Fragile X syndrome

fragile site, folic acid type, rare, Fra(X)(Q27.3)

Fragile X syndrome is characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. Distinctive physical features are sometimes present in affected males including a large head, long face, prominent forehead and chin, protruding ears, loose joints and large testes, but these features develop over time and may not be obvious until puberty. Motor and language delays are usually present but also become more apparent over time. Behavioral abnormalities including autistic behaviors are common.

Fragile X syndrome is characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. The physical features in affected males are variable and may not be obvious until puberty. These symptoms can include a large head, long face, prominent forehead and chin, protruding ears, loose joints and large testes. Other symptoms can include flat feet, frequent ear infections, low muscle tone, a long narrow face, high arched palate, dental problems, crossed eyes (strabismus) and heart problems including mitral valve prolapse. Delayed motor development, hyperactivity, behavior problems, toe walking, and/or occasional seizures can also occur in some patients. Autistic behaviors such as poor eye contact, hand flapping, and/or self-stimulating behaviors are also common. Motor and language delays are usually present but become more apparent over time.

As mentioned above, fragile X syndrome is caused by a mutation in the FMR1 gene located on the X chromosome at Xq27.3. Individuals with fragile X syndrome nearly always have (in greater than 99% of cases) a full mutation of the FMR1 gene which means that they have over 200 CGG repeats and abnormal methylation of the gene. Methylation is a chemical change to the DNA that carries the genetic code of a gene and the abnormal methylation associated with fragile X syndrome causes the gene to be unable to produce FMRP, the protein made by the FMR1 gene, needed for normal development. On rare occasions some patients with fragile X syndrome are partially or completely missing the FMR1 gene due to a deletion of the DNA on the X chromosome where FMR1 is located and have the syndrome because their cells do not produce FMRP. Ultra-rare patients with fragile X syndrome have been found to have a mutation in a single DNA base (called point mutations) resulting in absent or defective FMRP. FMRP is involved in making connections between neurons (nerve cells) in the brain. The absence or severe reduction of this protein leads to the symptoms of fragile X syndrome.

The fragile X syndrome affects about 1 in 4,000 males and 1 in 6,000 to 8,000 females in the USA; that is, it affects about twice as many males as it does females. However, about four times as many females appear to be carriers of the altered gene as do males (1:250 females and 1:1000 males). Fragile X syndrome has been found in all major ethnic groups and races.

Premutations of the FMR1 gene are associated with two other disorders and these conditions have been termed FMR1-Related disorders. Not all individuals with a premutation will develop FMR1 – Related disorders, but having a premutation increases the risks for developing these.

Fragile XE syndrome (FRAXE) is rare and caused by an abnormal FMR2 gene located on the X chromosome very close to the site of the FMR1 gene. The normal FMR2 gene contains 6-35 copies of CCG and people with the disorder have over 200 copies of CCG in the FMR2 gene. The effect of FMR2 genes with 35-200 copies of CCG has not yet been determined likely because the disorder has a mild clinical presentation. Common symptoms of FRAXE include mild intellectual disability, learning deficits, and possible developmental delays.


Fraser syndrome

Fraser syndrome is characterized by multiple physical abnormalities.

Fraser syndrome is caused by changes (mutations) in the FRAS1, FREM1, FREM2 or GRIP1 genes). More specifically, Fraser syndrome 1 (FRASRS1) is caused by mutations in the Fraser extracellular matrix complex subunit 1 (FRAS1) gene. Fraser syndrome 2 (FRASRS2) is caused by mutations in the FRAS1-related extracellular matrix protein 2 (FREM2) gene. Fraser syndrome 3 (FRASRS3) is caused by mutations in the glutamate receptor-interacting protein 1 (GRIP1) gene. FRAS1 gene mutations are the most common cause for Fraser syndrome, representing approximately half of the FS cases; whereas FREM2 gene and GRIP1 gene mutations account for a smaller percentage of cases.

Fraser syndrome affects males and females in equal numbers. The age of onset for this disorder is neonatal/antenatal, meaning an affected individual develops this disorder before birth. FS is seen to be more prevalent in gypsy populations (Roma ethnicity) of southern and eastern Europe.

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

Bilateral renal agenesis is the absence of both kidneys at birth. It is a genetic disorder characterized by a failure of the kidneys to develop in a fetus. This absence of kidneys causes a deficiency of amniotic fluid in a pregnant woman. Normally the amniotic fluid acts as a cushion for the developing fetus. When there is an insufficient amount of this fluid, compression of the fetus may occur resulting in further malformations of the baby. (For more information on this disorder, choose Renal Agenesis, Bilateral as your search term in the Rare Disease Database.)


Freeman-Sheldon syndrome

Certain problems are required to be present for diagnosis of FSS. All persons with FSS have the following problems: very small mouth (microstomia), whistling-face appearance (pursed lips), H or V shaped chin dimple and very obvious crease from the nostril to the corners of the mouth (nasolabial creases). Classically, persons also have restricted movement in joints (contractures) of two or more body areas, often hands and feet, with fingers and toes frequently overlapping.

There is no known link between FSS and environmental or parental factors, such as exposure to illnesses, toxins, drugs or harsh substances.

FSS appears to occur all ethnicities, both biologic genders and all geographic regions, evenly. FSS is an exceptionally rare disorder. It is estimated that 200-300 individuals worldwide may be affected, but the number of diagnosed and undiagnosed persons with FSS (population prevalence) remains uncertain.

Problems associated with other arthrogryposis and craniofacial disorders may resemble FSS. Generally, other disorders called distal arthrogryposis (DA) and arthrogryposis multiplex congenita (AMC), both broad groups of disorders that include hand, foot, head and face problems, may overlap with FSS. DAs and AMCs vary greatly in severity but are generally not inherited from parents. The major form of AMC is called amyoplasia. (For more information on this disorder, choose arthrogryposis multiplex congenita as your search term in the Rare Disease Database.)

FSS is diagnosed by thorough physical examination and medical history. Plastic surgeons and anesthesiologists who specialize in treating patients with skull and face problems are the best to diagnose and evaluate patients who may have FSS. The following problems must be present for diagnosis of FSS: small mouth (microstomia), whistling-face (pursed lips as in someone trying to whistle), down-slanting crease from the nostril to the corners of the mouth (nasolabial creases), and H or V shaped chin dimple. Classically, there must be two or more body areas with limited movement of joints, frequently the hands or feet and ankles, but FSS may be diagnosed without problems beyond the face. Patients who have the facial deformities plus two or more body areas with limited movement of joints are considered to have FSS type 1, classic. Patients who have only the facial deformities are considered to have FSS type 2, craniofacial. Patients who have the facial deformities plus one body areas with limited movement of joints are considered to have FSS type 3, mixed (upper or lower extremities). Patients with FSS type 2 tend to be the most mild and have the least complications, and patients with FSS type 1 or classic tend to be the most seriously affected and more likely to have medical complications. Patients with FSS type 3 fall between FSS types 1 and 2.


Frey syndrome

The symptoms of Frey syndrome typically develop within the first year after surgery in the area near the parotid glands. In some people, Frey syndrome may not develop until several years after surgery. The characteristic symptom of Frey syndrome is gustatory sweating, which is excessive sweating on the cheek, forehead and around the ears shortly after eating certain foods, specifically foods that produce a strong salivary response such as sour, spicy or salty foods.

The exact underlying cause of Frey syndrome is not completely understood. The most widely held theory is that Frey syndrome results from simultaneous damage to sympathetic and parasympathetic nerves in the region of the face or neck near the parotid glands. Parasympathetic nerves are part of the autonomic nervous system, which is the portion of the nerve system that controls or regulates involuntary body functions (i.e., those functions that occur without instruction from the conscious mind). One function of parasympathetic nerves is to regulate the activity of glands including the parotid glands, but not the sweat glands. Sweat glands and blood vessels throughout the body are controlled by sympathetic fibers.

The exact incidence of Frey syndrome is unknown. The disorder most often occurs as a complication of the surgical removal of a parotid gland (parotidectomy). The percentage of individuals who develop Frey syndrome after a parotidectomy is controversial and reported estimates range from 30-50 percent. In follow-up examinations, approximately 15 percent of affected individuals rated their symptoms as severe. Frey syndrome affects males and females in equal numbers.

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

A diagnosis of Frey syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a specialized test called the minor iodine-starch test. During this test, an iodine solution is applied to the affected areas of the face. Then, a starch powder such as corn starch is applied over the iodine solution. Individuals are then given an oral stimulus, usually a highly acidic food such as a lemon wedge. In affected individuals, discoloration (usually purple) due to excessive sweating occurs on the affected areas.


Friedreich ataxia

Friedreich’s ataxia (FRDA) is a genetic, progressive, neurodegenerative movement disorder, with a typical age of onset between 10 and 15 years. Initial symptoms may include unsteady posture, frequent falling, fatigue and progressive difficulty walking due to impaired ability to coordinate voluntary movements (ataxia). Affected individuals often develop slurred speech (dysarthria), characteristic foot deformities and an irregular curvature of the spine (scoliosis). FRDA is often associated with cardiomyopathy, a disease of cardiac muscle that may lead to heart failure or irregularities in heart rhythm (cardiac arrhythmias). About a third of the people with FRDA develop diabetes mellitus. The symptoms and clinical findings associated with FRDA result from degenerative changes in sensory nerves, including the point where they enter the spinal cord in structures known as dorsal root ganglia, and in specific nerve tracts in the spinal cord, which leads to a deficiency of sensory signals to the cerebellum, the part of the brain that helps to coordinate voluntary movements. A specific region of the cerebellum called the dentate nucleus also degenerates in FRDA. FRDA is caused by abnormalities (variants) in the FXN gene and people with FRDA inherit a pathogenic variant from each parent, so both copies of their FXN gene do not function normally. This pattern, wherein parents who are clinically unaffected because they only carry a single variant FXN gene but can have a child who is affected because they inherit pathogenic variants from both carrier parents, is called autosomal recessive inheritance.

