遗传性弥漫性白质脑病伴轴索球样变与神经胶质色素沉着

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia

hereditary diffuse leukoencephalopathy with spheroids (HDLS)

Early symptoms of ALSP often include mild psychological or cognitive changes, but, while rare, can present as disturbances in motor function, such as difficulty walking, falling, and slowness of movements. Eventually, as damage in the brain becomes more extensive, psychological, cognitive and motor symptoms exist together. Initial symptoms and rate of disease progression vary quite a bit from one individual to the next, including those within the same family when the condition is inherited.

ALSP is caused by an abnormal CSF1R gene variant that codes for the protein colony-stimulating factor-1 receptor found on many cell membranes, including those in the central nervous system, or CNS (consisting of the brain and spinal cord). This receptor plays a role in cell growth and cell specialization where cells take on specific functions in the body. Without a normally-functioning CSF-1 receptor, structural changes to the nerve cell, or neuron, eventually occur. Axons, the portions of neurons that transmit signals to the next neuron, are covered in a myelin sheath, or the white matter that is destroyed in ALSP and other leukodystrophies. In ALSP, the formation of swellings known as spheroids within axons causes immune cells known as macrophages to destroy myelin sheathing, further damaging nerve cell function. Microglia, another type of macrophage immune cell of the CNS that’s responsible for maintaining brain tissue, are highly dependent on the CSF-1 receptor. When the receptor is inhibited, microglia become underactive and are destroyed. Macrophages and microglia take on a pigmented appearance in brain biopsies of ALSP patients.

The estimated number of people thought to have ALSP in the United States is 10,000 with similar estimates in Europe and Japan. Average age of diagnosis is 43 years old, but symptoms have been reported to occur in patients as young as 18, and 95% of ALSP patients start having symptoms before age 60. Both men and women are equally affected but symptoms usually appear earlier in women, at age 40 versus 47 for men. Life expectancy ranges from 2 to over 30 years, with an average life expectancy of 8 years after symptom onset.

Many symptoms of ALSP overlap with other neurological disorders, including other types of leukodystrophies. Genetic testing is required for accurate diagnosis. Based on symptoms, ALSP is most similar to the following disorders:

Diagnosis of ALSP is made by a neurologist. ALSP is diagnosed through genetic testing that identifies a CSF1R gene variant associated with the disease. However, family history, clinical signs and brain imaging results are integral in raising suspicions enough to order genetic testing. When symptoms affecting cognition and movements or when seizures combined with either cognitive or motor symptoms are present before or by age 60, suspicion for ALSP should be raised. Cognitive testing by psychiatrists, neurologists or psychologists can identify behaviors that confirm frontal lobe dysfunction (e.g., reduced inhibition), especially when subtle, that is associated with ALSP.

There are currently no FDA-approved treatments for ALSP. Researchers are further investigating underlying disease mechanisms and symptom progression to develop more effective treatment options. Current treatment options do not reverse brain damage but instead are meant to manage symptoms. For patients with ALSP who have seizures, anti-epileptic medications are useful for controlling seizures. Antibiotics may be prescribed to help control infections, such as pneumonia or urinary tract infections that may arise as patients grow progressively weaker. Muscle relaxers may be recommended to target spasticity. Anti-depressants are often prescribed to treat psychological symptoms of ALSP but are not especially effective. Anti-psychotic medications may be used to control aggression in ALSP but side effects are generally not well-tolerated. Nutritional supplements and physical therapy are often recommended to slow overall decline and maintain the most optimal overall health possible.


Adult-onset Still disease

The symptoms, progression, and severity of AOSD are highly variable from one person to another, but three main patterns have been identified:

The cause of AOSD is unknown (idiopathic). Researchers believe that the disorder might be caused by a combination of genetic factors and an abnormal or exaggerated response to infections or other environmental exposures. AOSD is not a hereditary disease and usually does not run in families.

The exact incidence of AOSD is unknown, but it is thought to affect between 1 and 34 people per million, depending on the population studied. Because of the highly variable symptoms and rarity of the disorder, it often goes undiagnosed or misdiagnosed, making it difficult to determine its true frequency in the general population. AOSD seems to affect men and women in equal numbers, although some reports state that the disorder affects women slightly more often than men. It primarily affects young adults between the ages of 16-35 but can also occur in older individuals.

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

The diagnosis of AOSD is difficult to make because there is no specific test or distinguishing laboratory finding that clearly differentiates the disorder from similar disorders. A diagnosis of AOSD is usually made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and the exclusion of other possible disorders (diagnosis of exclusion). A variety of tests may be performed to aid in a diagnosis including blood tests as well as imaging studies that might reveal changes in the bones or joints or enlargement of the spleen or liver. An echocardiogram, which uses sound waves to create a picture of the heart, may reveal inflammation of the pericardium or myocardium.


睑缘粘连-外胚层发育不良-唇/腭裂综合征

Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome

The symptoms of AEC syndrome are highly variable, even among members of the same family. In addition, the small number of identified patients, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder prevent physicians from developing a completely accurate picture of associated symptoms and prognosis. Affected individuals or their parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

AEC syndrome is caused by a variant in the TP63 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant in a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the protein, this can affect many tissues and organs of the body.

AEC syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder in the general population is unknown. AEC syndrome is a rare disorder and fewer than 100 affected individuals have been described in the medical literature.

Several disorders in addition to AEC syndrome are caused by variants in different parts of the TP63 gene.

A diagnosis of AEC syndrome is based upon identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. A variety of specialized tests can aid in a diagnosis.


African Iron Overload

The symptoms of African iron overload can vary from one person to another. The disorder usually develops in middle-aged or older adults. Affected individuals often develop abnormal enlargement of the liver (hepatomegaly). In more serious cases, the accumulation of fibrous tissue (fibrosis) in the main vein that supplies blood to the liver (portal vein) may result in high blood pressure in the this vein (portal hypertension). Abnormal fluid retention in the abdominal cavity can cause swelling (ascites). In some cases, scarring of the liver (cirrhosis) and, potentially, liver failure may eventually occur.

African iron overload was originally believed to be caused in individuals who had a diet high in iron, especially individuals in rural African communities that drank a homemade beer with high amounts of iron. However, many individuals in these regions who did not drink excessive amounts of this iron-rich beer also developed African iron overload. Researchers now believe that African iron overload is caused by mutations of an as yet unidentified gene or genes and can be worsened by a diet high in iron.

African iron overload affects males and females in equal numbers. The exact incidence of the disorder is unknown. It has been reported in numerous countries in sub-Saharan Africa. Researchers believe that the disorder often goes unrecognized and is underdiagnosed, making it difficult to determine its true frequency in the general population. Some estimates suggest that iron overload affects more than 10 percent of the population in sub-Saharan Africa.

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

A diagnosis of African iron overload is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests such as blood tests, which can reveal elevated levels of ferritin in the blood plasma. Ferritin is a protein that binds to iron and is used as an indicator of the body’s iron stores. Another test measures transferrin saturation. Transferrin is a protein involved in the transport of iron from the intestine into the bloodstream.


Agammaglobulinemia

Agammaglobulinemia is a group of inherited immune deficiencies characterized by a low concentration of antibodies in the blood due to the lack of particular lymphocytes in the blood and lymph. Antibodies are proteins (immunoglobulins, (IgM), (IgG) etc) that are critical and key components of the immune system. They are essential if the immune system is to do its job of fighting off bacteria, viruses, and other foreign substances that threaten the body. The specialized precursor cells that produce gammaglobulins, fail to develop or function properly leading to the deficiency in the number of mature lymphocyte cells called B cells.

The major symptoms of agammaglobulinemia are serial bacterial infections resulting from failures in specific immune responses because of defects in B-lymphocytes. These lymphocytes govern the production of antibodies. Males with X-linked primary agammaglobulinemia usually begin to show signs of such infections only late in the first year of life, after the IgG antibodies from the mother have been depleted.

X-linked agammaglobulinemia (B-lymphocyte defect) is inherited as an X-linked recessive genetic trait.  The abnormal gene, named BTK, has been mapped to gene locus Xq21.3-q22. A different mutation in the BTK gene causes X-linked agammaglobulinemia with growth hormone deficiency.  The genetic cause of ARAG is much more complex involving  other genes that have been mapped to loci on different chromosomes: 22q11.21, 14q32.33, and 9q34.13. The genes at three sites are known as IGLL1, IGHM, and LCRR8 respectively.

Primary Agammaglobulinemia is a rare disorder that occurs almost exclusively in males although some females have been affected by certain types of this disorder.

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

Common Variable Immunodeficiency (CVID) is rare immunodeficiency disorder characterized by recurrent infections in the lungs, sinuses or ears.  The range and severity of symptoms and findings associated with CVI may vary from case to case.   In some cases, individuals with CVID have an increased tendency to develop infections of the gastrointestinal system and may have a higher risk for some types of cancer such as non-Hodgkin lymphoma and stomach cancer.  In addition, some individuals with CVID have an autoimmune disorder such as immune thrombocytopenia purpura that causes abnormal bruising and bleeding.  The symptoms of CVI usually become apparent during the second to the fourth decade of life.   CVID is thought to be caused by mutations in genes involved in the production of B cells that produce antibodies against infectious agents.  CVID is likely to be caused by a combination of genetic and environmental factors in most cases, but autosomal recessive and autosomal dominant inheritance has been described in some families.  (For more information on this disorder, choose CVID as your search term in the Rare Disease Database.)

