagnosis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected in infants or children with characteristic early signs.

Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in the diagnosis and treatment of neurological disorders in children (pediatric neurologists), neurologists, physicians who specialize in the diagnosis and treatment of disorders of the bones and skeleton (orthopedists), physicians who specialize in the diagnosis and treatment of eye disorders (ophthalmologists), physicians who specialize in the diagnosis and treatment of skin disorders (dermatologists), speech pathologists, physical therapists, pain specialists, and other healthcare professionals may need to systematically and comprehensively plan treatment.


Asherman Syndrome

Asherman’s syndrome is a rare, acquired, gynecological disorder of the uterus. It is characterized by the bonding of scar tissue that lines the walls of the uterus, which decreases the volume of the uterine cavity. The bonding of uterine scar tissue (intrauterine adhesions or synechiae) may occur as a result of surgical scraping or cleaning of tissue from the uterine wall (dilatation and curettage [D and C]), infections of the endometrium (e.g., genital tuberculosis), or other factors. Asherman’s syndrome  can be severe (greater than 75% of the front and back walls of the uterus can fuse together) to moderate and mild, where only smaller portions of the uterine wall fuses together. Patients can experience a range of symptoms depending on the severity of the disease, including reduced menstrual flow, increased cramping and abdominal pain, eventual stoppage of menstrual cycles (amenorrhea), and, in some women, infertility. Current treatment options include hysteroscopic surgery as well as preventive (Foley catheter) and restorative therapies (hormone treatment). Newer options like stem cell treatments are also currently being explored to treat severe cases of Asherman’s syndrome.

Most patients with Asherman’s syndrome experience menstrual blood flow that is sparse (hypomenorrhea) or absent (amenorrhea) along with increased cramping and abdominal pain. Some patients may experience interrupted menstrual blood flow with substantial pain, while others may not have any abnormal changes to their menstrual cycle or experience any pain. Recurrent miscarriages and/or infertility may also be signs of Asherman’s syndrome. In more severe cases, adhesion of uterine scar tissue can also lead to either a partial or full blockage of the uterus or cervical canal that can cause retrograde menstruation (menstruation blood that flows backwards into the fallopian tubes instead of being expelled from the body).

Asherman’s syndrome is most commonly caused by trauma to the uterus through surgical scraping or cleaning of the uterine wall (dilatation and curettage, also known as D & C). D & C is generally performed to clear the uterine lining following a miscarriage or abortion or to treat certain uterine conditions such as heavy bleeding.  D & C after a miscarriage is one of the highest risk factors for Asherman’s syndrome. The scraping of the uterine lining following this procedure can lead to scar tissue that can adhere, leading to Asherman’s syndrome. Other types of surgery to the uterus such as removal of fibroids or polyps or surgical repair of structural defects in the uterus can cause scar tissue formation which is also a risk factor for Asherman’s syndrome. Factors that trigger inflammation in the uterus known as endometriosis and sporadic inflammation of the uterus have been linked to Asherman’s syndrome. Infection and inflammation of the uterus caused by bacteria (genital tuberculosis) and parasites such as blood flukes are also risk factors for Asherman’s syndrome.

Since Asherman’s syndrome involves changes in the uterus, it is limited to the female population. While exact statistics on the prevalence of this condition are not known, the highest frequency of this condition has been reported in Israel, Greece, and South America. Overall, occurrence of Asherman’s syndrome does not seem to be related to any factor associated with geographic location. Genetic predisposition in patients to Asherman’s syndrome has not been identified. Women who have suffered miscarriages or underwent D & C in the first month postpartum have a higher risk for the condition.

Symptoms of the following disorders can be similar to those of Asherman’s syndrome. Comparisons may be useful for a differential diagnosis:

Primary amenorrhea is the absence of menstruation by the age of 15 or three years after the first signs of breast development. This is most often due to abnormal hypothalamic gonadotropic-releasing hormone levels (GnRH, sex cell growth hormone) Symptoms include incomplete or underdeveloped external genitalia and breasts, ovarian deficiency, and underactive pituitary.