The primary symptom of FRDA is progressive ataxia of the limbs during walking. Ataxia involves inadequate muscle coordination that results in an unsteady gait and poor control of fine movements of the limbs. Involvement of muscles in the mouth and throat may lead to slurred speech and impaired swallowing. Intellect is unaffected. Sideways curvature of the spine (scoliosis) and foot abnormalities may develop. A form of heart disease (cardiomyopathy) may develop in over half of the people with FRDA. The clinical features are progressive and after initially making use of walking aids people with FRDA ultimately require the use of a wheelchair for mobility.

FRDA is caused by pathogenic variants (mutations) in the FXN gene. The FXN gene codes for frataxin, a protein that is required for proper functioning of mitochondria, which are the energy producing parts of our cells. In people with FRDA, since both copies of the FXN gene are abnormal and they do not produce adequate amounts of frataxin, tissues that are especially dependent on mitochondrial energy production (e.g., nerve and heart cells) start to degenerate.

The prevalence of FRDA is approximately 1 in 40,000 people. FRDA is the most common inherited ataxia in Europe, the Middle East, South Asia (Indian subcontinent) and North Africa. It is rarely identified in other populations.

Symptoms of the following disorders can be similar to those of Friedreich’s ataxia. Careful examination and appropriate testing may be useful for differential diagnosis.

FRDA is suspected in an individual based on characteristic symptoms and clinical examination. The diagnosis is confirmed by molecular genetic testing to look for pathogenic variants in the FXN gene. The most common type of variant – which is observed in both the maternal and paternal copies of the FXN gene of more than 90% of individuals with FRDA – is an abnormally expanded GAA repeat in intron 1 of the gene.


Frontofacionasal dysplasia

Frontofacionasal dysplasia is a rare genetic disorder that is apparent at birth (congenital). The disorder is primarily characterized by malformations of the head and facial (craniofacial) area and eye (ocular) defects. Craniofacial malformations may include an unusually short, broad head (brachycephaly); incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); and underdevelopment (hypoplasia) of the nose with malformation of the nostrils. Affected infants may also have abnormal narrowing of the folds (palpebral fissures) between the upper and lower eyelids (blepharophimosis) and an unusually increased distance between the eyes (ocular hypertelorism). Additional eye abnormalities may include partial absence of tissue (coloboma) from the upper eyelids or the colored regions of the eyes (irides) and an inability to completely close the eyes (lagophthalmos). The signs and symptoms of frontofacionasal dysplasia are highly variable. Frontofacionasal dysplasia appears to be inherited in an autosomal recessive pattern.

Infants with frontofacionasal dysplasia typically have distinctive malformations of certain bones forming the skull as well as additional facial, nasal, and eye (ocular) defects. For example, the disorder may be associated with premature closure of the fibrous joints (sutures) between particular bones of the skull (craniosynostosis), causing the head to appear unusually short and broad (brachycephaly). In addition, there may be early conversion of fibrous tissue into bone (early ossification) within the base of the skull (sphenoid bone), and some of the air-filled cavities (i.e., paranasal ethmoidal sinuses) within certain bones around the nose may be abnormally large. Underdevelopment of the middle portion of the face (midface hypoplasia) also occurs.

Frontofacionasal dysplasia appears to be inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.

Since the disorder was originally described in 1981 (T.R. Gollop) in a brother and sister, fewer than 10 cases of frontofacionasal dysplasia have been reported in the medical literature. The two siblings as well as the third individual reported with the disorder are of Brazilian descent.

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

Craniofrontonasal dysplasia is a rare genetic disorder that is apparent at birth (congenital). Associated symptoms and findings may vary greatly in range and severity from person to person. However, in many affected individuals, such abnormalities may include an unusually broad, prominent forehead; widely spaced eyes (ocular hypertelorism); a broad nose with a grooved nasal tip; and a wide mouth. Additional malformations may sometimes be present, such as incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); split nails; unusually broad great toes; webbing of certain fingers or toes (syndactyly); and/or additional skeletal abnormalities. (For further information on this disorder, please choose craniofrontonasal as your search term in the Rare Disease Database.)


Frontonasal dysplasia

Frontonasal dysplasia is a rare disorder characterized by abnormal development of the head and face before birth. Major physical characteristics may include widely spaced eyes (ocular hypertelorism); a flat broad nose; and/or a vertical groove down the middle of the face. The depth and width of the vertical groove may vary greatly. In some cases, the tip of the nose may be missing; in more severe cases, the nose may separate vertically into two parts. In addition, an abnormal skin-covered gap in the front of the head (anterior cranium occultum) may also be present in some cases. There are at least three types of frontonasal dysplasia that can be distinguished by genetic causes and symptoms.

FND-1 is caused by mutations in the ALX3 gene; FND-2 is caused my mutations in the ALX4 gene; and FND-3 is caused by mutations in the ALX1 gene.

Frontonasal dysplasia is a very rare disorder that affects males and females in equal numbers. The number of people affected by this disorder is not known. There are at least 100 cases reported in the scientific literature.

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

Craniofrontonasal dysplasia is a rare disorder characterized by widely spaced eyes (ocular hypertelorism), a missing or grooved tip of the nose, a broad nasal bridge, and/or malformation of the bone forming the center of the chest (sternum). Other abnormalities associated with this disorder may include an unusually wide mouth, webbed fingers and/or toes (syndactyly), a broad index finger, split nails, malformed ears, and/or a broad, high forehead. Craniofrontonasal dysplasia is thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose craniofrontonasal dysplasia as your search term in the Rare Disease Database.)

Treatment of this disorder depends upon the severity of the physical characteristics in each individual case. Surgery may be performed to correct the craniofacial abnormalities (e.g., divided nose, cleft lip, etc.) associated with this disorder. In some cases, additional surgeries may be necessary when an affected child grows older.


Frontotemporal dementia

Frontotemporal degeneration clinical subtypes are organized according to:

Frontotemporal degeneration is caused by damage to the frontal and temporal lobes of the brain. The frontal lobe is the largest lobe in the brain and is located right behind the forehead. The frontal lobe is critical for thinking, planning, decision making and other higher mental processes. The frontal lobe helps people to manage and control emotional responses. The temporal lobes are located below and to both sides of the frontal lobe. The temporal lobes are believed to be involved in semantic memory, or our knowledge of objects, people, words and faces. They also play a role in language and emotion.

Frontotemporal degeneration is the second most common form of dementia in people under the age of 65 after Alzheimer’s disease. The mean age of onset is usually given as the late 50s, with an age range of 20-80. However, onset before 40 or after 75 is less common. Frontotemporal degeneration is estimated to affect about 50,000-60,000 people in the United States. Researchers believe that many people go undiagnosed or misdiagnosed with another condition. This makes it difficult to determine the true frequency of frontotemporal degeneration in the general population.

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

A diagnosis of frontotemporal degeneration is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A neuropsychological evaluation involves an interview and certain tests, often pencil and paper type tests. This evaluation will allow a physician to assess behavior, language, memory, visual-spatial and other cognitive functions. Early in the course of the disorder, people with the behavioral variant of frontotemporal degeneration tend to score very well on neuropsychological testing.


Fructose Intolerance, Hereditary

There are three inherited disorders of fructose metabolism that are recognized and characterized. Essential fructosuria, is a mild disorder not requiring treatment, while Hereditary fructose intolerance (HFI) and Hereditary fructose-1,6-biphosphatase deficiency (HFBP) are treatable and controllable but must be taken seriously.

Soon after fructose is added to the diet of an infant with HFI, symptoms become apparent.  These may include prolonged vomiting, failure to thrive, jaundice and growth retardation. There may be occasional episodes of unconsciousness.  Other symptoms include enlargement of the liver and frequently cirrhosis, and a tendency towards gastrointestinal bleeding because of deficiency of clotting factors. There are decreased levels of glucose and phosphate in the blood and increased levels of fructose in the blood and urine.

Studies of families in which HFI occurs leads geneticists to believe that the disorder is inherited as an autosomal recessive trait, The responsible gene has been mapped to the long arm (q) of chromosome 9 at gene  map locus 9q22.3.

Hereditary Fructose Intolerance may be diagnosed at birth or shortly thereafter when the infant is weaned. Like other autosomal disorders it is equally distributed among males and females.  Estimates of the incidence of the disorder range widely from 1:10,000 to 1:100,000 births.

Essential Fructosuria is characterized by the presence of fructose in the urine after ingesting fructose.  It arises as a result of a deficiency of the hepatic enzyme fructokinase and is an autosomal recessive genetic disorder.  The disorder is mild and it probably remains undiagnosed in many, many people.

A diagnosis of HFI can be definitively confirmed by either of two tests: an enzyme assay, requiring a liver biopsy, to determine the level of aldolase activity or a fructose tolerance test in which the patient's response to intravenous fructose feeding is carefully monitored. It should be carefully noted, however, that each of these tests carries with it a substantial risk, especially to a newborn child. A non-invasive DNA test is increasingly being recommended instead.


Fryns syndrome

Fryns syndrome is characterized by multiple congenital anomalies that vary in severity from person to person. Although not all patients present with the following characteristics, the most common clinical features in this condition are:

The specific gene/s that cause Fryns syndrome are not known, but due to patterns detected within families, it is thought that Fryns syndrome is an autosomal recessive condition.

Fryns syndrome is a rare disease that affects both males and females equally. A 1989 French study reported 7 cases per 100,000 live births, but no other recent estimates of prevalence have been published.