The administration of intravenous gammaglobulin replacement therapy is a standard treatment for agammaglobulinemia. Intravenous gammaglobulin or subcutaneou. is used to treat agammaglobulinemias and common variable immunodeficiency.


Adrenocortical carcinoma

Agenesis of corpus callosum (ACC) is a rare disorder that is present at birth (congenital). It is characterized by a partial or complete absence (agenesis) of an area of the brain that connects the two cerebral hemispheres. This part of the brain is normally composed of transverse fibers. The cause of agenesis of corpus callosum is usually not known, but it can be inherited as either an autosomal recessive trait or an X-linked dominant trait. It can also be caused by an infection or injury during the twelfth to the twenty-second week of pregnancy (intrauterine) leading to developmental disturbance of the fetal brain. Intrauterine exposure to alcohol (Fetal alcohol syndrome) can also result in ACC. In some cases mental retardation may result, but intelligence may be only mildly impaired and subtle psychosocial symptoms may be present.

Agenesis of corpus callosum (ACC) may initially become evident through the onset of epileptic seizures during the first weeks of life or within the first two years. However, not all individuals with ACC have seizures. (For more information on these types of seizures choose epilepsy as your search term in the Rare Disease Database).

In most cases, the cause of ACC is unknown. However, agenesis of corpus callosum can be inherited as an autosomal recessive trait or an X-linked dominant trait. This disorder may also be due in part to an infection during pregnancy (intrauterine) leading to abnormal development of the fetal brain.

Agenesis of Corpus Callosum produces symptoms during the first two years of life in approximately ninety percent of those affected. It has been thought to be a very rare condition but the increased use of neuro-imaging techniques, such as MRI, is resulting in an increased rate of diagnosis. This condition may also be identified during pregnancy through an ultrasound. Currently, the highest estimate of incidence is 7 in 1000 individuals.

Agenesis of corpus callosum can occur in conjunction with spina bifida. Spina bifida is a term meaning open (or non-fused) spine. In spina bifida, one or more of the individual bones of the spine fails to close completely, leaving a cleft or defect in the spinal canal. Part of the contents of the spine can protrude or herniate through this abnormal opening that produces a meningocele or meningomyelocele. (For more information on this disorder, choose spina bifida as your search term in the Rare Disease Database.)

Ultrasound and magnetic resonance imaging (MRI) are imaging techniques that aid in diagnosis of agenesis of corpus callosum.


Aicardi syndrome

agenesis of corpus callosum with chorioretinitis abnormality

Aicardi syndrome typically begins as involuntary muscle spasms between four months and four years of age. Other symptoms may include epilepsy, intellectual disability, profound muscle weakness (hypotonia), abnormally small eyes (microphthalmia), an incomplete development of the retina and nerve in the back of the eye (colobomas) and/or abnormalities of the ribs and/or spinal vertebral bones. In addition to the agenesis of the corpus callosum, imaging of the brain (by brain MRI) usually shows cysts in the brain as well as clumps of nerve cells that are in the wrong location (heterotopias). Children of all ages with Aicardi syndrome have significant delays in motor development. Aicardi syndrome can be life-threatening during childhood due to prolonged seizures and complications from upper respiratory infections.

Aicardi syndrome is likely caused by a new change (variant or mutation) in a gene located on the X chromosome. The gene that causes Aicardi syndrome is not known. A report describing changes in the genes TEAD1 and OCEL1 in two girls with Aicardi syndrome was not confirmed in a large cohort of other girls with Aicardi syndrome. Thus, these genes do not seem to be the cause of Aicardi syndrome. This condition is presumed to be lethal in males.

Aicardi syndrome usually affects only females. In very rare cases, males with Klinefelter syndrome (47, XXY) may have Aicardi syndrome. It has been estimated that there are between 300 and 500 people reported to have Aicardi syndrome worldwide. There do not appear to be any differences based on race or ethnicity.

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

Microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development (MCLMR) can be confused with Aicardi syndrome. In MCLMR, the eye abnormalities are on the edges of the retinas, in contrast to Aicardi syndrome, where the lacunae are in the central part of the retina. Additionally, in MCLMR, the head size is very small (severe microcephaly) whereas in Aicardi syndrome the head size is usually normal. Additionally, individuals with MCLMR do not typically have agenesis of the corpus callosum or other developmental brain abnormalities typical of Aicardi syndrome.


Aicardi-Goutières syndrome

AGS is a disease that affects the white matter of the brain (leukoencephalopathy) and may result in severe intellectual and physical disability. Some infants will present variably in the first few weeks of life with irritability, fever, abnormal muscle contractions (dystonia), microcephaly, basal ganglia calcifications, white matter tract abnormalities, CSF lymphocytosis and elevated CSF interferon-alpha. However, infants and young children may also present after a period of normal development, in some cases following a period of unexplained fever or rash due to inflammation. As the disease progresses, individuals with AGS may present with chilblain skin lesions, most commonly on the fingers, toes and ears, or with other atypical rashes. Some infants with AGS may present with symptoms resembling a congenital infection which should be ruled out prior to diagnosis. These signs include hepatosplenomegaly, elevated liver enzymes and thrombocytopenia (low platelets). Such infections include toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, HIV or Zika virus infections. Multiple organ systems may become involved including the eyes (glaucoma and uveitis), endocrine (hypothyroidism, diabetes, diabetes insipidus, growth delay), cardiovascular (cardiomyopathy, pulmonary hypertension and other abnormalities), gastrointestinal (autoimmune hepatitis, inflammatory bowel disease), musculoskeletal (myopathy, neuropathy, arthropathy), renal (renal insufficiency) and hematologic (thrombocytopenia, anemia, leukopenia). Due to the significant neurologic involvement of AGS, affected individuals typically display muscular spasticity and dystonia, decreased muscular tone of their trunk (truncal hypotonia), poor head control, and seizures.

Aicardi-Goutières syndrome is caused by changes (pathogenic variants or mutations) in several different genes including TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR1, IFIH, LSM11 and RNU7-1. These variants disrupt cellular signaling and production of immune-related molecules (interferons). AGS is characterized as an interferonopathy, meaning that it is a disease related to dysregulated or dysfunctional interferons (interferon alpha in this case).

The prevalence of AGS is unknown. Studies suggest that AGS is one of the most common genetic disorders affecting the white matter of the brain.

Since calcification of the basal ganglia can be seen in many disorders, it is important to rule out other potential causes of the clinical features. The following are a few conditions with similar symptoms

Aicardi-Goutières syndrome can be diagnosed when there is suspicion based on clinical features in addition to characteristic neuroimaging and laboratory findings. Neuroradiographic findings best visualized by CT scan or MRI include calcifications of the basal ganglia, particularly the putamen, globus pallidus and thalamus. Other neurologic findings include often diffuse white-matter changes and cerebral atrophy. Laboratory findings include characteristic features seen in the peripheral blood and cerebral spinal fluid (CSF). In the peripheral blood, abnormalities of the blood cells and elevated liver enzymes may be noted. In the CSF, leukocytosis (elevated white blood cell count), increased interferon-alpha and increased concentration of neopterin may all be found. Finally, the diagnosis can also be established through genetic and molecular testing. These tests include serial single-gene tests, a multigene panel and comprehensive genomic testing. These tests can search for pathogenic variants in genes known to cause AGS.


氨基乙酰丙酸脱水酶缺乏性卟啉症

Porphyria due to ALA dehydratase deficiency

The onset, severity and type of symptoms can vary greatly in individuals with a specific type of porphyria. This variation may depend on, in part, the amount of residual enzyme activity in each individual. Individuals with more significant enzyme deficiency may have more severe symptoms and earlier onset. Individuals with partial deficiency will have milder symptoms, and some individuals will not develop any symptoms (asymptomatic). It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their medical team about their specific case, associated symptoms and overall prognosis.

ALAD porphyria is caused by mutations in the ALAD gene, and the disease is inherited as an autosomal recessive disorder. This means that both copies of the ALAD gene have a mutation. 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.

ALAD porphyria is an extremely rare disorder with few cases reported in the medical literature. Most cases have occurred in Europe. However, the disorder can potentially occur in any population. More males have been identified with ALAD porphyria than females in the medical literature, but the disorder affects probably males and females in equal numbers. Researchers suspect that some cases of ALAD porphyria go undiagnosed or misdiagnosed, making it difficult to estimate the true frequency of this disorder in the general population. The onset of ALAD porphyria is usually during infancy or childhood, but late-onset of the disorder (well into adult life) has also been reported.

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

A diagnosis of ALAD porphyria is made based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation and of specialized tests that can detect delta-aminolevulinic acid in the urine.