Therapies for Asherman’s syndrome focus on restoring the uterus to its original size and shape. The therapies can be divided into three primary approaches: treatment – hysteroscopic surgery, re-adhesion prevention, and uterus restoration therapies. Mild cases of Asherman’s syndrome may only require surgical treatment, while more severe cases may require all three approaches. Most cases of Asherman’s syndrome can be cured with treatment.


Catastrophic antiphospholipid syndrome

Asherson’s syndrome is an extremely rare autoimmune disorder characterized by the development, over a period of hours, days or weeks, of rapidly progressive blood clots affecting multiple organ systems of the body. Conditions such as infections, immunizations, wounds caused due to physical trauma and failure in the anticoagulation mechanism of the body usually act as triggers.

The symptoms of Asherson’s syndrome are caused by complications resulting from the development of multiple blood clots (thromboses) in the body. Multiple blood clots may form in a matter of hours, days or weeks, potentially causing life-threatening multiorgan failure.

Asherson’s syndrome is a rare autoimmune disorder. Autoimmune disorders are caused when the body natural defenses (antibodies, lymphocytes, etc.) against invading organisms suddenly begin to attack perfectly healthy tissue. Researchers believe that multiple factors including genetic and environmental factors play a role in the development of autoimmune disorders.

Approximately 300 individuals have been identified with Asherson’s syndrome since the disorder was first defined in the medical literature in 1992. More women have been affected than men. The disorder can occur at any age, although most cases have been reported in young adults.

Symptoms of the following disorders can be similar to those of Asherson’s syndrome. Comparisons may be useful for a differential diagnosis.

A diagnosis of Asherson's syndrome is made based upon a thorough clinical evaluation, identification of characteristic findings (e.g., multiple blood clots affecting at least three different organ systems that arise simultaneously within one week), and a variety of tests including simple blood tests that can detect antiphospholipid antibodies.


Aspartylglucosaminuria

Aspartylglycosaminuria is a very rare genetic disorder that is concentrated among persons of Finnish decent, but is also found, even more rarely, in other populations around the world. It is an inborn error of metabolism, and one of the lysosomal storage diseases. It becomes apparent after the infant is a few months old. Major symptoms may include coarse facial features, spine and eye deformities, behavior problems and mental retardation. Aspartylglycosaminuria occurs as a result of deficient activity of a particular enzyme, leading to the accumulation of metabolic products in the body.

Aspartylglycosaminuria is a lysosomal storage disease characterized by normal development during the first months of life after which abnormal development begins to occur.  Diarrhea and infections that keep reoccurring are noticed. After the first few years facial features begin to get coarse which continues during the following years.  The skeleton may become deformed and the ocular lens may develop crystalline deposits.  Mental deterioration may begin to occur after age five and behavior problems are common.  Lung, heart and blood problems tend to occur in later years.  The patient may show mental retardation uneven development of the head and face with sagging cheeks, a wide nose and broad face.  The spine may be twisted (scoliosis) and the neck may be unusually short.  Adult stature is usually below normal.

Aspartylglycosaminuria is a lysosomal storage disease.  Lysosomes are cell particles containing enzymes that break down large molecules.  A deficiency of the lysosomal enzyme, aspartylglycosamidase, causes the accumulation of a substance known as aspartylglucosamine in the body, resulting in disorders in the various body systems.

Aspartylglycosaminuria is a rare disorder that affects males and females in equal numbers.  However, in Finland where the majority of cases are reported, there are an estimated 130 cases in 4.5 million persons.  In the rest of the world, the condition is extremely rare and affects persons of various heritages.