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

In studies, 1.3% to 4%-10% of persons with congenital diaphragmatic hernia have Fryns syndrome, making it the most common autosomal recessive condition associated with CDH. However, not all individuals with CDH have Fryns syndrome.


Fucosidosis

The symptoms of fucosidosis vary greatly even among individuals within the same family. Fucosidosis can be rapidly progressive causing severe, life-threatening complications in children or develop during adolescence and progress more slowly eventually causing serious complications in adulthood. In the past, fucosidosis was sometimes separated in type I and type II. However, researchers now believe that fucosidosis represents a disease spectrum with a wide variety of expression. Cases labeled fucosidosis type I (early onset, rapid progression) represent the severe end of the spectrum and those labeled fucosidosis type II represent the mild end.

Fucosidosis is caused by disruptions or changes (mutations) of the alpha-L-fucosidase (FUCA1) gene resulting in deficiency of the alpha-L-fucosidase enzyme. The symptoms of fucosidosis occur as a result of excessive accumulation of fucose-containing compounds (e.g., certain glycosphingolipids or certain glycoproteins) in the body due to abnormally low levels of this enzyme. Researchers do not know why the symptoms and severity vary so greatly in individuals with fucosidosis. Some researchers believe that mutation of the FUCA1 gene in combination with certain genetic and environmental factors all play a role in the severity of the disease in individuals. More research is necessary to determine what these factors may be.

Fucosidosis affects males and females in equal numbers. Fewer than 100 cases have been reported in the medical literature. One estimate place the incidence rates at below 1 in 200,000 live births. Some researchers believe fucosidosis is underdiagnosed making it difficult to determine its true frequency in the general population.

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

A diagnosis of fucosidosis may be suspected in infants with skeletal disease during the first year of life that is accompanied by neurological deterioration and intellectual disability. The diagnosis may be confirmed thorough clinical evaluation, detailed patient history, and a variety of specialized tests. For example, electron microscopic examination of tissue samples from the skin, liver, spleen, heart, lung, kidney, sweat glands, and/or other cells may reveal abnormal cavities (vacuoles) inside these cells. These vacuoles may be clear or filled with sand-like granules or thin, disc-like (lamellar) bodies. Advanced imaging techniques, such as magnetic resonance imaging (MRI) and computer-assisted tomography (CT scan) of the brain may confirm degeneration of the white matter of the brain. Laboratory analysis of urinary samples may reveal increased levels of certain fucose-containing complex compounds in the urine (e.g., oligosacchariduria and glycopeptiduria). In addition, reduced activity of the alpha-L-fucosidase enzyme may be confirmed by enzyme tests (assays) on cultured fibroblasts and leukocytes. (As some unaffected individuals may normally show reduced levels of alpha-L-fucosidase in the serum and plasma, assays conducted on the serum and plasma alone may not be conclusive; therefore, fibroblast and leukocyte assay testing is necessary.)


福山型先天性肌营养不良症

Fukuyama Type Congenital Muscular Dystrophy

cerebromuscular dystrophy, Fukuyama type

Fukuyama type congenital muscular dystrophy (FCMD) is one of several forms of a rare type of muscular dystrophy known as congenital muscular dystrophy. It is inherited in an autosomal recessive pattern. Symptoms of this disorder are apparent at birth and progress slowly. In addition to general muscle weakness and deformities of the joints (contractures), FCMD is often accompanied by seizures, intellectual disability and speech problems. This disorder is predominantly found in Japan.

Infants with FCMD are floppy at birth and usually have problems sucking and swallowing. They have a weak cry and there is a loss of muscle tone as well as weakness of the muscles. The joints in the knees and elbows may be in a fixed position (contractures) and reflexes of the tendons are poor.

FCMD occurs because of a change (mutation or variant) in the gene that gives instructions for the production of (codes for) a protein known as fukutin. The normal role of this protein isn’t yet well understood.

FCMD is almost nonexistent in the United States, but in Japan is second only to Duchenne muscular dystrophy in frequency. The incidence in Japan is reported as about 0.7-1.2 cases per 100,000 children.

Symptoms of the following disorders can be similar to those of Fukuyama type congenital muscular dystrophy. Comparisons may be useful for a differential diagnosis:

Becker muscular dystrophy (BMD) is much like Duchenne muscular dystrophy and is characterized by weakness of the muscles of the legs that usually first is noticed in a boy’s pre-teen and teen years. The muscle weakness is progressive but milder in severity than in Duchenne muscular dystrophy. (For more information on this disorder, choose Becker as your search term in the Rare Disease Database.)


Functional Neurological Disorder

原发性醛固酮增多症伴癫痫和神经系统异常综合征

functional neurological symptom disorder

Functional neurological disorder (FND) is a medical condition in which there is a problem with the functioning of the nervous system and how the brain and body sends and/or receives signals, rather than a structural disease process such as multiple sclerosis or stroke. FND can encompass a wide variety of neurological symptoms, such as limb weakness or seizures.

FND patients can experience a wide range and combination of symptoms that are physical, sensory and/or cognitive. The most common include:

The exact cause of FND is unknown, although ongoing research is starting to provide suggestions as to how and why it develops. Many different predisposing factors can make patients more susceptible to FND such as having another neurological condition, experiencing chronic pain, fatigue or stress. Childhood abuse, maltreatment or neglect and life stress, particularly around the time of symptom onset, is also more common in people with FND than in the general population. However, many people with FND have none of these risk factors which are also unfortunately common in all, including healthy, populations. As with most complex disorders affecting the brain, it’s likely that genetic factors play a role in the condition, but it is not a problem that someone should expect to pass on genetically.

The exact prevalence of FND is unknown. However, research suggests FND is the second most common reason for a neurological outpatient visit after headache/migraine, accounting for one sixth of diagnoses. This means FND could be as common as multiple sclerosis or Parkinson’s disease.

It is common for FND to co-exist with other illnesses. FND can have similar symptoms to most other types of conditions seen in neurological practice such as multiple sclerosis, stroke and epilepsy. Some patients have another neurological disease diagnosis such as stroke and FND. A neurologist is normally required to assess which symptoms relate to FND and to monitor where required for any new symptoms.

FND is not a diagnosis of exclusion. It should be diagnosed on the basis of positive physical signs and clinical features, and usually requires a neurologist or a doctor familiar with neurological diagnosis. There are dozens of these clinical features but some examples are:


Galactosemia

galactose-1-phosphate uridylyl transferase deficiency

Galactosemia is a rare, hereditary disorder of carbohydrate metabolism that affects the body’s ability to convert galactose to glucose. Galactose is a sugar contained in milk, including human mother’s milk as well as other dairy products. It is also produced by the human body, and this is called endogenous galactose. Glucose is a different type of sugar. The disorder is caused by a deficiency of an enzyme galactose-1-phosphate uridylyl transferase (GALT) which is vital to this process. Early diagnosis and treatment with a lactose-restricted (dairy-free) diet is absolutely essential to avoid profound intellectual disability, liver failure and death in the newborn period. Galactosemia is inherited as an autosomal recessive genetic condition. Classic galactosemia and clinical variant galactosemia can both result in life-threatening health problems unless lactose is removed from the diet shortly after birth. A biochemical variant form of galactosemia termed Duarte is not thought to cause clinical disease due to lactose consumption.

An infant with galactosemia appears normal at birth, but within a few days or weeks loses their appetite and starts vomiting excessively. Yellowing of the skin, mucous membranes, and whites of the eyes (jaundice), enlargement of the liver (hepatomegaly), appearance of amino acids and protein in the urine, growth failure, and, ultimately, accumulation of fluid in the abdominal cavity (ascites) with abdominal swelling (edema) may also occur. Diarrhea, irritability, lethargy and a bacterial infection may also be early signs of galactosemia. In time, wasting of body tissues, marked weakness, and extreme weight loss occur unless lactose is removed from the diet.

Galactosemia occurs due to disruptions or changes (mutations) in the GALT gene resulting in deficiency of the GALT enzyme. This leads to abnormal accumulation of galactose-related chemicals in various organs of the body causes the signs and symptoms and physical findings of galactosemia.

Classic galactosemia is diagnosed in the range of 1/16,000 to 1/48,000 births through newborn screening programs around the world, depending on the diagnostic criteria used by the program. The disorder has been reported in all ethnic groups. An increased frequency of galactosemia occurs in individuals of Irish ancestry. Clinical variant galactosemia occurs most often in African Americans and native Africans in South Africa who have a specific  gene mutation.

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

Galactokinase (GALK) deficiency is associated with cataracts, increased blood concentration of galactose and increased concentration of galactitol in the urine. Galactitol accumulates in the lens of the eye where it causes lens swelling and protein precipitation and subsequently, cataracts. GALK deficiency is an autosomal recessive genetic disorder caused by mutations in the GALK1 gene and diagnosed by reduced GALK enzyme activity.


Galloway-Mowat syndrome

Galloway-Mowat syndrome is an extremely rare genetic disorder that is characterized by a variety of physical and developmental abnormalities, particularly neurological abnormalities and early onset progressive kidney disease. Physical features may include microcephaly, (a condition that indicates that the head circumference is significantly smaller than would be expected based upon an infant’s age and gender) and, in some cases, protrusion of part of the stomach through an abnormal opening in the diaphragm (hiatal hernia). Neurological abnormalities can include: various malformations of the brain, seizures, muscle spasms and abnormal movements (dystonia), diminished muscle tone throughout the body (generalized hypotonia), and visual impairment and abnormal eye movements (nystagmus). Infants and children exhibit a delay in obtaining developmental milestones. The majority of affected children do not obtain independent sitting or ambulation or the acquisition of any purposeful hand use or verbal communication. Severe/profound intellectual disability is typically present. Kidney disease is characterized by damage to the clusters of capillaries in the kidneys (focal glomerulosclerosis and/or diffuse mesangial sclerosis) resulting in loss of protein in the urine and abnormal kidney function with associated swelling of the face and peripheries resistant to current medical treatment (steroid resistant nephrotic syndrome). Most affected individuals do not survive beyond teenage years, with the commonest causes of death being nephrotic syndrome or seizures. Galloway-Mowat syndrome appears to be genetically heterogeneous and is believed to be inherited in an autosomal recessive manner, a significant proportion of cases identified to date have been shown to be caused by biallelic alterations (mutations) in the WDR73 gene.