Alagille syndrome

Alagille syndrome (ALGS) is a rare genetic disorder that can affect multiple organ systems of the body including the liver, heart, skeleton, eyes and kidneys. The specific symptoms, organ system involvement and severity of Alagille syndrome can vary greatly from one person to another, even within the same family. Some individuals may have mild forms of the disorder while others may have more serious forms. Common symptoms, which often develop during the first three months of life, include blockage of the flow of bile from the liver (cholestasis), yellowing of the skin and mucous membranes (jaundice), poor weight gain and growth and severe itching (pruritis). Additional symptoms include heart murmurs, congenital heart defects, vertebral (back bone) differences, thickening of the ring that normally lines the cornea in the eye (posterior embryotoxon) and distinctive facial features. Most people with Alagille syndrome have changes (variants or mutations) in one copy of the JAG1 gene. A small percentage (2%) of patients have variants in the NOTCH2 gene. These variants can be inherited in an autosomal dominant pattern, but in about half of cases, the variant occurs as a new change (de novo) in the individual and was not inherited from a parent. The current estimated incidence of ALGS is approximately 1/30,000 –1/45,000.

The symptoms and severity of Alagille syndrome can vary greatly from one person to another, even among members of the same family. Some individuals may have a mild form of the disorder that can virtually go unnoticed; other individuals may have a serious form of the disorder that can potentially cause life-threatening complications. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

Alagille syndrome is caused by variants in one of two genes – the JAG1 gene or the NOTCH2 gene. Variants in the JAG1 gene have been identified in approximately 94% of patients. Variants in the NOTCH2 gene have been found in 2-4% of patients. These gene variants are inherited in an autosomal dominant pattern. In some people, the variant occurs randomly due to a spontaneous genetic change (de novo).

Alagille syndrome affects males and females in equal numbers. The incidence of Alagille syndrome has been estimated to be approximately 1 in 30,000-45,000 individuals in the general population. Some cases of Alagille syndrome may go undiagnosed or misdiagnosed making it difficult to determine the true frequency of Alagille syndrome in the general population.

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

A diagnosis of Alagille syndrome is made based upon identification of characteristic symptoms and genetic testing, along with a detailed patient history, a thorough clinical evaluation and other specialized tests. Because the symptoms of Alagille syndrome are highly variable, obtaining a diagnosis can be difficult. Surgical removal and microscopic study of liver tissue (liver biopsy) can reveal bile duct paucity. Although bile duct paucity is considered a key characteristic of Alagille syndrome, this finding is not always present in infants with the disorder.

The treatment of Alagille syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, gastroenterologists, cardiologists, ophthalmologists and other healthcare professionals may need to plan an affect child’s treatment systematically and comprehensively. Individuals with Alagille syndrome should have a baseline echocardiogram (ultrasound of the heart) to screen for heart involvement, ultrasound of the abdomen to screen for liver and kidney anomalies, a chest X-ray to screen for skeletal involvement, and a screening eye (ophthalmology) exam. In addition, if not previously obtained for specific symptoms, a screening imaging study of the blood vessels of the head (MRI/MRA) is recommended for children who are old enough to sit through the study without need for anesthesia or sedation. Supplemental treatment with vitamins and nutrients is essential for individuals with malabsorption. Such treatment may include restoring vitamins A, D, E and K. Young children may be given formula with medium chain triglycerides because this form of fat is better absorbed by individuals with Alagille syndrome who have cholestasis. Some affected children may need to receive extra calories through a tube that runs from the nose to the stomach (nasogastric tube) or through a tube placed directly into the stomach through a small incision in the abdominal wall and stomach (gastrostomy tube).


Alexander disease

Historically, three forms of Alexander disease have been described based on age of onset, Infantile, Juvenile and Adult; but an analysis of a large number of patients concluded that the disease is better described as having two forms, Type I, which generally has an onset by age 4, and Type II, which can have onset at any age, but primarily after age 4. Each type accounts for about half of the reported patients. Symptoms associated with the Type I form include a failure to grow and gain weight at the expected rate (failure to thrive); delays in the development of certain physical, mental, and behavioral skills that are typically acquired at particular stages (psychomotor impairment); and sudden episodes of uncontrolled electrical activity in the brain (seizures). Additional features typically include progressive enlargement of the head (macrocephaly); abnormally increased muscle stiffness and restriction of movement (spasticity); lack of coordination (ataxia); and vomiting and difficulty swallowing, coughing, breathing or talking (bulbar and pseudobulbar signs). Nearly 90% of infantile patients display developmental problems and seizures, and over 50% the other symptoms mentioned; however, no single symptom or combination of symptoms is always present.

About 95% of Alexander disease cases are caused by mutations in a gene called GFAP for a structural protein called glial fibrillary acidic protein that is found exclusively in astrocytes in the CNS. The cause of the other 5% of cases is not known.

Alexander disease has been estimated to occur at a frequency of about 1 in 1 million births. No racial, ethnic, geographic, or sex preference has been observed, nor is any expected given the de novo (new) nature of the mutations responsible for most cases. Although initially diagnosed primarily in young children, it is now being observed with similar frequency at all ages.

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

Hydrocephalus is a condition in which the normal flow of cerebrospinal fluid (CSF) is restricted and the spaces in the brain (ventricles) become abnormally enlarged. Fluid accumulates beneath the skull and puts pressure on the brain. Hydrocephalus is characterized in children by an abnormally enlarged head (megalencephaly). The scalp may be thin and transparent, and the forehead may bulge (frontal bossing). Other symptoms of hydrocephalus may include convulsions, abnormal reflexes, a slowed heartbeat, headache, vomiting, weakness and/or problems with vision. (For more information on this disorder, choose Hydrocephalus as your search term in the Rare Disease Database.)


Alkaptonuria

Alkaptonuria is a rare genetic metabolic disorder characterized by the accumulation of homogentisic acid in the body. Affected individuals lack enough functional levels of an enzyme required to breakdown homogentisic acid. Affected individuals may have dark urine or urine that turns black when exposed to air. However, this change may not occur for several hours after urination and often goes unnoticed. Aside from dark urine that is present from infancy, affected individuals generally do not develop symptoms (asymptomatic) during infancy or childhood and often remain unaware of their condition until adulthood. Affected individuals eventually develop ochronosis, which is the bluish-black discoloration of connective and other tissue within the body. Affected individuals may develop discoloration of the skin overlying cartilage within the body such as over part of the outer ear. In some cases, the whites of the eyes (sclera) may also become discolored. In adulthood, affected individuals also develop progressive arthritis of the spine and large joints. The HGD gene codes for the enzyme required for the breakdown of homogentisic acid. Mutations in the HGD gene cause alkaptonuria.

Alkaptonuria is a genetic disorder, and urine that turns dark is present from birth. However, additional symptoms usually do not appear until adulthood. Symptoms are generally slowly progressive. The urine of individuals with alkaptonuria may be abnormally dark or it may turn black upon long-standing exposure to the air. However, since this change often takes several hours, it often goes unnoticed. During infancy, diapers may be stained black (from urine exposure to air), although this is often missed or ignored.

Alkaptonuria is caused by mutation of the homogentisate 1,2-dioxygenase (HGD) gene. The HGD gene contains instructions for creating (encoding) an enzyme known as homogentisate 1,2-dioxygenase. This enzyme is essential for the breakdown of homogentisic acid. Mutations of the HGD gene result in deficient levels of functional homogentisate 1,2-dioxygenase, which, in turn, leads to excess levels of homogentisic acid. Although homogentisic acid is rapidly cleared from the body by the kidneys, it also slowly accumulates in the various tissues of the body, especially connective tissue such as cartilage. Over time (rarely before adulthood), it eventually changes the color of affected tissue to a slate blue or black. Long-term, chronic accumulation of homogentisic acid eventually weakens and damages affected tissue and leads to many of the characteristic symptoms of alkaptonuria.

Alkaptonuria affects males and females in equal numbers, although symptoms tend to develop sooner and become more severe in males. More than 1,000 affected individuals have been reported in the medical literature. The exact incidence of alkaptonuria is unknown. In the United States it is estimated to occur in 1 in 250,000-1,000,000 live births. Alkaptonuria has been reported in all ethnic groups. Areas with increased frequencies of the disorder have been identified in Slovakia, the Dominican Republic and Germany.

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

The diagnosis of alkaptonuria is made upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Identification of vastly elevated levels of homogentisic acid in the urine is indicative of alkaptonuria. Alkaptonuria should be suspected in individuals with dark urine. However, since some individuals with alkaptonuria do not have dark urine, it may be advisable to rule out the disorder for all individuals with osteoarthritis, especially those with an early onset of symptoms.


Alopecia Areata

Alopecia areata is a disorder characterized by loss of hair. Sometimes, this means simply a few bare patches on the scalp. In other cases, hair loss is more extensive. Although the exact cause is not known, this is thought to be an autoimmune disorder in which the immune system, the body’s own defense system, mistakenly attacks the hair follicles, the tiny structures from which hairs grow. Unpredictable hair loss is the only noticeable symptom of this disorder. Regrowth of hair may or may not occur.  Hair loss is usually confined to the head and face, although the entire body may be involved.

Alopecia areata often begins suddenly with oval or round bald patches appearing most commonly on the scalp.  Other areas of hairy skin may also be involved.  Gradually, the affected skin becomes  smooth.  New patches may spread by joining existing bald patches.  These larger bald areas can appear while hair is regrowing in older hairless patches.  Loss of hair can be permanent in some cases.  Hair follicles may deteriorate, but oil producing glands in the skin (sebaceous glands) usually change very little. The skin does not become hard or atrophied.  In a very few cases, all body hair may be lost.  Cases beginning during childhood tend to be more severe than cases with an onset during adulthood.

