Schindler Disease is a rare inherited metabolic disorder characterized by a deficiency of the lysosomal enzyme alpha-N-acetylgalactosaminidase (alpha-NAGA). The disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain fats and carbohydrates. In individuals with Schindler Disease, deficiency of the alpha-NAGA enzyme leads to an abnormal accumulation of certain complex compounds (glycosphingolipids) in many tissues of the body.
There are two forms of Schindler Disease. The classical form of the disorder, known as Schindler Disease, Type I, has an infantile onset. Affected individuals appear to develop normally until approximately 1 year of age, when they begin to lose previously acquired skills that require the coordination of physical and mental activities (developmental regression). Additional neurological and neuromuscular symptoms may become apparent, including diminished muscle tone (hypotonia) and weakness; involuntary, rapid eye movements (nystagmus); visual impairment; and episodes of uncontrolled electrical activity in the brain (seizures). With continuing disease progression, affected children typically develop restricted movements of certain muscles due to progressively increased muscle rigidity, severe mental retardation, hearing and visual impairment, and a lack of response to stimuli in the environment.
Schindler Disease, Type II, which is also known as Kanzaki Disease, is the adult-onset form of the disorder. Associated symptoms may not become apparent until the second or third decade of life. In this milder form of the disease, symptoms may include the development of clusters of wart-like discolorations on the skin (angiokeratomas); permanent widening of groups of blood vessels (telangiectasia), causing redness of the skin in affected areas; relative coarsening of facial features; and mild intellectual impairment. The progressive neurological degeneration characteristically seen in the infantile form of the disease has not occurred in association with Schindler Disease, Type II.
Both forms of Schindler Disease are inherited as autosomal recessive traits. According to investigators, different changes (mutations) of the same gene are responsible for the infantile- and adult-onset forms of the disease. The gene has been mapped to the long arm (q) of chromosome 22 (22q11).
Schindler Disease is an extremely rare inherited metabolic disorder characterized by a deficiency of the lysosomal enzyme alpha-N- acetylgalactosaminidase (alpha-NAGA). (The specific enzyme deficiency in Schindler Disease is sometimes referred to as "alpha-galactosidase B deficiency.") There are two forms of the disease with different ages of onset and varying severity.
Schindler Disease, Type I, the classic form of the disease, begins in infancy. Affected children develop normally until approximately 9 months to 1 year of age. They then begin to exhibit a delay in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor retardation). After a period of such developmental delay, they begin to lose previously acquired physical and mental abilities (developmental regression); such regression may begin at approximately 2 years of age. Affected children may then start to exhibit a variety of neurological symptoms, such as muscular weakness and diminished muscle tone (hypotonia); crossing of the eyes (strabismus); involuntary, rapid eye movements (nystagmus); and/or visual impairment due to the gradual deterioration of the nerves of the eyes (optic atrophy). They may also experience brief, shock-like muscle spasms of the arms, legs, or entire body (myoclonic seizures) and/or seizures characterized by loss of consciousness and muscle contractions (grand-mal seizures). (For more information on seizures, use "Epilepsy" as your search term in the Rare Disease Database.)
Neurological impairment continues to progress in affected children and may be characterized by blindness due to abnormal tissue changes (lesions) in the outer layer of the brain (cortical blindness); deafness; an inability to move voluntarily (immobility); sudden involuntary muscle spasms (spasticity); and/or uncontrolled, rigid extension and rotation of the arms, legs, fingers, and toes due to lesions on the brain (decerebrate rigidity). Affected children may also exhibit severe mental retardation, little or no response to stimuli in the environment, and an increased susceptibility to repeated infections of the respiratory tract.