Although researchers have been able to establish a syndrome with characteristic or core symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genetic causes aside from WDR73 and other yet undiscovered genetic factors influencing the disorder, have prevented physicians from developing a complete picture of associated symptoms and prognosis. Some researchers believe that Galloway-Mowat syndrome represents a clinically and genetically heterogeneous group of disorders, which means disorders that have different underlying causes (e.g. different aberrant genes), but that result in the same symptoms or spectrum of symptoms. Consequently, the specific symptoms present and overall severity can vary greatly from one person to another.

In 2014, Galloway-Mowat syndrome was shown to be caused by alterations (mutations) in the WDR73 gene in a subset of cases. 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.

Galloway-Mowat syndrome affects males and females in equal numbers. More than 70 cases have been reported in the medical literature. Because cases may go misdiagnosed or undiagnosed, determining the true frequency of Galloway-Mowat syndrome in the general population is difficult.  There is a WDR73 founder mutation present at high frequency in the Old Order Amish population, leading to an increased frequency of Galloway-Mowat syndrome within this population.

Because of the varied symptoms and presentation of Galloway-Mowat syndrome, there are many disorders that can have overlapping symptoms or similar disease expression.

Galloway-Mowat syndrome can be diagnosed after birth (postnatally) by a thorough clinical evaluation, characteristic physical findings, specialized laboratory tests, imaging techniques, and genetic testing. Several main symptoms associated with the disorder such as nephrotic syndrome, and a small brain (microcephaly) may be obvious at birth.

Treatment is directed toward the specific symptoms that are apparent in each individual and may require the coordinated efforts of a team of specialists. Pediatricians, kidney specialists (nephrologists), gastroenterologists, neurologists, surgeons, physical therapists, and/or other healthcare professionals may need to work together to ensure a systematic, comprehensive approach to treatment. Genetic counseling may be of benefit for affected individuals and their families.


Gastrointestinal stromal tumor

GIST can present with a wide spectrum of subjective symptoms, such as nausea, early satiety, bloating and weight loss. Patients can also experience objective signs of a tumor, such as anemia (low red blood cell count) or a lump in the abdomen. These signs and symptoms depend on the tumor location (e.g., stomach versus rectum), size and pattern of growth.

Current research suggests that disease-causing gene variants underlie the processes by which cells become cancerous. Specifically, malignancies most often develop due to variants in genes known as oncogenes or tumor suppressor genes. Oncogenes promote cell division, while tumor suppressor genes block cell division and ensure that cells die at the proper time; abnormalities of either type of gene can contribute to cancer development. In the case of GIST, most tumors have variants in the KIT oncogene and a minority have variants in the PDGFRA oncogene. Both genes encode proteins called tyrosine kinases, a finding that has been critical for better understanding and treating the disease. Most of these cancer-causing variants are acquired during life, rather than being inherited, and are found only in the cancerous cells.

The exact incidence and prevalence of GIST are unknown, but estimates range from 3.2–19 people per million in the general population. GISTs are the most common sarcomas of the GI tract, though they account for only a small fraction of all GI cancers. The typical GIST patient presents in the fifth to seventh decade of life, with some studies suggesting that males are affected more often than females. Children have also been found to present with GIST, but these cases are very rare and usually occur as SDH-deficient GIST in the setting of CSS (males or females) or Carney triad (females only). The disease in children may have a slower time course, but this is not always so; in rare cases, the disease may be more aggressive. As a better understanding of GIST biology has emerged, and potential links between the incidence of GIST and ethnic backgrounds have been revealed. In the U.S., the highest rate is within the black population, followed by Asian/Pacific Islanders, whites and Hispanics.

GIST diagnosis can be confirmed by biopsy during endoscopy or by percutaneous biopsy (through the skin). The use of endoscopic ultrasound for lesions in the stomach can be helpful, as these tumors can be below the surface of the stomach and therefore not seen by standard endoscopy. If tumors are larger than 2 cm, a biopsy suggesting a benign lesion should be interpreted with caution.


Gastroparesis

Gastroparesis (abbreviated as GP) represents a clinical syndrome characterized by sluggish emptying of solid food (and more rarely, liquid nutrients) from the stomach, which causes persistent digestive symptoms especially nausea and primarily affects young to middle-aged women, but is also known to affect younger children and males. Diagnosis is made based upon a radiographic gastric emptying test. Diabetics and those acquiring gastroparesis for unknown (or, idiopathic) causes represent the two largest groups of gastroparetic patients; however, numerous etiologies (both rare and common) can lead to a gastroparesis syndrome.

The digestive symptom profile of nausea, vomiting, abdominal pain, reflux, bloating, a feeling of fullness after a few bites of food (early satiety), and anorexia can vary in patients both in combination and severity. A small percentage of patients who live with poorly managed symptoms despite numerous treatment interventions, and an inability to meet their nutritional needs represent the extreme end of the gastroparesis spectrum of gastric failure. For most, the prevailing symptom experience is persistent nausea that often intensifies a few hours after eating. Nausea may become so intense as to trigger vomiting even after a few sips of water. Vomiting, also commonly reported, typically starts a couple of hours after eating so that the food is still recognizable and undigested. Chronic abdominal pain, which may also occur, is felt to result from visceral neuropathy. The pain, often diffuse, is described as burning, shearing or gnawing in character. The nature of pain may also be complex with some individuals experiencing acute pain, trigged by eating, layered on top of the chronic pain. This acute, sharp pain may be related to intestinal cramping and/or to spasms in the upper portion of the stomach caused by its failure to relax and accommodate the just-eaten food. As well, a gall bladder that is sluggish to empty (paresis) is commonly found in association with a poorly emptying stomach. This may all add to the pain experienced soon after eating. A poorly emptying stomach additionally predisposes patients to regurgitation of solid food, as well as gastric esophageal reflux disease (GERD). The reflux may range from mild through to severe. GERD complications can create esophageal spasm (also called non-cardiac chest pain) and can add to the burden of chronic pain. In severe cases, reflux aspiration pneumonitis compounds the clinical picture.

The etiologies (causes) for gastroparesis are extensive and varied. Reports from one tertiary referral center found that out of their 146 patients with gastroparesis: 36% were idiopathic (unknown causes), 29% were diabetic, 13% were post-surgical, 7.5% had Parkinson’s disease and 4.8% had collagen diseases. Any disease of metabolic, neurological (psychiatric, brainstem, autonomic including sympathetic and parasympathetic or enteric), or connective tissue (autoimmune) origin has the potential to disrupt gastric neural circuitry. Regional areas of the stomach may show various degrees of dysfunction, such as: failure of fundic relaxation, weakened postprandial antral contractions, pylorospasm, and / or gastric hyperalgesia; yet, rarely is gastroparesis restricted exclusively to the stomach. If perturbation of stomach function occurs, this will indirectly impact function in many other regions along the GI tract due to the complex enteric reflexes and neuronal relays which exist throughout the gastrointestinal (GI) system. The ability of the GI track to cross-talk is essential for coordination of normal digestion. Gastroparesis then is a complex, multifactor, chronic, digestive disease state with possible genetic, physiological, immune, psychological, social and environmental interplays.

Gastroparesis demonstrates a gender bias affecting more women than men. Approximately 80% of idiopathic cases are women. Idiopathic gastroparesis may be linked to an as yet-to-be-elucidated enteric autoimmune disease. The prevalence of delayed gastric emptying in Type 1 diabetics has been reported to be 50% and in type 2 diabetics, reports range from 30% to 50%. Post surgical gastroparesis is a recognized as inadvertent vagal nerve damage or entrapment following upper abdominal surgery, examples are: fundoplication for the treatment of GERD, bariatric surgery, peptic ulcer surgery, anterior approach for spinal surgery (scoliosis), heart, lung transplant, or pancreatic surgery.

A stomach motor disturbance known as dumping syndrome whereby food or liquids empty too quickly from the stomach can present with similar symptoms as are found in gastroparesis. Other disorders that may clinically present as gastroparesis (gastritis, gastric ulcers, pyloric stenosis, celiac disease, and GI obstructions) need to be ruled out.

A diagnosis of gastroparesis is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. Tests may first be performed to rule out other causes of delayed gastric emptying such as obstruction of the gastrointestinal tract. Additional tests are then performed to confirm a diagnosis of gastroparesis.


Gastroschisis

Gastroschisis is apparent at birth and can also be detected prenatally with ultrasound. Infants with this disorder have a 2-5 cm opening at the umbilical ring in which prolapsed abdominal organs appear on the outer surface of the abdomen. The abdominal cavity is smaller than normal, and the prolapsed intestines and other organs have no membranous sac covering it. This opening is typically found to the right, adjacent to the umbilical cord attached on the left side. The stomach, small intestine and large intestine are the most common organs that extend outside the abdomen. If the liver is also prolapsed, this should not be considered a gastroschisis.

The exact mechanism of gastroschisis is not known; however, several theories have been suggested.

As of 2023, this condition is estimated to affect about 2 to 5 per 10,000 newborns. The Centers for Disease Control and Prevention (CDC) estimates that there are about 1,953 babies born with gastroschisis in the United States each year.