Symptoms of the following disorders can be similar to those of Aspartylglycosaminuria. Comparisons may be useful for a differential diagnosis:

The Mucopolysaccharidoses (MPS) are a group of hereditary lysosomal storage diseases.  They are characterized by abnormal accumulation of mucopolysaccharides, especially in the cartilage and bones.  These deposits are also found in the arteries, skeleton, eyes, joints, ears, skin and teeth. In general these disorders are progressive.  The child may appear normal at birth and around the age of one begin to show signs of both growth and mental retardation.  (For more information on this disorder, choose Mucopolysaccharidoses as your search term in the Rare Disease Database.)

Treatment of Aspartylglycosaminuria is symptomatic and supportive. Genetic counseling may be of benefit for families.


Aspergillosis

Aspergillosis is a fungal infection caused by Aspergillus, a species of mold that is found all over the world. More than 180 different types of Aspergillus have been identified and more are continuing to be identified. Most of these molds are harmless. However, some types can cause a variety of diseases in humans ranging from simple allergic reactions to life-threatening invasive disease. Collectively, this group of diseases is referred to as aspergillosis and is broadly broken down into three categories – allergic, chronic and invasive. There are several different forms including allergic bronchopulmonary aspergillosis, allergic Aspergillus sinusitis, invasive aspergillosis, cutaneous (skin) aspergillosis and chronic pulmonary aspergillosis, which also has several different presentations. Aspergillosis rarely develops in healthy individuals; most people breathe in these spores every day without any issues. An infection is much more likely to develop in individuals who have an underlying condition such as asthma, cystic fibrosis and previous lung disease, or who have taken corticosteroid drugs for a long period of time, or in individuals who have a weakened immune system, including people who have low levels of neutrophils, a type of white blood cell that helps the body fight off infection and heal itself (neutropenia), or who are taking drugs that suppress the immune system (immunosuppressive drugs) such as people who have had a bone marrow or organ transplant. In most instances, aspergillosis develops when susceptible individuals breathe in (inhale) Aspergillus spores. Aspergillosis is not contagious and cannot be transmitted from one person to another.

The symptoms of aspergillosis vary depending upon the specific form of the disorder present. The lungs are usually affected. Aspergillosis can present as an allergic reaction, an isolated finding affecting a specific area of the body (e.g., the lungs, sinuses or ear canals), or as an invasive infection that spreads to affect various tissues or organs of the body.

Aspergillosis is a fungal infection caused by certain types of molds. They are found throughout nature (ubiquitous) and can be found in the soil and decaying organic matter like decaying vegetation. They can be found indoors, especially in heating or cooling ducts or in insulation. There are about 180 species of Aspergillus, but only about 40 are known to be associated with disease in humans.

Aspergillosis is a rare fungal infection. The exact number of people who develop this infection in the United States is not known because there is no national surveillance of this infection. Mild cases may go undiagnosed. According to the medical literature, the incidence of aspergillosis is increasing. Aspergillosis has been reported all over the world. Allergic bronchopulmonary aspergillosis has been estimated to affect about 1-4 million people worldwide. Chronic pulmonary aspergillosis is estimated to affect about 3 million people worldwide. Invasive aspergillosis is uncommon, as it affects specific patient populations. Many forms are rare. Aspergillosis can potentially affect individuals of any age.

Symptoms of the following disorders can be similar to those of aspergillosis. Comparisons may be useful for a differential diagnosis.

A diagnosis of aspergillosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests such as bronchoscopy with biopsy, x-rays, antigen skin tests, tissue culture or blood tests. Allergic bronchopulmonary aspergillosis should be suspected in individuals with difficult to control asthma or cystic fibrosis.


Asphyxiating Thoracic Dystrophy

ATD is characterized by abnormal development of the rib cage (thorax) resulting in a small thoracic cavity. The characteristic bell-shaped chest cavity restricts the growth of the lungs and results in a variable degree of lung hypoplasia and breathing problems (respiratory distress) in the newborn period.

Mutations in 24 genes have been found to cause ATD to date. The genes are: IFT43/52/80/81/122/140/172, WDR19/34/35/60, DYNC2H1, DYNC2LI1, CEP120, NEK1, TTC21B, TCTEX1D2, INTU, TCTN3, EVC 1/2 and KIAA0586/0753.