The exact cause of alopecia areata is not known.  An autoimmune mechanism is suspected in this disorder.  Autoimmune disorders are caused when the body’s natural defenses against foreign or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons.  Some cases may be linked to abnormal reactions by blood cells (serum antibodies) to a thyroid protein (thyroglobulin), stomach (parietal) cells, or adrenal cells.

Alopecia areata affects males and females in equal numbers.  It may appear at any age, but most typically begins during childhood.  There are approximately 2.5 million individuals in the United States affected by alopecia areata.

Loss of hair (alopecia) can occur from a wide variety of causes.  Symptoms of the following disorders can be similar to those of alopecia areata. Comparisons may be useful for a differential diagnosis:

Trichotillomania, also known as hair pulling, is a neurotic habit that usually appears in children.  It may remain undiagnosed for a long time.  The hairs may be broken off or pulled out.  Stubby regrowth may replace damaged hair or bald areas.  This mental illness may be hard to distinguish from alopecia areata without careful observation of the affected child’s habits.  Hair can be similarly damaged by permanent wave solutions, softeners or hot combs.  (For more information on this disorder, choose trichotillomania as your search term in the Rare Disease Database.)

Treatment of alopecia areata is directed at producing regrowth of hair. Although there is no cure for alopecia areata at the present time, the hair may sometimes return by itself. In some cases, it may also fall out again after returning. The course of this disorder varies among individuals, and is difficult to predict.


Alpers Disease

Alpers Diffuse Degeneration of Cerebral Gray Matter with Hepatic Cirrhosis

Alpers disease is a progressive neurologic disorder that begins during childhood and is complicated in many instances by serious liver disease. Symptoms include increased muscle tone with exaggerated reflexes (spasticity), seizures, and loss of cognitive ability (dementia).

Alpers disease usually begins during early childhood, usually indicated by seizures at any age between 3 months and 5 years.  It is characterized by lack of coordination of motor movement, partial paralysis, seizures, and muscle twitching. The child is unable to achieve normal muscle tone (hypotonia), yet the limbs appear to be stiff. On MRI examination an increased density of the grey matter in the brain is noted. Usually, but not always, Alpers disease is associated with liver damage.  Mental retardation may be severe and is progressive.  The loss of intellectual functions such as thinking, remembering, and reasoning may also interfere with a person’s daily functioning (dementia).   In later stages, patients may lose control of the movement of their arms and legs (spastic quadriplegia). The liver may become cirrhotic and fail completely, or may not progress beyond signs of jaundice. Affected individuals may also become blind as a result of optic atrophy as the optic nerve degenerates.

Many researchers believe that Alpers Syndrome, rather than being a distinct disorder, is a clinical entity (i.e., cerebral gray matter degeneration in association with liver disease) that may be due to a number of different causes.  In some cases, it is believed that the syndrome may be inherited as an autosomal recessive genetic trait.  In other cases, clinicians attribute the disorder to a prion or prion-like molecule. Some researchers believe that certain individuals may inherit a genetic predisposition for the disorder; in such cases, certain environmental factors in combination with such a genetic predisposition may ultimately result in expression of the disorder.  Research has also indicated that certain metabolic defects or mitochondrial abnormalities may play some role in causing the disorder.

It is thought that Alpers disease affects males and females in equal numbers usually during early childhood.  However, some clinicians are convinced that the difficulty of diagnosis makes estimating the frequency of this disorder less accurate.  It is probable that Alpers disease affects fewer, than one (1) person per 200,000 of population.

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

Myoclonic epilepsy is a hereditary neurologic disorder inherited through recessive genes.  It is characterized by sudden brief contractions of groups of muscles.  Onset is usually between the ages of six and sixteen.  During the initial period of seizures there is loss of consciousness.  After years of attacks of increasing frequency and severity, spasms involving the muscles of the face, trunk, arms, and legs intensify.  Untreated, this type of epilepsy can lead to progressive dementia.  (For more information on this disorder, choose Epilepsy as your search term in the Rare Disease Database.)


X连锁α地中海贫血-智力障碍综合征

X-linked alpha-thalassemia-intellectual disability syndrome

Alpha Thalassemia X-linked Intellectual Disability Syndrome

The specific signs and symptoms present and their severity vary greatly from person to person. Many of the signs associated with ATR-X syndrome are apparent during infancy. Affected infants may exhibit diminished muscle tone (hypotonia), feeding difficulties and significant delays in reaching developmental milestones especially speaking or walking. Some affected individuals do not walk independently or fail to develop the ability to speak outside of a limited vocabulary. Intellectual disability is the most important of the clinical findings, but genital abnormalities, seizures and stiff movements of the legs also occur. Growth deficiency occurs after birth (postnatally) but may not become apparent until adolescence. Ultimately, growth deficiency may result in short stature.

ATR-X syndrome is inherited as an X-linked recessive genetic condition. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene, he will develop the disease.

ATR-X syndrome affects males. More than 200 families have been reported by laboratories conducting molecular genetic testing. However, because this disorder is underdiagnosed it is difficult to determine its true frequency in the general population. Female carriers of the mutated gene do not usually develop any manifestations.

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

ATR-X syndrome may be suspected at birth or during infancy based upon a thorough clinical evaluation and identification of characteristic findings (e.g., intellectual disability, distinctive facial features, genitourinary abnormalities). Blood tests (e.g., brilliant cresyl blue stain) that demonstrate the presence of hemoglobin H inclusion bodies in red blood cells may assist in diagnosis. However, HbH is a variable finding in ATR-X syndrome and failure to detect HbH inclusion bodies does not rule out ATR-X syndrome. A diagnosis of ATR-X syndrome may be confirmed by molecular genetic testing that identifies a mutation of the ATRX gene. A specific DNA methylation profile is available to help clarify the pathogenicity of alterations of uncertain significance in the ATRX gene.

The treatment of ATR-X syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dental specialists, speech pathologists, eye specialists, specialists in treating skeletal disorders (orthopedists) and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.


Alpha Thalassemia

The specific symptoms and severities of the alpha thalassemia conditions vary greatly from one person to another. Individuals with alpha thalassemia silent carrier do not develop symptoms, while individuals with alpha thalassemia minor do not develop any symptoms or are only mildly anemic. Many individuals with either form of alpha thalassemia go through life never knowing they carry an altered gene(s) for the disorder. In some cases, a diagnosis is made incidentally while they are being evaluated for another condition.

Alpha thalassemia is caused by alterations (mutations) in two adjacent genes, the HBA1 and the HBA2 genes. Every person has two copies of the HBA1 gene (one from each parent) and two copies of the HBA2 gene (also one from each parent). Affected individuals may have a mutation or combination of mutations in one gene, two genes, three genes, or all four copies of these genes. 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 either function normally but be reduced in quantity, or function abnormally and be produced at normal levels. Depending upon the functions of the protein, this can affect many organ systems of the body.

Alpha thalassemia is one of the most common autosomal recessive disorders in the world. Increased immigration of people from areas with a higher incidence of alpha thalassemia has led to an increased incidence of the alpha-globin disorders in the US and other Western nations. Although the incidence and prevalence is increasing in United States and Northern Europe, the exact incidence or prevalence remains unknown. Severe forms of alpha thalassemia (HbH disease and Hb Bart’s hydrops fetalis) have been estimated to occur in approximately 1 in 1,000,000 individuals in the general population in Northern Europe and North America. However, some studies have shown that alpha thalassemia may be under-recognized and underdiagnosed in these countries, making it difficult to determine their true frequency.

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

A diagnosis of alpha thalassemia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Hb Bart’s hydrops fetalis can be diagnosed before birth in most cases.


Alpha-1 Antitrypsin Deficiency

α-1-抗胰蛋白酶缺乏症

Alpha-1 antitrypsin deficiency (A1AD) is a hereditary disorder characterized by low levels of a protein called alpha-1 antitrypsin (A1AT) which is found in the blood. This deficiency may predispose an individual to several illnesses and most commonly manifests as chronic obstructive pulmonary disease (including bronchiectasis) and liver disease (especially cirrhosis and hepatoma), or more rarely, as a skin condition called panniculitis.

Alpha-1 antitrypsin deficiency (A1AT) is caused by disease-causing variants in the SERPINA1 gene that is responsible for producing the alpha-1 antitrypsin protein. Normally, this protein is produced in the liver and released into the bloodstream and functions to protect the body from the neutrophil elastase enzyme which is contained within the white blood cells called neutrophils. Neutrophil elastase is released from white blood cells to fight infection, but it can attack normal tissues (especially the lungs) if not tightly controlled by alpha-1 antitrypsin.

Alpha-1 antitrypsin deficiency is a disorder that occurs most frequently in Americans of Northern or Central European descent, affecting approximately 100,000 Americans. However, because most patients with A1AD go unrecognized, the disorder is very much under-diagnosed. Estimates suggest that only 10% or fewer of these estimated 100,000 Americans with severe deficiency of A1AT have been diagnosed, with the others either having chronic obstructive pulmonary disease (COPD) that has not been recognized to be caused by A1AD or being unaffected.