In the adult-onset form of Schindler Disease (also known as Schindler Disease, Type II or Kanzaki Disease), symptoms may not appear until the second or third decade of life. In affected individuals, the abnormal accumulation of certain complex compounds (glycosphingolipids) due to deficiency of the alpha-NAGA enzyme causes the permanent widening of groups of small blood vessels (telangiectasia). Wart-like growths (angiokeratomas) may also appear on the skin that are similar to those seen in Fabry Disease (also known as Angiokeratoma Corporis Diffusum). (For more information on Fabry Disease, see the Related Disorders section of this report.)
The angiokeratomas may first be restricted to a single area (localized), such as the lower torso, and then "spread" to additional locations (e.g., from the lower torso to the chest area). These growths may be flat or raised and vary in color, and larger angiokeratomas may consist of clusters of warts and small blood vessels in an area of thickened skin. Affected individuals may also exhibit widened (dilated) blood vessels in other areas of the body, such as the mucous membrane covering part of the eye (anterior sclera) and the inner part of the eyelids (ocular conjunctiva); the back of the eyeball (fundus); and/or the mucous membrane of the stomach (gastric mucosa).
Individuals with Schindler Disease, Type II may also exhibit slightly coarse facial features; mild shortness of stature; and/or severe swelling or puffiness in different parts of the body due to the accumulation of fluid (lymph) in the soft layers of tissue under skin (lymphedema). They may also experience episodes of chest pain (angina pectoris) due to a lack of oxygenated blood (ischemia) to the middle, muscular layer of the heart (myocardium). Other features may include degeneration of nerve cells (axons) outside of the brain and spinal cord (peripheral neuroaxonal degeneration) and/or mild intellectual impairment. However, in this milder, adult-onset form of Schindler Disease, progressive neurological and neuromuscular deterioration has not been documented.
Schindler Disease, Types I (infantile onset) and II (adult onset) are inherited as autosomal recessive genetic traits. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
The gene that causes Schindler Disease, Type I is thought to be located on the long arm (q) of chromosome 22 (22q11). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." In order for researchers to locate and clearly refer to the thousands of genes that may be present on one chromosome, both the long arm and short arm of each chromosome is divided into many bands that are numbered.
In Schindler Disease, Type II, the same gene at the same chromosomal location (22q11) is responsible for the disorder; however, the gene's amino acids are arranged slightly differently (base substitution) than in the case of Schindler Disease, Type I. This slight rearrangement is felt to be responsible for the later onset of Schindler Disease, Type II as well as its less severe symptoms.
The symptoms of both the infantile- and adult-onset forms of Schindler Disease develop due to a deficiency of the enzyme alpha-N- acetylgalactosaminidase (alpha-NAGA). (The specific enzyme deficiency in Schindler Disease is sometimes referred to as "alpha-galactosidase B deficiency.") Low levels of the enzyme lead to the abnormal accumulation of certain complex compounds (glycosphingolipids) as well as alpha-NAGA residues in certain tissues of the body.
For example, in Schindler Disease, Type I, symptoms are caused by the abnormal accumulation of glycosphingolipids and alpha-NAGA residues in the outer layer of the brain (cerebral cortex). This causes the swelling and degeneration of nerve cell endings (axons) in the brain (dystrophic axonal swellings or "spheroids"). Such lysosomal deposits and degeneration may also be seen in nerve endings (axons) in the rectum's muscular layer (myenteric plexus). It is believed that other tissues and organs of the body may also contain such deposits; however, in cases reported in the medical literature, no such deposits were found in organs in the abdominal cavity (viscera), which often occurs in other lysosomal storage diseases.
In Schindler Disease, Type II, symptoms result from the abnormal accumulation of glycosphingolipids and alpha-NAGA residues in blood vessel (vascular), skin (dermal), lymphatic, sweat gland (eccrine), kidney (renal), and other cells in many tissues of the body. Lysosomal deposits in the outer layer of the brain, such as those seen in Schindler Disease, Type I, have not been found in Schindler Disease, Type II.