The incidence of ATD is about 1 in 100,000 to 150,000 live births. Males and females appear to be affected in equal numbers, as do persons of various ethnic or racial backgrounds.

The following disorders have presentations that can be similar to those of ATD and should be considered for a differential diagnosis.

ATD is diagnosed based on clinical presentation as well as radiologic findings of short ribs and abnormalities of the pelvis and limbs. A combination of breathing difficulties in the presence of a small, narrow chest, along with obvious shortened limb development is usually sufficient for a diagnosis. Molecular genetic testing is available to confirm the diagnosis.


Astrocytoma

An astrocytoma is a tumor that arises from the star-shaped cells (astrocytes) that form the supportive tissue of the brain. Other supportive cells of the brain include oligodendrocytes and ependymal cells. Collectively, these cells are known as glial cells and the tissue they form is known as glial tissue. Tumors that arise from the glial tissue, including astrocytomas, are collectively referred to as gliomas.

Symptoms of grade I and grade II astrocytomas are subtle because the brain is able to temporarily adapt to the presence of a slow-growing tumor. Symptoms of grade III and grade IV astrocytomas may be sudden and debilitating. Symptoms can result from increased pressure within the brain and may include headaches, vision changes and nausea or vomiting. Symptoms may also occur based on the location of the tumor due to interference with normal brain function and include focal seizures, difficulty with speaking, loss of balance and weakness, paralysis or loss of sensation of one side of the body. Fatigue and depression are common in individuals with an astrocytoma.

The cause of most astrocytomas is not known. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation), diet, stress, and/or other factors may play contributing roles in causing specific types of cancer. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.

Grade I astrocytoma occurs most often in children and teens and account for 2% of all brain tumors. Grade II astrocytoma occurs most often in adults between the ages of 20 and 60. Grade III astrocytoma occurs most often in adults between the ages of 30 and 60, is more common in men and accounts for 4% of all brain tumors. Grade IV astrocytoma occurs most often in adults between the ages of 50 and 80, is more common in men and accounts for 23% of all primary brain tumors.

Symptoms of the following disorders can be similar to those of astrocytomas. Comparisons may be useful for a differential diagnosis:

Motor neuron disease is a group of neuromuscular disorders characterized by the progressive degeneration of motor neurons, the nerve cells that control movement and reflex. Symptoms of Motor Neuron Diseases may include muscle weakness, spasms and exaggerated reflexes.

Grade I astrocytoma: Surgery is the standard treatment. Total surgical removal of accessible astrocytomas is often possible and successful. Accessible tumors are those that can be operated on without causing unacceptably severe damage to other parts of the brain. If surgery is performed, the surgeon will attempt to remove all identifiable parts of the astrocytoma when possible. When the astrocytoma involves a crucial part of the brain, partial removal of the growth usually reduces pressure, relieves symptoms and helps control seizures.


Bainbridge-Ropers syndrome

ASXL3基因缺陷所致严重喂养困难-发育停滞-小头畸形综合征

ASXL3-related disorder, also known as Bainbridge-Ropers syndrome, is a neurodevelopmental disorder that was first described by Bainbridge et al. in 2013. It is associated with changes (pathogenic variants or mutations) in the ASXL3 gene.

Developmental delay and intellectual disability

ASXL3-related disorder is caused by pathogenic or likely pathogenic variants in the ASXL3 gene. The majority of variants are new mutations that result in a shortened protein product that does not function properly.

ASXL3-related disorder has been described all over the world and is not population specific.

The characteristics of ASXL-related disorder can be similar to other disorders including ASXL1-Bohring-Opitz syndrome and ASXL2-Shashi-Pena syndrome.

ASXL-related disorder may be suspected based on the signs and symptoms associated with the disorder. The diagnosis is confirmed with genomic testing that shows a pathogenic variant in the ASXL3 gene.