Symptoms of the following disorders can be similar to those of alpha-1 antitrypsin deficiency:

The diagnosis of A1AD is based on a low concentration of A1AT in the blood in combination with a high-risk phenotype (demonstrated by a test called isoelectric focusing) or by genotype analysis (i.e., detecting specific abnormal alleles [usually the Z or S alleles and sometimes for additional abnormal alleles called the F and I alleles]). In some instances, further testing to sequence the SERPINA1 gene is needed to confirm the diagnosis. Testing for at-risk family members and prenatal and preimplantation genetic testing are possible once the SERPINA1 variants have been identified in the family.

Treatments for emphysema associated with A1AD include standard medications used in managing patients with emphysema of all causes (such as inhaled bronchodilators, inhaled steroids, anticholinergics, oxygen therapy and the administration of antibiotics or phosphodiesterase 5 inhibitors for the frequent respiratory infections) as well as (in some cases) specific A1AT treatment called augmentation therapy (see below). Exercise programs (pulmonary rehabilitation) and good nutrition may help increase overall quality of daily living.


Alpha-mannosidosis

The symptoms, progression and severity of alpha-mannosidosis vary widely from one person to another, including between siblings who share the same gene variant. Alpha-mannosidosis represents a spectrum or continuum of disease and is highly individualized. Some individuals develop symptoms shortly after birth and may develop potentially life-threatening complications in infancy or early childhood. Other individuals develop more moderate symptoms usually with onset before the age of 10. Some individuals may not be diagnosed until adulthood.

Alpha-mannosidosis is caused by changes (variants or mutations) in the MAN2B1 gene. The MAN2B1 gene contains instructions for producing the enzyme lysosomal alpha-mannosidase (LAMAN). This enzyme is essential for breaking down (metabolizing) certain glycoproteins. Without proper levels of functional version of this enzyme, these glycoproteins abnormally accumulate in and damage various tissues and organs of the body. Variants of the MAN2B1 gene result in the lack of production of the alpha-D-mannosidase enzyme or the production of a defective, inactive form of the enzyme.

The prevalence of alpha-mannosidosis is estimated to be 1 in every 500,000 people in the general population. Alpha-mannosidosis affects males and females in equal numbers and can potentially affect individuals of any ethnic group worldwide.

Symptoms of the following disorders can be similar to alpha-mannosidosis. Comparisons may be useful for a differential diagnosis:

Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies. There are nearly 50 of these disorders, and they may affect different parts of the body, including the skeleton, brain, skin, heart and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases. (For more information choose lysosomal storage disease as your search term in the Rare Disease Database.)


Alport syndrome

The onset, symptoms, progression and severity of Alport syndrome can vary greatly from one person to another due, in part, to the specific subtype and gene variant present. Some individuals may have a mild, slowly progressive form of the disorder, while others have earlier onset of severe complications.

Alport syndrome results from disease-causing variants in the DNA sequences of specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a disease-causing variant in the DNA sequence of genes 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.

Alport syndrome is estimated to affect approximately 1 in 5,000-10,000 people in the general population in the United States, which means that approximately 30,000-60,000 people in the United States have the disorder.  However, recent population studies suggest that disease-causing variants in the COL4A3, COL4A4 and COL4A5 genes may be more prevalent than previously realized (Groopman et al, 2019; Gibson et al, 2021) Alport syndrome is estimated to account for 3% of children with chronic kidney disease and 0.2% of adults with end-stage renal disease in the United States. In XLAS, males are affected more severely than females. In the autosomal forms of Alport syndrome, males and females are affected with equal severity.

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

A diagnosis of Alport syndrome is suspected based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. The likelihood of diagnosis increases in individuals with a family history of Alport syndrome, kidney failure without known cause, early hearing loss or hematuria. A variety of specialized tests can help to confirm a suspected diagnosis.


Alström Syndrome

Alström syndrome may potentially affect several different organ systems of the body. The specific symptoms associated with Alström syndrome, their severity and their rate of progression vary greatly from one person to another, even among members of the same family. It is important to note that affected individuals will not have all of the symptoms discussed below and individual cases may be dramatically different. Some symptoms may present in the first weeks of life, others symptoms may not develop until adolescence or early adulthood.

Alström syndrome is caused by mutations in the ALMS1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

Alström syndrome affects males and females in equal numbers. The exact incidence is unknown. Estimates have ranged from 1 in 10,000 to less than 1 in 1,000,000 individuals in the general population. Approximately 1200 affected individuals have been identified worldwide. Because some cases of Alström syndrome may go unrecognized or misdiagnosed, the disorder may be under-diagnosed, making it difficult to determine its true frequency in the general population.

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

A diagnosis of Alström syndrome is made upon a thorough clinical evaluation, identification of characteristic findings (e.g., cone-rod dystrophy, sensorineural hearing impairment, cardiomyopathy, obesity, kidney dysfunction, diabetes), and a variety of specialized tests. A diagnosis of Alström syndrome may be difficult because of delayed onset of certain key characteristics including diabetes, cardiomyopathy, and kidney disease. The absence of certain findings (e.g., polydactyly, intellectual disability) distinguishes Alström syndrome from similar syndromes such as Bardet-Biedl syndrome or Laurence-Moon syndrome.


Alternating hemiplegia of childhood

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder characterized by repeated episodes of weakness or paralysis that may affect one side of the body or the other (hemiplegia) or both sides of the body at once (quadriplegia). Additional episodic symptoms usually include intermittent abnormal eye movements, episodes of muscle stiffness or posturing (dystonia), and in a substantial percentage of cases, seizures. Delays in attaining developmental milestones (developmental delays), cognitive impairment, and persistent issues with balance and the presence of continuous dance-like movements of limbs or facial muscles (chorea) may occur independently of episodes of paralysis, weakness or stiffness and persist between episodes. The severity of AHC and the specific types of episodes that occur can vary dramatically from one individual to another. First symptoms usually begin before the age of 18 months. AHC is caused by mutations in the ATP1A3 gene in the majority of those affected. AHC is a rare disorder that was first reported in the medical literature in 1971 by doctors Simon Verret and John C. Steele. They described an unusual disorder in eight children who demonstrated intermittent episodes of weakness, affecting first one side of the body, then the other, with onset in early childhood, including one child who manifested symptoms as early as 3 months of age. However, the disorder remained poorly understood for many years, in part, because of its rarity and complex and highly variable symptoms. More research is necessary to improve early diagnosis, understand the full range of symptoms, and develop more effective treatments. The identification of a causative gene for AHC should lead to a better understanding of the disorder and open new avenues for treatment. The spectrum of related disorders with overlapping symptoms continues to expand, and has led to the increasingly common use of the term ATP1A3-related neurologic disorders. This umbrella includes patients with rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. However, an increasing number of patients with overlapping symptoms that further expand the phenotypes even beyond these well-described disorders, initially thought to be completely distinct, continues to expand.

AHC is a highly variable and unpredictable disorder and the specific symptoms and severity of the disorder can vary greatly from one person to another. Some individuals may have mild forms of the disorder with a good prognosis, and develop almost normally. However, others may have a severe form with the potential for serious and disabling complications that can disrupt various aspects of life and manifest as persistent neurologic disability.

In at least 2/3 of individuals, AHC is caused by a mutation in the ATP1A3 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

AHC affects males and females in equal numbers. It is estimated to occur in approximately 1 in 1,000,000 births. However, since cases may go unrecognized or misdiagnosed, it is difficult to determine the true frequency of AHC in the general population. Symptoms usually become apparent within the first 18 months.

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

A diagnosis of AHC is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Specific diagnostic criteria have been proposed for AHC. The seven criteria are: (1) onset of symptoms before 18 months; (2) repeated episodes of hemiplegia that sometimes involve both sides of the body; (3) quadriplegia that occurs as an isolated incident or as part of a hemiplegic attack; (4) relief from symptoms upon sleeping; (5) additional paroxysmal attacks such as dystonia, tonic episodes, abnormal eye movements or autonomic dysfunction; (6) evidence of developmental delay or neurological abnormalities such as choreoathetosis, ataxia or cognitive disability; (7) cannot be attributed to another cause.


Congenital alveolar capillary dysplasia

先天性肺泡毛细血管发育不良

Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins

Within the first few days after birth, infants with ACDMPV develop severe breathing problems and lack of oxygen in the blood (hypoxemia). They experience shortness of breath and cyanosis, a condition marked by abnormal bluish discoloration of the skin that occurs because of low levels of oxygen in the blood. High blood pressure in the arterial blood vessels of the lungs (pulmonary hypertension) also occurs. Breathing issues become progressively worse and most infants experience respiratory failure. Very rarely, infants may not show signs of the disorder until weeks or even months after birth, usually when pulmonary hypertension of variable severity is noted.

In most affected children, ACDMPV is caused by a point mutation in the FOXF1 gene, or by a loss of genetic material on chromosome 16q24.1 that includes the FOXF1 gene or non-coding elements (promoter and lung-specific enhancer) that regulate the expression of FOXF1. 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 or inefficient. Depending upon the functions of the protein, this can affect many organ systems of the body. For a minority of infants (~10-20%) with ACDMPV, the molecular cause remains unknown. In most instances, the disorder is sporadic, which means that the genetic changes occur at the time of fertilization and are not inherited from the parents. However, there are very rare instances where ACDMPV has been reported to run in families and can be inherited.