Clinical findings of the following disorders can be similar to those of gastroschisis. Comparisons may be useful for a differential diagnosis:

Omphalocele is a herniation of internal abdominal organs located within the umbilicus from a defect of an enlarged umbilical ring. The umbilical cord is inserted centrally in the distal membrane of the protruded organs. The umbilical ring is intact. The protrusion may be very small with just a few loops of bowel protruding or may contain all the intestines, liver and stomach. Unlike gastroschisis, the organs that are protruding are covered with a membranous sac. It has been suggested that omphalocele and gastroschisis may be the same disorder but that the omphalocele may rupture during fetal growth thus absorbing the membranous sac. This theory has not been proven to date.


Gaucher disease

Researchers have identified three distinct forms of Gaucher disease separated by the absence (type 1) or presence and extent (type 2 or type 3) of neurological complications. Additional forms of Gaucher disease include perinatal-lethal form and cardiovascular form. The specific symptoms present in individuals with Gaucher disease vary greatly from person to person. Some individuals exhibit few or no symptoms (asymptomatic); others experience chronic, and sometimes severe, complications.

Gaucher disease is caused by changes (mutations) in the GBA gene.

All forms of Gaucher disease affect males and females in equal numbers. Gaucher disease type 1 is the most common type, accounting for more than 90 percent of cases among Caucasians. Individuals with Gaucher disease type 1 usually exhibit symptoms during adolescence, but the age of onset ranges from childhood to adulthood. The age of onset for Gaucher disease type 2 is during early infancy. The age of onset of Gaucher disease type 3 varies, but the disorder generally begins during childhood or adolescence. The frequency of neuropathic forms of Gaucher disease, that is, the proportion of such cases, is higher among non-Caucasians.

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

Niemann-Pick disease (NPD) is a group of rare inherited disorders of fat metabolism. At least five types of Niemann-Pick disease have been identified (NPD types A, B, C, D, and E). Symptoms of types A and B occur as a result of a deficiency of the enzyme acid sphingomyelinase (ASM), which is needed to break down sphingomyelin, a fatty substance found in all tissues, especially in the brain and nervous system. This deficiency results in abnormal accumulation of excessive amounts of sphingomyelin in many organs of the body such as the liver, spleen, and brain. Symptoms of type C occur because of an inability to mobilize cholesterol and other substances, which results in excessive amounts of these materials in various organs of the body. Symptoms common to all types of Niemann-Pick disease include yellow discoloration of the skin, eyes, and/or mucous membranes (jaundice), progressive loss of motor skills, feeding difficulties, learning disabilities, and an abnormally enlarged liver and/or spleen (hepatosplenomegaly). The different types of Niemann-Pick disease are inherited as autosomal recessive traits. (For more information on this disorder, choose Niemann Pick as your search term in the Rare Disease Database.)


Generalized arterial calcification of infancy

Generalized Arterial Calcification of Infancy

Newborns with GACI may exhibit symptoms such as difficulty breathing, reduced or absent pulses, cardiomyopathy, cardiomegaly or accumulation of fluid in the extremities (edema). They may struggle with heart failure or high blood pressure (hypertension). Newborns with GACI may also present with feeding difficulties, irritability or failure to thrive. On ultrasound or echocardiograph, the condition is characterized by calcification of the arteries or the valves of the heart accompanied by thickening of the lining of the arteries (intima).

In 2003 it was discovered that variants in the ENPP1 gene were the cause of approximately 75% of cases of GACI. The ENPP1 gene provides the instructions for making a protein that helps to break down a molecule called adenosine triphosphate (ATP), when it is found outside the cell (extracellular). Extracellular ATP is broken down into adenosine monophosphate (AMP) and pyrophosphate (PPi). Variants in the ENPP1 gene result in low levels of pyrophosphate. Pyrophosphate is important in controlling calcification and other mineralization in the body. Low pyrophosphate levels allow calcification to develop in the arteries. Low AMP levels lead to narrowing of the blood vessels, with restriction of blood flow.

GACI affects males and females equally and occurs in populations all across the world. There have been slightly over 200 cases documented since GACI was first described in the medical literature in 1899. It is estimated to occur in approximately 1 out of every 200,000 pregnancies with the carrier rate being 1:223. Survival statistics vary greatly but are currently estimated at around 50%.

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a very rare disease typically caused by variants in the ENPP1 gene. It is also a component of ENPP1 deficiency. Patients with ARHR2 suffer from low phosphate levels in the blood (hypophosphatemia) as a result of renal phosphate wasting. The correct balance of phosphate is essential for the normal formation of teeth and bones. The frequency of the disease is unknown. (For more information on this condition, search for ARHR2 in the Rare Disease Database.)

GACI should always be considered in infants and children presenting with hypertension, cardiac failure or sudden death. Ultrasonography can aid in the diagnosis. The preferred imaging modality to assess calcifications extension is whole-body computed tomography (CT) scan combined with CT angiography.


Generalized pustular psoriasis

generalized pustular psoriasis of von Zumbusch

Signs and symptoms of GPP vary, but general symptoms include the widespread appearance of pustules and skin redness (erythema). Pustules are white, pus-filled bumps on the skin that are painful. The pustules of GPP are sterile (i.e., not infected with bacteria or viruses and not contagious).

GPP is thought to be linked to a variety of triggers, but some cases of GPP are not associated with any trigger. Some triggers include emotional stress, infections, injuries, certain medications, vaccines, low calcium levels, sunlight, smoking, menstruation and pregnancy.

The estimated incidence of GPP worldwide is 2 to 7 per million people. GPP can affect anyone at any age, but it is more likely to occur in people aged 40 to 60 years old. Females are slightly more likely to be affected than males.

Other disorders that affect the skin can resemble GPP. A history of how the condition started, the appearance of the skin lesions and skin biopsies to examine the appearance of skin under a microscope are helpful in distinguishing between GPP and disorders with similar symptoms.

A diagnosis of GPP is based on the history of how the rash started, signs and symptoms, and skin biopsy results. The presence of widespread pustules on red skin should increase suspicion for GPP, along with any other signs and symptoms consistent with GPP including skin scales and dryness, swelling, pain, itching, burning sensations, and in cases of acute GPP, systemic symptoms such as fever, fatigue, headaches and body aches.


Gerstmann Syndrome

Gerstmann syndrome is a rare neurological disorder that can occur as the result of a brain injury or as a developmental disorder. The syndrome is characterized by the loss or absence of four cognitive abilities- the loss of the ability to express thoughts in writing (agraphia, dysgraphia), to perform simple arithmetic problems (acalculia), to recognize or indicate one’s own or another’s fingers (finger agnosia), and to distinguish between the right and left sides of one’s body. Additional cognitive defects may occur in some cases.

Gerstmann syndrome is a rare disorder characterized by the loss of four specific neurological functions: Inability to write (dysgraphia or agraphia), the loss of the ability to do mathematics (acalculia), the inability to identify one’s own or another’s fingers (finger agnosia), and inability to make the distinction between the right and left side of the body. It is very rare for a person with learning disabilities to have all four of these neurologic dysfunctions. Only when all four symptoms appear together without mental retardation is the classic syndrome present.

In adults, the syndrome can arise in adults as a result of impaired blood flow to the brain (cerebrovascular disease) such as a stroke or other damage to the brain. The parietal lobes (upper side lobes) of the brain are affected in Gerstmann syndrome. The parietal lobes are involved with sensation and perception as well as understanding sensory input.

Gerstmann syndrome affects males and females in equal numbers. The incidence of Gerstmann syndrome in the general population is unknown. The disorder was first described by Dr. Josef Gerstmann, a Viennese neurologist, in 1924.

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

Alzheimer disease is a progressive condition of the brain that affects memory, thought, and language. The degenerative changes of Alzheimer disease lead to patches or plaques in the brain and the entanglement of nerve fibers (neurofibrillary tangles). Memory loss and behavioral changes occur as a result of these changes in brain tissue. The characteristic findings associated with Gerstmann syndrome can occur due to Alzheimer disease. (For more information on this disorder, choose Alzheimer’s as your search term in the Rare Disease Database).


Gerstmann-Sträussler-Scheinker Disease

Gerstmann-Sträussler-Scheinker (GSS) disease is a rare genetic degenerative brain disorder. The symptoms, the progression of the disorder, and the overall severity can vary greatly among affected families and individuals. This is true even among members of the same family. A common symptom is a progressive loss of coordination that may present as unsteadiness of gait, difficulty walking, and clumsiness. As the disease progresses, other symptoms become apparent including dementia, in which there are worsening problems with thought, cognition, memory, language, and behavior. In all instances, GSS is caused by an abnormal variant of the prion protein (PRPN) gene. The PRNP gene encodes the human prion protein (PrPc). Alterations in this gene lead to the generation of abnormally-shaped (misfolded) prion protein (PrPSc), also known simply as a prion, which is toxic to the body. In GSS, the abnormal prions build up primarily within the brain. This leads to the progressive loss of nerve cells (neurons) and the various symptoms associated with this disorder. The disorder most often affects people in their 40s through 50s. There is no cure, but investigators are researching ways to best treat and manage GSS.

The initial symptoms associated with Gerstmann-Sträussler-Scheinker disease are progressive loss of coordination and mild difficulty with speech (dysarthria). Loss of coordination may present as unsteadiness, difficulty walking, and clumsiness. Affected may have problems coordinating voluntary movements (ataxia). Speech problems may present as slurred speech and progress to severe dysarthria in which people have difficulty speaking and other people have difficulties understanding what they are trying to say. There may be problems with swallowing (dysphagia) due to lack of coordination of the muscles needed for swallowing.