Multidisciplinary care is recommended and includes management of multiple subspecialty appointments, equipment, medications and supplies. Ongoing assessment for palliative care involvement and/or home nursing is needed.


Ataxia Telangiectasia

Ataxia telangiectasia (AT) is a complex neurodegenerative disorder. Symptoms associated with AT usually present during the preschool years between one and four years of age. An unsteady gait (ataxia) is often the first sign of AT. Symptoms that distinguish AT from other disorders include an impaired ability to coordinate eye movements (oculomotor apraxia) and episodes of involuntary movements (choreoathetosis). Progression of ataxia is associated with cerebellar degeneration, and many school-age children with AT are dependent on wheelchair assistance.

The name ataxia telangiectasia refers to two major symptoms associated with AT. One major symptom is diminished muscle coordination and voluntary muscle control (ataxia). Another is the development of red or purple clusters of dilated blood vessels (telangiectasias) on mucous membranes and the sun-exposed areas of the skin, often visible by age six. The severity of symptoms can vary, but AT usually affects coordination of muscle control and immune and pulmonary responses to infection and stress. The symptoms are discussed below.

AT is caused by pathogenic variants (mutations) in the ATM gene. The ATM gene codes for a serine/threonine protein kinase. A kinase is a biological catalyst (enzyme) that speeds up the addition of phosphate groups to other molecules. The serine/threonine protein kinase belongs to the PI3 kinase-like kinases (PIKKs) family. It is primarily located in the cell nucleus. The ATM kinase activates and interacts with multiple different molecules. Currently, the best-known function of the ATM protein is to coordinate the repair of double strand breaks in DNA, the hereditary material that carries the genetic code. Double strand breaks in DNA can damage the cell. The ATM protein can activate certain enzymes to fix broken strands of DNA. This repair is essential to maintain the stability of the cell’s genetic information.

In the United States, the prevalence of AT is approximately 1:40,000 to 1:100,000 live births. Males and females are affected in equal numbers. Certain ethnic groups may have a higher prevalence of AT due to a founder effect.

There are several disorders that present similar symptoms or laboratory findings to AT. These symptoms are typically related to the loss of motor functions. Information is provided below about such disorders. Comparisons may be useful for a differential diagnosis.

A diagnosis of ataxia telangiectasia is made based upon a detailed patient history, thorough clinical evaluation, identification of characteristic symptoms and a variety of specialized tests including genetic testing, blood tests and magnetic resonance imaging (MRI).


Ataxia with vitamin E deficiency

共济失调伴维生素E缺乏症

Individuals usually show symptoms between 5 and 20 years of age. Symptoms and the severity of AVED may be different from person to person. Without treatment, symptoms may get worse as the person grows older.

AVED is caused by changes (mutations or pathogenic variants) in the TTPA gene, which provides instructions to synthesize the alpha-tocopherol transfer protein (αTTP) . This protein controls the distribution and transportation of vitamin E from the liver to other cells and tissues throughout the body, including the brain. Individuals with AVED have non-working genes for TTPA and therefore, vitamin E cannot be properly distributed throughout the body especially to the brain where it is necessary for proper function. AVED is characterized by very low levels of vitamin E in the blood and tissues in the brain. Without normal levels of vitamin E in the tissues, an individual with AVED experiences damage to the body from lack of protection from damaging free radicals.

AVED affects both males and females equally. The disorder is estimated to occur in fewer than 1 in 1,000,000 people. North African populations are most affected with AVED. Other cases have been reported in the Mediterranean region and Northern European countries. There have been cases in Asian countries such as Japan, China and the Philippines. The onset of AVED can occur during childhood or adulthood with cases reported ranging in children as young as 2 and adults as old as 52. Typically, the disease presents in individuals between ages 5 and 20 years. The disorder was first described in the medical literature in 1981.