ACDMPV is a very rare disorder. The incidence and prevalence are unknown. More than 200 people with this disorder have been reported in the medical literature. However, many infants may go misdiagnosed or undiagnosed, so determining the true frequency of ACDMPV in the general population is difficult.

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

ACDMPV may be suspected in any infant who presents with severe cyanosis (hypoxemia) and high pulmonary blood pressure (pulmonary hypertension) that is unresponsive to treatment in the neonatal intensive care unit (NICU). The diagnosis is confirmed through a histopathological examination of lung tissue at biopsy or autopsy by an experienced pathologist for characteristic tissue changes. The characteristics that a pathologist will look for can include a relative lack of capillaries near the alveoli, thickening of the walls (septa) of alveoli, misalignment of pulmonary veins and increased muscularization of the small arteries of the lungs (arterioles).


Alveolar Soft Part Sarcoma

Alveolar soft part sarcoma (ASPS) is a rare, slow growing soft tissue tumor of an unclear cause. It is among the least common sarcomas, representing 0.2-1 percent of large studies of soft tissue sarcomas. ASPS is characterized by a painless mass that most commonly arises in the leg or buttock, with a particular affinity to travel to the lungs as multiple nodules, presumably while the sarcoma itself is still small. This disorder is very rare because it involves a specific breaking and joining event between two chromosomes, called an unbalanced translocation. This finding is observed in essentially all people with ASPS examined so far. This finding cannot be passed on to children, however, as the finding occurs only in the tumor cells, not in the body cells. In addition, there are no families in which multiple family members have the disorder. ASPS tends to occur more often in younger individuals, specifically adolescents and young adults.

The typical clinical findings are of a painless thigh or buttock mass, although ASPS can occur in the trunk, arm or elsewhere. Sometimes these masses cause pain by stretching of the surrounding tissues, and cause limping or other difficulty with movement. These masses are usually soft and slow growing. In children, these masses most often occur in the head and neck, most commonly the tongue and the eye socket (orbit). In adults, the thighs and buttocks are most often affected.

There is no exposure or infection that is known to predispose to ASPS. It is known that two chromosomes break and rejoin is a certain way (unbalanced translocation) and bring together two genes, normally separated on chromosomes X (the sex chromosome) and 17.

ASPS tends to affect younger people, especially those between 15 and 35 years of age. It is rare in children under 5 or in adults over 50. Women outnumber men, especially under age 25. There appears to be no link of this tumor to a particular ethnicity. ASPS accounts for about 0.2-1% of all soft tissue sarcomas. In turn, soft tissue sarcomas account for approximately 1% of all cancers.

The exact same chromosomal changes are found in a rare form of kidney cancer, ASPSCR1-TFE3 translocation renal cell carcinoma in which the chromosomal translocation is balanced as opposed to the unbalanced translocation seen in ASPS. This is a cancer of an entirely different nature. Researchers are unsure why the ASPSCR1-TFE3 gene fusion causes ASPS in some people and a form of renal cell carcinoma in others.

Biopsy is the fastest way to come to a diagnosis of soft-tissue sarcomas. A biopsy involves taking a small sample of affected tissue and examining it under a microscope. There are more than 50 different types of sarcomas, of which ASPS is only one rare subtype. Often times, a core needle biopsy of the leg mass is enough to make the diagnosis. If a core needle biopsy is not diagnostic, then an incisional biopsy that obtains more tissue will make the diagnosis.

The therapeutic management of individuals with ASPS may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis (pathologists)and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses, and other specialists (depending upon the area(s) of tumor involvement). Given the rarity of this disease, it is recommended that patients be treated at a high-volume referral center for sarcomas.


Ameloblastic Carcinoma

Ameloblastic carcinoma is a rare malignant (cancerous) tumor that normally begins in the bones of the jaw. It is classified as an odontogenic tumor, meaning that it arises from the epithelium that forms the enamel of the teeth. The pattern of epithelial growth is similar to the developing tooth germ and distinctive enough to separate it from other epithelial malignances. Symptoms may include progressive pain and swelling of the jaw. Ameloblastic carcinoma may spread (metastasize) to affect other organs of the body.

Some individuals with ameloblastic carcinoma may not experience any symptoms (asymptomatic). Symptoms that may occur include progressive pain and swelling of the jaw. Bleeding and headaches may also occur. Rare findings include the inability to open the mouth (trismus) or dysphonia, a voice disorder characterized by hoarseness, weakness, tingling or numbness (paresthesia), and, in rare cases, voice loss (my note: disruption of the voice because of laryngeal involvement (vocal cords) would be quite unusual but dysphagia, trouble eating, can be a problem if the tumor is large enough to cause obstruction or malocclusion). Nasal discharge and blockage of the nasal passages may occur if the tumor involves the sinuses of the maxilla. The size of the tumor may result in dental abnormalities such as causing the upper and lower teeth to fail to meet properly (malocclusion).

The exact cause of ameloblastic carcinoma is unknown. Most cases arise spontaneously without a previous history of cancer (de novo). 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.

Ameloblastic carcinoma affects males and females in equal numbers. They may affect individuals of any age including children, but the mean age of affected individuals is approximately 30 years old.

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

A diagnosis of ameloblastic carcinoma is made based upon a thorough clinical evaluation, a detailed patient history, and microscopic examination of the tumor. Most cases are found incidentally. One procedure is known as fine needle aspiration, in which a thin, hollow needle is passed though the skin and inserted into the nodule or mass to withdraw small samples of tissue for study.


Ameloblastoma

Ameloblastoma is a rare disorder of the jaw involving abnormal tissue growth. The resulting tumors or cysts are usually not malignant (benign) but the tissue growth may be aggressive in the involved area. On occasion, tissue near the jaws, such as around the sinuses and eye sockets, may become involved as well. The tissues involved are most often those that give rise to the teeth so that ameloblastoma may cause facial distortion. Malignancy is uncommon as are metastases, but they do occur.

Ameloblastoma is characterized by an abnormal growth in the sinus area or jaw, often at the site of the third molar.  The tumors or cysts may be aggressive and may spread to the nose, eye socket and skull.  It is important for ameloblastoma to be diagnosed and treated early in order to stop growth of the tumors and possible progression to cancer.  Although it is uncommon, ameloblastomas have been known to become malignant and spread to other parts of the body, especially to the lungs. The initial surgical treatment must be carefully and scrupulously done to avoid recurrence.

The cause of ameloblastoma is not understood.  Causes may include injury to the mouth or jaw, infections of the teeth or gums, or inflammation of these same areas.  Infections by viruses or lack of protein or minerals in the persons diet are also suspected of causing the growth or development of these tumors.  In general, however, scientists do not understand the cause of cysts and tumors, nor the reasons why they can become malignant.

Ameloblastoma is a rare disorder that affects males and females in equal numbers.  It affects persons of all ethnic backgrounds and of all age groups.

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

Hard Odontoma is a tumor of dental origin.  It is composed of several characteristics of teeth such as enamel, dentin and cement.  The Hard Odontoma grows by spreading directly; the ameloblastoma grows by infiltrating other spaces.


Amelogenesis Imperfecta

Amelogenesis imperfecta (AI) refers to a group of rare, inherited disorders characterized by abnormal enamel formation. The term is typically restricted to those disorders of enamel development not associated with other abnormalities of the body.

AI is characterized by defective or missing tooth enamel.

Just as the classification of AI is complex, so too is the contribution of genetics to these disorders. Changes (variants or mutations) in specific genes have been identified as the cause of 19 subtypes of AI. The causal gene and mode of inheritance for these subtypes based on the OMIM (Online Mendelian Inheritance in Man) is listed below:

AI affects 1 of 14,000 to 16,000 children in the United States. Of this number, about 40% have the hypocalcified dominant type. The autosomal dominant and recessive forms of the disorder affect males and females in equal numbers. The X-linked dominant type of the disorder affects twice as many males as females. The X-linked recessive type affects only males.

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

There are many syndromic conditions that affect enamel formation (or whole tooth formation). One example is tricho-dento-osseous (TDO) syndrome. TDO syndrome is one of a group of congenital disorders known as ectodermal dysplasias. The condition primarily affects hair which is strikingly curly, and the teeth. X-ray examination of persons with TDO syndrome usually shows a mild increase in bone density, particularly in the skull. Thin and brittle fingernails also occur. Children with this disorder may have to wear dentures. A person with TDO syndrome may have AI as well. Intelligence and life span are usually normal for individuals with this disorder. (For more information on this disorder, choose TDO as your search term in the Rare Disease Database.)


Amniotic band syndrome

Amniotic band syndrome is a well-known condition associated with a variety of birth defects. The abnormalities occur in the early weeks of pregnancy after the affected parts of the body have formed normally. The severity of amniotic band syndrome can range from a single, isolated finding to multiple, disfiguring complications. The arms and legs are most often affected. The head and face and, in some patients, various internal organs can also be affected. The exact cause of amniotic band syndrome is unknown and is controversial.

Several different patterns of birth defects have been identified with amniotic band syndrome. The three most common patterns are amniotic band syndrome characterized by one or more limbs being affected; the limb-body-wall complex; and amniotic band syndrome characterized by abnormalities of the head and face (craniofacial abnormalities), defects of the brain and serious malformation of the arms and legs.