GSS is caused by an abnormal variant (gene mutation) of the PRNP gene. Genes provide instructions for encoding proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

The exact incidence or prevalence of GSS is unknown. Estimates range from 1 to 10 in 100,000,000 people in the general population. CJD affects about 1 in 1,000,000 people in the general population per year. Genetic prion diseases are believed to make up about 15% of all individuals with prion diseases. Because rare diseases often go undiagnosed or misdiagnosed, it is difficult to determine their true frequency in the general population. GSS affects men and women in equal numbers. The average age of onset is 35-50 years old, the youngest describe occurrence was in a 10-year-old child.

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

A diagnosis of GSS is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis of GSS cannot be confirmed through laboratory tests or imaging studies.


Gestational Trophoblastic Disease

The female ovum and the male sperm are called human gametes. Each gamete carries half of the total genetic information required to form the future fetus. Typically, an ovum will be fertilized by exactly one sperm. Each human gamete carries 23 chromosomes, referred to as a haploid genome. Upon fertilization, the chromosomes from each parent combine and reassemble in complementary pairs of two. The hydatiform moles result from abnormal fertilization of the female ovum by male sperm. There are many aberrant forms of fertilization. Several scenarios are described throughout this report, but the trigger factor for these reactions is unknown. Farther along in this section, we describe the biology of normal pregnancy in more detail to explain where the trophoblastic cell population arises and what its normal role is.

There is a strikingly, ethnic predisposition to hydatiform moles in groups of women with Asian, Hispanic, and Native American ethnicity. Additionally, women who are adolescents and women over forty years old have a higher risk.


Gianotti Crosti Syndrome

Gianotti-Crosti Syndrome is a rare skin disease affecting children between the ages of nine months and nine years. Major symptoms may include blisters on the skin of the legs, buttocks and arms. The disorder is usually preceded by a viral infection.

Gianotti-Crosti Syndrome is characterized by blisters on the skin that may or may not itch.  They are usually found on the face, buttocks, arms or legs. The blisters consist of large, flat-topped, fluid filled sacks.  They usually occur along with upper respiratory tract infection.  The blisters usually last from twenty to twenty-five days; they do not usually recur.  There may be an enlargement of the lymph nodes in the trunk area of the body. Gianotti-Crosti Syndrome usually occurs after a bout with a viral disease such as:  Coxsackievirus, Hepatitis-B, Infectious Mononucleosis or Cytomegalovirus, or after vaccination with a live virus serum.

The cause of Gianotti-Crosti Syndrome is thought to be a reaction to a previous viral infection.  In many countries the predisposing cause is usually the Hepatitis-B virus.  In North America other viruses are more often the predisposing cause.  The exact reasons for this cause and effect situation are unknown.

Gianotti-Crosti Syndrome usually affects children between the ages of nine months and nine years of age.  It affects males and females in equal numbers. Although the disorder is regularly associated with Hepatitis-B infections in other countries, in North America it is rarely the cause.

The following viral infections can cause Gianotti-Crosti.

Because Gianotti-Crosti Syndrome is a self-limiting disorder, the treatment of affected children is primarily symptomatic and supportive. For example, in some cases, the use of topical ointments or certain medications by mouth may be recommended to help alleviate mild to potentially severe itching (pruritus). The skin lesions associated with Gianotti-Crosti Syndrome typically spontaneously resolve within approximately 15 to 60 days. When associated findings include enlargement of the lymph nodes (lymphadenopathy) and/or enlargement of the liver (i.e., in association with liver inflammation [hepatitis]), such findings may persist for several months after initial symptom onset.


Giant axonal neuropathy

Giant axonal neuropathy is a rare neuropathy that severely affects the peripheral as well as the central nervous system. The first symptoms appear in early childhood. This disorder is characterized by abnormalities in the peripheral and central nervous systems including low muscle tone (hypotonia), muscle weakness, decreased reflexes, impaired muscle coordination (ataxia), seizures and intellectual disability. Pale, tightly curled hair is frequently seen in those affected. Giant axonal neuropathy follows autosomal recessive genetic inheritance.

Symptoms of giant axonal neuropathy occur in early childhood before the age of seven years. Both the central and peripheral nervous systems are affected. The central nervous system includes the brain and spinal cord and the peripheral nervous system spreads out from the brain and spinal cord to all other areas of the body. Characteristics include low muscle tone (hypotonia), muscle weakness, decreased reflexes, impaired muscle coordination (ataxia), seizures and intellectual disability. In contrast to purely peripheral neuropathies, the reflex of the toes known as Babinski’s sign is often positive, indicating involvement of central motor pathways. Most affected children have pale, tightly curled hair unlike their parent’s hair. Cranial nerves may also be affected leading to facial weakness, abnormal eyes and poor vision. An unusual leg posture is present in some affected children. Skeletal abnormalities such as scoliosis and foot deformities have been described and are thought to be a result of the nervous system dysfunction. Mental development is in most cases initially normal, but later in childhood degenerative mental changes (dementia) may occur as the disorder progresses. Giant axonal neuropathy is rapidly progressive, usually leading to dependence on a wheel chair by the second decade of life and death in the second or third decade.

Giant axonal neuropathy is an autosomal recessive genetic disorder. This condition is caused by an abnormality in the GAN gene located on chromosome 16 at 16q24.1 that codes for the gigaxonin protein. The abnormal gigaxonin protein causes a portion of the nerve cell called the axon to swell up with deposits of tiny threads of protein called neurofilaments, giving the appearance of giant axons. The giant axons cause degeneration and abnormal functioning of the peripheral nervous system.

Giant axonal neuropathy is a rare disorder that presents in early childhood. This disorder affects equal numbers of males and females. The prevalence of giant axonal neuropathy and the frequency of carriers of one defective copy of the GAN gene is not known, but it is known that giant axonal neuropathy is a very rare disease.

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

Charcot-Marie-Tooth (CMT) hereditary neuropathies are a group of disorders in which the motor and sensory peripheral nerves are affected, resulting in muscle weakness and atrophy, primarily in the legs and sometimes in the hands. In contrast to giant axonal neuropathy, the overwhelming majority of patients with CMT shows no, or only very mild, central nervous system (CNS) involvement. The differential diagnosis between the rather common CMT and giant axonal neuropathy is, therefore, rarely difficult. CMT group hereditary neuropathies affect mainly the peripheral nerves that control many muscles in the body. The nerve cells in individuals with this disorder are not able to send electrical signals properly because of abnormalities in the nerve axon or abnormalities in the insulation (myelin) around the axon. Specific gene mutations are responsible for the abnormal function of the peripheral nerves. Charcot Marie Tooth hereditary neuropathy can be inherited in an autosomal dominant, autosomal recessive or X-linked mode of inheritance. (For more information about this condition, choose Charcot as your search term in the Rare Disease Database.)


Giant Cell Arteritis

Giant cell arteritis (GCA) is the most common blood vessel disorder in persons over 50 years old that causes inflammation of medium and large-sized arteries in the body (vasculitis). GCA causes changes in blood vessel walls leading to poor blood circulation. Arteries most affected in giant cell arteritis are the temporal artery and other cranial arteries (now called cranial-GCA), but inflammation of the aorta and other large arteries in the body can occur as well and may present differently (now called large vessel-GCA). If left untreated, this can lead to a medical emergency where sudden blindness occurs without early detection and treatment. Signs and symptoms when the temporal or other cranial arteries are involved include arm pain, pulsing headaches on one side or on the back of the head, jaw pain, scalp tenderness, double vision or other visual disturbances, bulging temporal artery that is tender with skin edema and redness. It can also present with constitutional symptoms such as polymyalgia, fevers, anorexia, and weight loss, a presentation of LV-GCA. The cause of giant cell arteritis is still unknown but is thought to be from the immune system causing damage to the body’s own blood vessels. Polymyalgia rheumatica is an inflammatory disorder that is closely related to giant cell arteritis and occurs in 40% to 60% of patients with giant call arteritis. 15% to 20% of persons with polymyalgia rheumatica will have giant cell arteritis. Treatments available include steroids (corticosteroids) that will help with symptoms and reoccurrence and medications that weaken the immune system.

Common symptoms when the temporal arteries (located on each side of the head) are affected are headaches with the artery being tender, thicker, nodular, and pulsating early-on but may become blocked later-on. Headaches are present in more than 60% of patients. The temporal artery and its parietal and frontal branches may bulge while appearing twisted/ knotted under the scalp and feel tender with skin edema and redness and may become pulseless.

The cause of giant cell arteritis is still not fully known, however, studies linking genetic factors and infections have shown that the body’s immune system may play a role in the inflammation. Giant cell arteritis is thought to be an autoimmune disorder, where the body’s defense system used against invading organisms is used instead to attack normal healthy tissues. These immune cells come together at the site where they are attacking the body and form giant cells. These giant cells produce substances that damage walls of the artery and lead to further inflammation.

Giant cell arteritis most commonly affects those over 50 years old (mostly above 65 years) and is more common in Caucasians, people of Nordic or northern European descent, and others in northern latitudes. Women are 2 to 3 times more likely to develop GCA than men in persons of northern European descent while there is no higher risk for women from Spain, Israel, Turkey, other Mediterranean countries, and India. Specifically, about 20 per 100,000 people among whites in northern European populations are affected, 10 per 100,000 people affected among southern European populations, and about 1 per 100,000 people affected among American populations of Asian or African descent.

The condition that presents most commonly with giant cell arteritis is polymyalgia rheumatica, which is characterized by muscle pain, stiffness, fatigue, and with or without fever. It presents abruptly as stiffness and pain in the neck, shoulders, and hips. It is also most common in persons over the age of 50.