The following disorders present with symptoms that can be similar to those of AVED. Comparisons of these disorders may be useful for a differential diagnosis:

Friedreich’s ataxia is a genetic, progressive, neurologic movement disorder that typically shows symptoms before adolescence. AVED and Friedreich’s ataxia share many similar symptoms, however Friedreich’s ataxia is not associated with any vitamin E deficiency. In Friedreich’s ataxia, the nerves in the spinal cord and the peripheral nerves gradually become thinner, causing symptoms to worsen over time. Symptoms in the beginning may include unsteady posture, frequent falling and progressive difficulties walking due to an impaired ability to coordinate voluntary movements (ataxia). Affected individuals may also develop abnormalities of certain reflexes; characteristic foot deformities; increasing incoordination of the arms and hands; slurred speech (dysarthria), and an irregular curvature of the spine (scoliosis). Friedreich’s ataxia may also be associated with cardiomyopathy, a disease of cardiac muscle that may be characterized by shortness of breath upon exertion (dyspnea), chest pain and irregularities in heart rhythm (cardiac arrhythmias). Friedreich’s ataxia is inherited in an autosomal recessive pattern. (For more information on this disorder, choose Friedreich’s ataxia as your search term in the Rare Disease Database.)


16号染色体连锁α-地中海贫血-智力障碍综合征

Alpha-thalassemia-intellectual disability syndrome linked to chromosome 16

alpha-thalassemia-intellectual disability syndrome, chromosome 16-related

Researchers have experienced difficulty establishing a clear syndrome with characteristic or core symptoms and much about the disorder is not fully understood. In many cases, there are other chromosomal abnormalities (in addition to the deletion on chromosome 16) and it is difficult to determine what symptoms are associated with what chromosomal abnormality. In addition, the small overall number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Not surprisingly, the specific symptoms and severity of ATR-16 syndrome can vary greatly from one individual to another. But it is clear that the larger the loss of genetic material from chromosome 16 the more severe the consequences.

ATR-16 syndrome is caused by the loss or deletion of genetic material affecting multiple genes that are next to (adjacent) to one another on chromosome 16, specifically from band 13.3 on the short arm (p) to the end (terminus) of the chromosome.

ATR-16 syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder is unknown. Cases may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. More than 20 cases have been reported in the medical literature.

Symptoms of the following disorders can be similar to those of ATR-16 syndrome. Comparisons may be useful for a differential diagnosis.

A diagnosis of ATR-16 syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.


Congenital atransferrinemia

Atransferrinemia is an extremely rare genetic disorder characterized by low levels of healthy, functional red cells in the blood (hypochromic, microcytic anemia) and by the accumulation of excess iron in the body (hemosiderosis). Symptoms may vary based upon the severity of anemia and upon the extent of iron accumulation in the body and the specific organs affected. Common symptoms include recurrent infections and growth delays. Atransferrinemia is principally caused by mutations of the transferrin (TF) gene and is inherited as an autosomal recessive trait. Atransferrinemia is classified as an iron overload disorder. A milder form of atransferrinemia, known as hypotransferrinemia, is caused by mutations in the same gene.

The symptoms and severity of atransferrinemia vary from one person to another depending upon the specific location and extent of iron accumulation in the body. Some individuals may develop mild symptoms, others may develop serious, life-threatening complications.

Atransferrinemia / hypotransferrinemia is principally caused by mutations of the transferrin (TF) gene. It is inherited as an autosomal recessive trait. 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.

Atransferrinemia is an extremely rare disorder. Approximately 10 cases in 8 families have been reported in the medical literature. Because atransferrinemia may go unrecognized or misdiagnosed, determining its true frequency in the general population is difficult. Atransferrinemia affects males and females in equal numbers. Atransferrinemia was first described in the medical literature in 1961.

Symptoms of the following disorders can be similar to those of hereditary atransferrinemia/hypotransferrinemia. Comparisons may be useful for a differential diagnosis.

A diagnosis of atransferrinemia is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Laboratory tests can reveal low or undetectable levels of transferrin in the blood.