The proposed causes and underlying mechanisms that cause amniotic band syndrome are complex. The two main theories are known as the extrinsic theory and the intrinsic theory. The extrinsic theory states that amniotic band syndrome occurs due to factors found outside of the fetus (externally). The intrinsic theory states that amniotic band syndrome occurs due to factors found within the fetus (internally).

Amniotic band syndrome is estimated to occur in anywhere from 1 in 1,200 to 15,000 live births. No gender or ethnic predispositions have been identified with amniotic band syndrome.

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

Amniotic band syndrome is typically diagnosed at birth or soon after birth based upon characteristic physical findings. The minimal diagnostic criteria consist of the detection of certain abnormalities of the arms, legs, fingers and/or toes, i.e., ring-like constriction or amputation defects, fusion (syndactyly) between some digits and/or strands of tissue attached to the ends of affected fingers.


Amniotic Fluid Embolism

Amniotic fluid embolism (AFE) is an extremely rare, but life-threatening complication that affects pregnant women shortly before, during, or immediately following labor and childbirth. Most instances occur during labor. In this disorder, it is hypothesized that a pregnant woman has a severe, allergic reaction to amniotic fluid or other fetal material such as fetal cells, which enter the mother’s bloodstream. Amniotic fluid is contained within the amniotic sac. This fluid supports, cushions, and protects a developing fetus. Amniotic fluid embolism is unpredictable and no risk factors have been identified.  AFE can cause a severe, rapid decline in the mother’s health. For years, some researchers believed that the amniotic fluid and fetal cells cause obstruction within the mother’s blood vessels, but now most researchers believe that the mother’s immune system reacts to the amniotic fluid and fetal cells causing an overwhelming immune system response, which ends up harming the mother and the fetus. Breathing problems, cardiac arrest, and excessive bleeding are some of the life-threatening complications that can occur. Researchers and physicians do not fully understand why amniotic fluid or fetal cells entering the mother’s bloodstream causes this reaction in some women. Amniotic fluid embolism is a medical emergency that develops suddenly and rapidly and can be fatal. Early recognition and prompt supportive treatment are essential.

The signs and symptoms of amniotic fluid embolism often develop rapidly. Nonspecific symptoms including headaches, chest pain, cough, sweating, nausea, and vomiting have been reported as early signs. Other common initial symptoms include difficulty breathing or shortness of breath (dyspnea), abnormally rapid breathing (tachypnea), low blood pressure (hypotension), an abnormally rapid heartbeat (tachycardia), bluish discoloration of the skin and mucous membranes due to a lack of oxygen (cyanosis) in the blood, and a deficiency in the amount of oxygen reaching the tissues of the body (hypoxia). There may be rapidly high blood pressure in the blood vessels of the lungs (pulmonary hypertension) and sudden narrowing of blood vessels (vasospasm).

Amniotic fluid embolism is a condition that occurs because there is systemic reaction similar to that found in an allergic response to amniotic fluid or fetal cells or fetal tissue debris by the pregnant mother. The amniotic fluid and other material enters the mother’s bloodstream, most likely due to small tears in the lower part of the uterus, the part of the cervix that forms a canal connecting the vagina to the uterus (endocervix), or because of damage or abnormality affecting the placenta. The cervix is the narrow passage that forms the lower end of the uterus. The placenta is the organ that joins or connects the developing fetus to the mother. The placenta allows the transfer of oxygen and nutrients from the mother to the fetus.

Amniotic fluid embolism is a rare complication that occurs just before, during, or immediately after birth. The number of women who have experienced this complication is unknown.  Amniotic fluid embolism is a rare disorder. Rare disorders often go unrecognized or misdiagnosed, making it difficult to determine their true frequency in the general population. Estimates have ranged from 1 in 8,000 to 1 in 80,000 pregnancies.

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

A diagnosis of amniotic fluid embolism is based upon identification of characteristic clinical symptoms only. To date, there are no diagnostic assays, imaging studies or pathologic markers that have been validated for the diagnosis of AFE. Prompt diagnosis and early, aggressive advanced life support techniques are essential in assuring the best possible outcomes in amniotic fluid embolism. There is a lack of internal consensus in the medical community as to diagnostic criteria for this disorder, although there have been proposed diagnostic criteria for the research reporting of AFE (Clark SL, 2016). The diagnosis is made by identifying characteristic symptoms and excluding other possible causes of the signs and symptoms (diagnosis of exclusion).

Amniotic fluid embolism is a medical emergency. Treatment is aggressive and supportive. A team of specialists is required to treat affected individuals. This team will include specialists in treating pain and in managing care of a patient before, during and after surgery (anesthesiologists); physicians who specialize in pregnancy, childbirth and a woman’s reproductive system (obstetricians); obstetricians who specialize in maternal and fetal health (maternal-fetal medicine specialists); physicians who specialize in the diagnosis and treatment of blood disorders (hematologists); and physicians who specialize in the treatment of critically ill patients (intensivists).


Amyloidosis

Amyloidosis is usually a multisystem disease resulting in a wide spectrum of clinical presentations. Consequently, a patient may present to, or be referred to, one of several subspecialists, most commonly a nephrologist, cardiologist or neurologist. Recent advances in therapy have rendered early and precise diagnosis critical if the patient is to fully benefit. Most patients have more than one organ involved and therefore the finding of a combination of any of the features below should heighten the suspicion of amyloidosis:

Amyloidosis is caused by abnormal folding of normal soluble proteins leading to fibril formation in one or more body organs, systems or soft tissues. These clumps of protein are called amyloid deposits and the accumulation of amyloid deposits causes the progressive malfunction and eventual failure of the affected organ. Normally, proteins are broken down at about the same rate as they are produced, but these unusually stable amyloid deposits are deposited more rapidly than they can be broken down.

It is estimated that there are approximately 4,000 new cases of AL amyloidosis annually in the United States, though actual incidence may be somewhat higher as a result of under-diagnosis and/or misdiagnosis. While the incidence is thought to be equal in males and females, about 60% of patients referred to amyloid centers are male. AL amyloidosis has been reported in individuals as young as 20 years of age but is typically diagnosed at about age 50-65.

The following disorders may be associated with amyloidosis. Amyloidosis may appear in conjunction with or as a result of the following disorders:

Particularly in the case of AL amyloidosis, early diagnosis is the key to survival and post treatment regaining of quality of life. The diagnosis of amyloidosis is suspected following a detailed patient history and clinical evaluation but requires aspiration of abdominal fat pad and/or biopsy of the involved organ. If the disease is suspected on clinical grounds, a biopsy of the involved organ will give the highest yield. The biopsy material is examined microscopically and is stained with a dye called Congo red that will produce a green color when looked at in a polarizing microscope if amyloid is present. When amyloidosis is diagnosed on a tissue biopsy it is essential that the affected individual be further evaluated to determine what organs are affected.


Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive degeneration and eventual death of nerve cells (neurons) in the brain, brainstem and spinal cord. The neurons involved in ALS facilitate communication between the nervous system and voluntary muscles of the body (motor neurons). Normally, motor neurons in the brain (upper motor neurons) send messages to motor neurons in the spinal cord and brainstem (lower motor neurons), which then relay the message to various muscles. ALS affects both the upper and lower motor neurons so that the transmission of messages is interrupted and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. ALS affects the muscles needed to move the arms and legs, to speak and swallow, to support the neck and trunk, and to breathe. The symptoms of ALS progress over time and, ultimately, the disease leads to ventilatory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. Although two therapies are approved to slow the progression of the disease by a small amount (disease-modifying therapy) in the United States, the mainstay of therapy for ALS is centered on symptom control and supportive care.

ALS causes a combination of upper and lower motor neuron disease, and the symptoms vary depending on the muscle controlled by the affected neurons and whether upper or lower motor neurons are predominantly affected. The main manifestations of upper motor neuron disease are muscle weakness, increased muscle tone and stiffness (spasticity), increased reflexes (hyperreflexia), and abnormal speech and swallowing. Lower motor neuron disease causes muscle weakness and wasting (atrophy), decreased muscle tone, decreased reflexes (hyporeflexia), twitching of muscle fibers (fasciculations), muscle cramps, and abnormalities of speech, swallowing, and breathing. When ALS affects the limb and trunk muscles, it leads to symptoms such as difficulty walking or falls and difficulty performing activities of daily living. When ALS affects nerves of the head and neck (cranial nerves), it can leads to bulbar symptoms, which include difficulty swallowing (dysphagia) or speaking (dysarthria) and weakness of the muscles of the face or tongue. Dysphagia can lead to complications such as difficulty feeding, choking, excess saliva or drooling, and weight loss. Dysphagia can also lead to pneumonia because of aspiration of food contents (aspiration pneumonia), when food or liquids enter the airway due to dysfunctional swallowing. Bulbar symptoms can also include emotional lability characterized by episodes of sudden, uncontrollable, and inappropriate laughing or crying (pseudobulbar affect).

The underlying cause of sporadic ALS is not known. It is thought that dysfunction in a variety of interconnected molecular mechanisms contribute to the disease. These mechanisms include dysfunction of protein balance, folding and transport, excessive neuron stimulation (excitotoxicity), oxidative stress, neuroinflammation and dysfunction of mitochondria (the powerhouse of the cell). Ultimately, these anomalies lead to damage and death of motor neurons, hence leading to the symptoms of ALS. Only age and family history are clearly established risk factors for ALS.