There are no universally accepted diagnostic criteria and giant cell arteritis may be diagnosed by laboratory evaluation or physical examination. The American College of Rheumatology developed provisional classification criteria which requires at least 3 of the following: age of more than 50 years, localized headache that had not happened before, temporal artery abnormalities like tenderness or pulsations, increased time it takes red blood cells to settle (erythrocyte sedimentation rate) of greater than or equal to 50mm per hour, and or abnormal arterial biopsy. Confirmation of the diagnosis can be done by obtaining a temporal artery biopsy up to 14 days after the start of treatment, however, some patients can be positive for giant cell arteritis and respond to treatment and have a negative biopsy result. The use of ultrasound and magnetic resonance are becoming more reliable to help confirm or establish early diagnosis to prevent vision loss. Internationally, the European League Against Rheumatism (EULAR) guidelines have similar recommendations with vascular ultrasound as the first diagnostic test and if not available, the temporal artery biopsy.


Giant Cell Myocarditis

Giant cell myocarditis is a rare cardiovascular disorder that occurs for unknown reasons (idiopathic). It is characterized by inflammation of the heart muscle (myocardium), a condition referred to as myocarditis. Inflammation is caused by widespread infiltration of giant cells associated with other inflammatory cells and heart muscle cell destruction. Giant cells are abnormal masses produced by the fusion of inflammatory cells called macrophages. Individuals with giant cell myocarditis may develop abnormal heartbeats, chest pain and, eventually, heart failure. Many individuals eventually require a heart transplant. The disorder most often occurs in young adults.

The onset of symptoms of giant cell myocarditis is often rapid. Initial symptoms may include swelling of the ankles, chest pain, heart palpitations, fatigue and shortness of breath (dyspnea) especially upon exertion or lying flat. Affected individuals eventually develop irregular heartbeats (arrhythmias) such as abnormally fast (tachycardia) or slow (brachycardia) heartbeats. Arrhythmias may cause sudden episodes of lightheadedness or loss of consciousness.

The exact cause of giant cell myocarditis is unknown. Approximately 20 percent of cases occur in individuals with autoimmune disorders suggesting that autoimmunity may play a role in the development of giant cell myocarditis. Autoimmune disorders are caused when the body’s natural defenses against foreign or invading organisms begin to attack healthy tissue for unknown reasons.

Giant cell myocarditis affects males and females in equal numbers. It can affect individuals of any age although most cases occur in young or middle-aged adults (median age 42 years). Approximately 300 cases have been reported in the medical literature.

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

Cardiac sarcoidosis refers to the heart abnormalities sometimes associated with sarcoidosis, a rare disease characterized by the abnormal formation of inflammatory masses or nodules (granulomas) consisting of certain granular white blood cells (modified macrophages or epithelioid cells) in certain organs of the body. The range and severity of symptoms associated with sarcoidosis vary greatly, depending upon the specific organ(s) involved and the degree of such involvement. In some cases, only the heart may be involved (isolated cardiac sarcoidosis). The exact cause of sarcoidosis is not known. However, infectious, environmental, genetic and immunological factors are under investigation as possible causes of the disorder. (For more information on this disorder, choose sarcoidosis as your search term in the Rare Disease Database.)


Large congenital melanocytic nevus

Large/giant CMN are obvious at birth, most commonly covering an aspect of the trunk and less common on the head, neck and extremities. Affected areas of large CMN have been designated as cape, bathing trunk, tippet or garment CMN due to their respective distributions. Lesions may have irregular or geographic borders. In about 75% of cases, multiple small CMN will accompany the large CMN, usually in a generalized manner. Satellite is a commonly used description of discrete small or medium CMN or tardive nevi in the presence of a large/giant CMN, though semantically and molecularly, it is more accurate to refer to disseminated lesions. These additional smaller, disseminated CMN may be present at birth and/or may increase to significant numbers over the first few years of life. These multiple CMN should be noted in number, as greater numbers (>20) have been correlated with neurological anomalies.

Both CMN and acquired melanocytic nevi are associated with somatic mutations in intracellular proteins of the microtubule-associated protein signal transduction pathway. For 4 in 5 cases, a single mutation in the DNA encoding the NRAS enzyme can be found, and for up to one in 6 cases, a single mutation in the DNA for the BRAF enzyme. The currently identified mutations cause the enzymes to become permanently active, and have been found in many apparently unrelated cancers as well, perhaps driving cells to proliferate. These findings imply that other, less common and not yet identified, mutations may also contribute to cause CMN.

People of all races and colors of skin can be affected with large/giant CMN.  A slight female preponderance has been noted in large/ giant CMN (male/female ratio of 1 to 1.4), but is not observed in the smaller population of people affected by NCM.

Neurocutaneous melanocytosis is present in an estimated 5-15% of patients with large/giant CMN, while melanoma can occur in an estimated 1-2%.

Making the diagnosis of a CMN is most often done by examining clinical and dermoscopic features. The larger CMN can easily be diagnosed based solely on their size. For smaller CMN, their history of presence since birth, surface topography, presence of hair or globular dermoscopic pattern can assist in diagnosis. When biopsied, the histological features of CMN are similar to those found in common acquired nevi which arise later in life; however, CMN tend have a greater cellularity with deeper extension of nevus cells into the deep dermis and subcutis, and cells extend along adnexal structures such as hair follicles and around blood vessels and nerves. Histological criteria alone cannot be used to dictate with absolute certainty whether a nevus is congenital or acquired.


Gilbert Syndrome

欧洲非罕见：吉尔伯特综合征

Gilbert syndrome is a mild genetic liver disorder in which the body cannot properly process bilirubin, a yellowish waste product that is formed when old or worn out red blood cells are broken down (hemolysis). Individuals with Gilbert syndrome have elevated levels of bilirubin (hyperbilirubinemia), because they have a reduced level of a specific liver enzyme required for elimination of bilirubin. Most affected individuals have no symptoms (asymptomatic) or may only exhibit mild yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Jaundice may not be apparent until adolescence. Bilirubin levels may increase following stress, exertion, dehydration alcohol consumption, fasting, and/or infection. In some individuals, jaundice may only be apparent when triggered by one of these conditions. Gilbert syndrome is inherited as an autosomal recessive trait.

Although Gilbert syndrome may become apparent shortly after birth, it may not be recognized for many years. Episodes of mild jaundice may appear in young adults and is more common in males than females. Frequently, episodes of jaundice are overlooked. Gilbert syndrome is associated with fluctuating levels of bilirubin in the blood (hyperbilirubinemia). Bilirubin levels may increase with stress, strain, dehydration, fasting, infection or exposure to cold. In many individuals, jaundice is only evident when one of these triggers raises the bilirubin levels.

Gilbert syndrome is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Gilbert syndrome is diagnosed more often in males than females. The disorder affects approximately 3-7 percent of individuals in the general population. Gilbert syndrome affects individuals of all races. It is present at birth, but may remain undiagnosed until the late teens or early twenties. Gilbert syndrome was first described in the medical literature in 1901.

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

A diagnosis of Gilbert syndrome is often made when blood, drawn for routine health check up or another illness, such as an infection, detects mildly elevated bilirubin levels. Because the levels of bilirubin fluctuate, blood tests may not always show elevated bilirubin. Individuals are determined to have Gilbert syndrome by the presence of hyperbilirubinemia in the absence of hemolysis (premature breakdown of red blood cells) or structural liver damage.


Gitelman Syndrome

Gitelman syndrome usually becomes apparent anywhere from late childhood (usually over the age of six) to early adulthood. The disorder is highly variable, even among individuals in the same family. Some people do not develop any symptoms (asymptomatic), while others can develop chronic issues that can impact their quality of life.

Most cases of Gitelman syndrome are caused by mutations in the SLC12A3 gene. In a minority of cases, mutations in the CLCNKB gene cause the disorder. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or not inserted in a tubule membrane properly. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In the case of Gitelman syndrome, defective protein structure causes failure to reclaim filtered sodium and chloride (channelopathy). More severe salt wasting is caused by a defect in a different channel in Bartter syndrome.

Gitelman syndrome affects males and females in equally. The disorder occurs in approximately 1 in 40,000 Caucasian individuals. However, many cases of these disorders may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of Gitelman syndrome in the general population. The prevalence of individuals with one mutated copy of a gene (known as heterozygotes or carriers of the disease) is approximately 1% of European populations. These heterozygotes may enjoy a benefit of a small degree of salt wasting: they have lower blood pressures than the general population.

Symptoms of the following disorders can be similar to those of Gitelman syndrome.

A diagnosis of Gitelman syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected after other more common causes of hypokalemia and metabolic alkalosis are ruled out.


Glanzmann Thrombasthenia

Glanzmann thrombasthenia (GT) is a rare inherited blood clotting (coagulation) disorder characterized by the impaired function of specialized cells (platelets) that are essential for proper blood clotting. Symptoms of this disorder usually include abnormal bleeding, which may be severe. Prolonged untreated or unsuccessfully treated hemorrhaging associated with Glanzmann thrombasthenia may be life threatening.

The symptoms of Glanzmann thrombasthenia usually begin at birth or shortly thereafter and include the tendency to bruise and bleed easily and sometimes profusely, especially after surgical procedures. Other symptoms may include susceptibility to easy bruising, nosebleeds (epistaxis), bleeding from the gums (gingival), intermittent gastrointestinal bleeding and/or variably small or large red or purple-colored spots on the skin that are caused by bleeding in the skin (purpura). Women with GT often also have unusually heavy menstrual bleeding, irregular uterine bleeding and excess bleeding in childbirth. Rarely, gastrointestinal bleeding and blood in the urine (hematuria) can occur. The severity of the symptoms varies greatly. Some affected individuals have mild bruising and others have severe hemorrhages that can be life threatening.