ALS is a rare disorder that develops in 1.5 to 3 per 100,000 people every year in North American and European populations. Approximately 30,000 people are affected in the United States, with an estimated 5,000 new cases diagnosed each year. ALS affects more males than females, as about 60% of affected individuals are males. Further research on the epidemiology of ALS needs to be done, as the vast majority of epidemiologic research is centered on North American and European populations.

ALS is a clinical diagnosis. This means that no single test can reliably diagnose the disease. The diagnosis of ALS is therefore centered on a careful patient history and neurologic examination. Laboratory and imaging tests may be helpful to exclude other conditions depending on the clinical presentation. The diagnosis of ALS requires a history of progressive muscle weakness spreading to one or more anatomical regions and clinical evidence of upper and lower motor neuron disease, although only one type of motor neuron dysfunction might be predominant early in the disease course (see the Signs & Symptoms section above for more details on the clinical manifestations of upper and lower motor neuron disease). Electrodiagnostic studies such as electromyography (EMG) and nerve conduction studies (NCS), which evaluate transmission of nerve impulse to muscles and conduction of nerve impulse across neurons, can complement the physical examination and show further evidence of motor neuron dysfunction. Brain imaging, such as magnetic resonance imaging (MRI), is often performed in patients with suspected ALS. Although some level of brain atrophy can be seen in ALS, imaging is mostly performed to rule out other causes of motor neuron disease. Genetic testing is particularly helpful in cases of suspected familial ALS. Diagnostic delay is a common problem with ALS, with an average diagnostic delay of 1 year from symptom onset.


Anaplastic Astrocytoma

Anaplastic astrocytoma is a rare malignant brain tumor. Astrocytomas are tumors that develop from certain star-shaped brain cells called astrocytes. Astrocytes and similar cells form tissue that surrounds and protects other nerve cells found within the brain and spinal cord. Collectively, these cells are known as glial cells and the tissue they form is known as glial tissue. Tumors that arise from glial tissue, including astrocytomas, are collectively referred to as gliomas. The symptoms of anaplastic astrocytomas vary depending upon the specific location and size of the tumor. The specific cause of this tumor is unknown.

The symptoms of anaplastic astrocytoma vary depending upon the exact location and size of the tumor. Most symptoms result from increased pressure within the brain. An anaplastic astrocytoma usually develops slowly over time, but may develop rapidly.

The exact cause of anaplastic astrocytomas is unknown. 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.

Anaplastic astrocytomas affect males slightly more often than females. The exact incidence of these tumors is unknown. Anaplastic astrocytoma and glioblastoma multiforme are estimated to affect 5-8 people per 100,000 in the general population. Anaplastic astrocytomas are more common in adults than children. In adults, anaplastic astrocytomas usually develop between 30 and 50 years of age. Astrocytomas and a related tumor (oligodendroglioma) are the most common primary brain tumors in adults.

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

A diagnosis of anaplastic astrocytoma is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of imaging techniques including computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Such imaging techniques may also be used to may be used to help evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures.


糖原分支酶缺乏所致糖原贮积病

Glycogen storage disease due to glycogen branching enzyme deficiency

Andersen disease is a multisystem disorder that may affect the liver, voluntary (skeletal) muscles, the heart, the nervous system, and other bodily tissues. Disease nature and course may vary in several aspects, including age at onset, associated symptoms and signs, degree of abnormal glycogen accumulation in various tissues, and specific organs affected.

As noted above, Andersen disease is a disorder of glycogen metabolism. Metabolism refers to all the chemical processes in the body, including the breakdown of complex substances into simpler ones and processes in which complex substances are built up from simpler ones. Metabolic disorders result from abnormal functioning of a specific protein or enzyme that accelerates particular chemical activities in the body.

As noted above, the classic hepatic form of Andersen disease typically becomes apparent during the first months of life. However, other forms of the disease have also been described that may be evident at birth, during late childhood, or in adulthood. Males and females appear to be affected in relatively equal numbers.

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

There are a number of other diseases and conditions that may be characterized by certain symptoms and signs similar to those potentially associated with Andersen disease. These include additional disorders of glycogen metabolism (i.e., glycogen storage diseases). As noted above, these diseases are due to deficiency of one or more enzymes involved in the formation or breakdown of glycogen, resulting in the accumulation of abnormal amounts or forms of glycogen within certain body tissues, particularly the liver, skeletal muscle, and/or heart muscle. Most of these diseases are inherited as an autosomal recessive trait. (For further information, please choose the exact disease name in question or glycogen storage disease as your search term in the Rare Disease Database.)


Andersen-Tawil syndrome

Andersen-Tawil syndrome is defined by three main features (i.e. a clinical triad), specifically periodic paralysis, arrhythmias and heart abnormalities, and distinctive physical features. However, the disorder is highly variable and not all affected individuals will develop all three of these characteristic symptoms. Andersen-Tawil syndrome can vary greatly in expression and severity from one person to another, even among members of the same family.

In approximately 60% of cases, Andersen-Tawil syndrome is caused by a mutation in the KCNJ2 gene. In the other 40% of cases, the underlying genetic mutation is unknown, suggesting that additional as-yet-unidentified genes also cause the disorder.

Andersen-Tawil syndrome affects males and females in equal numbers. The exact incidence or prevalence of the disorder is unknown. More than 100 cases have been reported in the medical literature. Because many cases go undiagnosed or misdiagnosed, determining the true frequency of Andersen-Tawil syndrome in the general population is difficult.

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

A diagnosis of Andersen-Tawil syndrome is based upon identification of characteristic symptoms (e.g. periodic paralysis, symptomatic arrhythmias, and/or distinctive facial and skeletal features), a detailed family and patient history, a thorough clinical evaluation and a variety of specialized tests.


Anemia of Chronic Disease

Anemia of chronic disease, also called the anemia of inflammation, is a condition that can be associated with many different underlying disorders including chronic illnesses such as cancer, certain infections and autoimmune and inflammatory diseases such as rheumatoid arthritis or lupus. Anemia is defined by low levels of circulating red blood cells or hemoglobin, the part of red blood cells that carries oxygen. Anemia of chronic disease is usually a mild or moderate condition. In mild cases, anemia may not be associated with any symptoms or may cause fatigue, paleness of the skin (pallor) and lightheadedness. The underlying mechanisms that cause anemia of chronic disease are complex and not fully understood.

Anemia of chronic disease varies in severity from one person to another. In most people, anemia is usually mild or moderate. Affected individuals may develop a variety of symptoms such as fatigue, paleness of the skin (pallor), lightheadedness, shortness of breath, a fast heartbeat, irritability, chest pain and additional findings. These symptoms may occur in any individual who has a comparable degree of anemia. In most cases, the symptoms associated with the underlying disease usually take precedent over the mild or moderate anemia symptoms. In rare cases, anemia of chronic disease can be severe and cause more serious complications.

The exact cause of anemia of chronic disease may vary. Usually, several processes occur at the same time. Anemia can be caused by a slight shortening of normal red blood cell survival. In addition, the production of red blood cells (erythropoiesis) or of erythropoietin (a hormone that stimulates red blood cell production) may be impaired. Red blood cells carry oxygen to the body. The exact cause of anemia of chronic disease may depend upon the underlying condition. For example, cancer cells or inflammatory diseases like rheumatoid arthritis can cause the secretion of certain substances (cytokines) that may suppress production of erythropoietin or limit the ability of immature red blood cell progenitors to respond to erythropoietin. These cytokines may also have effects on iron metabolism, as discussed below. In some cases, cancer cells or disease-causing microorganisms may infiltrate the bone marrow, the soft spongy material found in long bones where blood cells are formed.

Anemia of chronic disease affects males and females in equal proportion. Individuals of any age who have a chronic, inflammatory condition can potentially develop the condition. The exact incidence of anemia of chronic disease is unknown and some researchers believe that it is underreported or often goes unrecognized. Anemia of chronic disease is believed to be the second most common cause of anemia in the United States after iron-deficiency anemia.

Iron deficiency anemia is a common condition in which individuals have insufficient levels of iron in the body and cannot produce enough red blood cells to carry oxygen through the body. Iron deficiency anemia can cause a variety of symptoms including fatigue, weakness, pale skin, shortness of breath, headaches and lightheadedness. Additional symptoms that can occur in individuals with iron deficiency anemia include cold hands or feet, irritability, irregular heartbeats and an increased susceptibility to developing infections. Iron deficiency anemia is caused by insufficient levels of iron in the body, which can occur due to blood loss, a diet that supplies little iron, or an inability to absorb enough iron in the gastrointestinal tract. Anemia of chronic disease and iron deficiency anemia may be confused because both are associated with decreased circulating iron.

A diagnosis of anemia of chronic disease is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Such tests can measure the levels of certain substances in the body including hemoglobin levels, levels of iron in the serum, total iron binding capacity, overall red blood cell count, or normal or increased levels of ferritin in the blood. Ferritin is a protein that binds to iron and is used as an indicator of the body’s iron stores in the blood plasma. Another test that may be performed measures transferrin saturation. Transferrin is a protein that is involved in the transport of iron from the intestines into the bloodstream. Methods to allow the reliable measurement of hepcidin in plasma have been developed but are not available or approved for use in the diagnosis of anemia of chronic disease at present.