Glanzmann thrombasthenia is inherited in an autosomal recessive pattern. An abnormality in either the gene for aIIb (glycoprotein IIb; GPIIb) or the gene for β3 (glycoprotein IIIa; GPIIIa) results in an abnormal platelet aIIbβ3 (GPIIb/IIIa) integrin family receptor and prevents platelets from forming a plug when bleeding occurs. Many different changes (mutations or variants) in these genes have been identified. Recent evidence suggests that approximately 0.5% of healthy individuals in the general population are probably carrying one gene with an abnormal (pathogenic) variant of αIIb or β3.

Glanzmann thrombasthenia is a rare disorder that affects males and females in equal numbers. The symptoms of this disease are usually apparent at birth (neonates) or during infancy. Approximately 500 cases have been reported, but many cases have probably not been reported. This condition occurs with greater frequency in populations in which intermarriage within a group (consanguinity) is more prevalent such as in some regions of the Middle East, India and France.

Symptoms of other disorders listed below can be similar to those of Glanzmann thrombasthenia. Comparisons may be useful for a differential diagnosis:

Hemophilia is a rare inherited blood clotting (coagulation) disorder caused by an inactive or deficient blood protein, usually factor VIII or IX, both of which are needed for normal blood clotting. Factors VIII and IX are two of several proteins that enable the blood to clot. Hemophilia due to abnormalities in either factor VIII or IX is found in males almost exclusively because these genes are on the X chromosome and these disorders can be classified as mild, moderate or severe. The most common forms of bleeding are hemorrhage in joints and muscles and the most serious symptom of hemophilia is bleeding in the brain. Bleeding may begin spontaneously, that is, without any apparent cause. Bleeding may cause permanent damage to the joints and muscles. People with hemophilia bleed for a longer period of time than people who have the normal amount of clotting factors in their blood. Bruises and trauma can trigger episodes of serious internal bleeding in people with this disorder. (For more information on this disorder, choose hemophilia as your search term in the Rare Disease Database.)


Glioblastoma

Patients with glioblastoma have two types of symptoms, generalized and focal. Generalized symptoms tend to occur in many types of brain tumors. These symptoms include headaches, seizures, nausea/vomiting, memory loss and decrease in normal function. Focal symptoms are dependent on the location and size of the tumor. The size and location of the tumor often influences the signs and symptoms seen in patients. For example, if the tumor is in the part of the brain required for language processing, the patient may have more issues speaking or understanding speech. Other focal symptoms can include seizures, muscle weakness, sensory loss and visual changes.

The exact cause of glioblastoma is unknown. However, there are factors that can influence the risk of glioblastomas. A risk factor known to be associated with glioblastoma is prior ionizing radiation therapy that uses high energy waves or particles to destroy cancer cells but can also cause normal cells to be damaged and even lead to new cancer cells forming. Other risk factors include employment in synthetic rubber manufacturing, petroleum refining and exposure to vinyl chloride or pesticides. It is important to note that most individuals who are diagnosed with glioblastoma may not have any of these risk factors. Likewise, those with these risk factors may never develop glioblastoma in their lifetime. Causation due to risk factors has not been established and further research is needed.

3/100,000 people per year are affected by glioblastoma in the United States. The average age of diagnosis is 64 years of age with a slightly higher rate in males than females. Caucasians have the highest rate of glioblastoma diagnoses compared to other ethnic groups such as African Americans, Asians and Native Americans.

It is important to differentiate glioblastoma from other tumors that can affect the brain. These include but are not limited to chordomas, central nervous system (CNS) lymphomas, ependymoma, medulloblastomas, lower grade brain tumors and other cancers that have spread to the brain from other areas. Other conditions such as stroke, brain abscesses, brain bleeds and cavernous malformations can be mistaken for glioblastoma and should also be ruled out before a diagnosis is made.

Individuals who are suspected of having a glioblastoma should first undergo a full physical and neurological examination. Neurological examinations are used to assess patient sensory and muscle responses. If any signs or symptoms of glioblastoma are present, the patient will require brain imaging using contrast-enhanced magnetic resonance imaging (MRI). MRI is often used to identify glioblastomas. It is a technique that creates detailed images of the human body. An MRI machine produces a strong magnetic field and directs radio waves towards the body. Computers interpret changes in the body caused by radio waves and produce images. Contrast dye is used to further enhance imaging. This makes it easier to distinguish tumors from normal cells. Although MRI can help identify possible glioblastomas, a tissue sample from a biopsy is required to make a definite diagnosis. A biopsy is an operation that removes tissues. A diagnosis should only be made when these tissues are confirmed to be a form of glioblastoma.


Glial tumor

The symptoms associated with gliomas are similar among all types but can vary depending on the individual and the location of the tumor. Seizures (focal or generalized), language impairment (aphasia), weakness of part of the body (hemiparesis), sensory changes on part of the body and headaches are common. Other possible symptoms include gait disturbances, fatigue, dizziness, visual changes, vomiting and changes in urination. Psychological symptoms such as cognitive impairment, personality changes, depression, anxiety and memory impairment can also occur. Most of the symptoms are a consequence of the compressive effect of the tumor and fluid that surrounds it on the brain. Malignant gliomas (grade 3 and 4) are also associated with the development of blood clots in the deep veins, notably of the legs, (deep vein thrombosis) that can dislodge and migrate to occlude the arteries of the lungs (pulmonary embolism).

Gliomas are caused by the accumulation of genetic mutations in glial stem or progenitor cells, leading to their uncontrolled growth. Mutated genes are typically involved in functions such as tumor suppression, DNA repair and regulation of cell growth. Examples of mutated genes in certain types of gliomas include TP53, PTEN (tumor suppressor genes), ATRX (involved in the remodeling of chromatin, a DNA-RNA-protein complex), TERT (encoding a subunit of telomerase, an enzyme that can lead to an infinite division potential in cells) BRAF (involved in cell growth) and IDH (involved in cellular metabolism).

Excluding metastases from other cancers that reach the central nervous system, gliomas make up 26% of all brain tumors, (primary brain tumors) and 81% of all malignant brain tumors. They develop in approximately 6.6 per 100,000 individuals each year and 2.94 per 100,000 individuals under age 14. The median age (meaning that half of affected individuals are younger than this age and the other half are older) for the development of glioma is between 12 and 65 years, depending on the subtype. Pilocytic astrocytoma is the most common glioma in individuals under age 14 (34.4% of all gliomas) whereas glioblastoma is the most common glioma in adults (56.6% of all gliomas) (for more information on these types of gliomas, choose the specific glioma name as your search term in the Rare Disease Database).

A diagnosis of glioma requires an extensive patient history as well as a complete physical and neurological examination. Signs that further investigation might be required include a new onset of seizures, abrupt onset of cognitive decline and presence of other neurological symptoms. Headaches that develop or worsen abruptly, that begin to occur after age 50, that awaken the affected person from sleep even when they are mild and that are associated with cognitive impairment are warning signs that could indicate a brain mass.


经典型葡萄糖转运体1缺乏综合征

Classic glucose transporter type 1 deficiency syndrome

Glucose Transporter Type 1 Deficiency Syndrome

Glut1DS represents a clinical spectrum disease. The symptoms and severity can vary dramatically from one individual to another. Mild cases often go undiagnosed, while other cases can potentially lead to severe, debilitating complications. It is important to note that affected individuals may not have all the classic symptoms discussed below or may have less severe symptoms. Affected individuals should talk to their physician and medical team about their specific clinical features, standard management and prognosis.

Glut1DS is caused by mutations in the SLC2A1 gene. These mutations are inherited in an autosomal dominant (or rarely recessive) pattern. Most individuals with Glut1DS have a spontaneous genetic change (i.e., new mutation) in the SLC2A1 gene. In essence, the mutation started with the individual, was not inherited from the parents, but can be passed on to future generations.

Glut1DS affects males and females in equal numbers. The incidence and prevalence of Glut1DS in the general population is unknown. Because the disorder may go unrecognized or misdiagnosed, determining its true frequency in the general population is difficult. Several hundred cases have been identified and described in the medical literature since 1991. The prevalence estimates have ranged from 1:90,000 to 1:24,000 suggesting that there are several thousand cases of Glut1DS in the USA.

Symptoms of the following disorders can be shared with Glut1DS. Comparisons may be useful for a differential diagnosis.

A diagnosis of Glut1DS is confirmed by the presence of characteristic clinical features, hypoglycorrhachia and a disease-causing mutation in the SLC2A1 gene.


葡萄糖-6-磷酸酶缺乏所致肝糖原贮积症

Glycogen storage disease due to glucose-6-phosphatase deficiency

As stated above, most G6PD-deficient persons are asymptomatic most of the time; however, any one of them, when exposed to certain triggering factors, can develop acute hemolytic anemia (AHA), which may be life-threatening especially in children. Triggers for AHA in G6PD deficient persons include: (a) certain drugs (see Causes section), (b) certain infectious diseases, (c) ingestion of fava beans. The onset of symptoms is within 2-3 days after exposure to the trigger (even less with fava beans).

G6PD deficiency is caused by an alteration (mutation) in the G6PD 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. In people with G6PD deficiency, the gene mutation and resultant enzyme deficiency is not sufficient by itself to cause symptoms. The development of symptoms requires the specific interaction of an alteration in the G6PD gene in combination with a specific environmental factor.

G6PD deficiency is one of the most common forms of enzyme deficiency and is believed to affect more than 400 million people worldwide. Although the prevalence is high, the vast majority of people remain clinically asymptomatic throughout their lives. Many medical sources state that the disorder is more common in males, but this is not accurate.

Symptoms of the following disorders can be similar to those of G6PD deficiency. Comparisons may be useful for a differential diagnosis.

A diagnosis is based upon the identification of characteristic physical findings and symptoms, a thorough clinical evaluation, a detailed patient history, and/or specialized tests. If a person experiences symptoms, e.g. blood in the urine, and spontaneously reports eating fava beans and comes from an area or a population where G6PD deficiency is common, suspicion of the disorder should be high.