Schindler Disease is an extremely rare inherited metabolic disorder that was first recognized by the medical community in the mid- to late-1980s. The infantile form of the disorder (Schindler Disease, Type I) was originally recognized in two sons of German parents who were remote blood relatives (consanguineous). In this form of the disease, symptoms appear when the affected child is approximately 9 months to 1 year of age.
The adult-onset form of the disease (Schindler Disease, Type II) was first described in a Japanese woman who was the daughter of closely related parents (first-cousin consanguinity). In Schindler Disease, Type II, symptoms may not appear until the second or third decade of life.
A small number of additional cases of Schindler Disease, Types I and II have since been reported in the medical literature. It is believed that both forms of Schindler Disease affect males and females in equal numbers.
Symptoms of the following disorders can be similar to those of Schindler Disease. Comparisons may be useful for a differential diagnosis:
Seitelberger Disease (Infantile Neuroaxonal Dystrophy) is a rare inherited disorder characterized by the progressive degeneration of the central nervous system. Children with Seitelberger Disease develop normally until approximately 6 months to 2 years of age, at which time their psychomotor development slows and they may then start to lose previously acquired skills. Neurological symptoms then begin to appear including involuntary, rapid eye movements (nystagmus) and crossing of the eyes (strabismus); visual impairment due to the gradual deterioration of the nerves of the eyes (optic atrophy); severely diminished muscle tone (hypotonia) and muscle weakness; sudden involuntary muscle spasms (spasticity); and/or hearing impairment. Later in the course of the disease, affected children may exhibit increasing impairment of intellectual function (dementia) and loss of function of the two hemispheres of the brain (decerebration). Seitelberger Disease is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "Seitelberger" as your search term in the Rare Disease Database.)
Hallervorden-Spatz Disease (Late Infantile Neuroaxonal Dystrophy) is a rare neurological movement disorder characterized by the progressive degeneration of the nervous system and abnormal accumulation of iron pigment in certain areas of the brain. Symptoms, which can vary greatly from case to case, typically develop during childhood; however, they occasionally begin during adulthood. The most common neuromuscular symptoms may include slow writhing and distorting muscle contractions (dystonia), uncontrolled tightening of muscles (rigidity), sudden involuntary muscle spasms (spasticity), and/or the inability to coordinate movement (ataxia). Neurological symptoms may include progressive confusion, disorientation, and/or deterioration of intellectual abilities (dementia). Other symptoms of Hallervorden-Spatz Disease that occur less frequently may include difficulty speaking (dysphasia), mental retardation, and/or visual impairment due to the gradual deterioration of the nerves of the eyes (optic atrophy). Hallervorden-Spatz Disease is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "Hallervorden-Spatz" as your search term in the Rare Disease Database.)
Fabry Disease (also known as Angiokeratoma Corporis Diffusum) is a rare inherited disorder of lipid metabolism characterized by a deficiency of the enzyme alpha-galactosidase A. Low levels or inactivity of this enzyme lead to the abnormal accumulation of a substance consisting of fatty material and carbohydrates (i.e., glycolipids such as glycosphingolipid) in various organs of the body, particularly blood vessels and the eyes. Symptoms of Fabry Disease may include the appearance of clusters of wart-like discolorations on the skin (angiokeratomas), as seen in Schindler Disease, Type II; abdominal pain; and/or visual impairment. Later in the course of the disease, kidney failure, heart problems, and/or neurological symptoms may cause serious complications. Fabry Disease, which is inherited as an X-linked recessive genetic trait, primarily affects males. A milder form of the disease has been identified in females. (For more information on this disorder, choose "Fabry" as your search term in the Rare Disease Database.)
Schindler Disease may be diagnosed before birth (prenatally) by specialized tests such as amniocentesis and/or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During chorionic villus sampling, tissue samples are removed from a portion of the placenta. Studies performed on these fluid or tissue samples can reveal that there is reduced activity of the alpha-N- acetylgalactosaminidase enzyme (alpha-NAGA).
Schindler Disease may be diagnosed after birth (postnatally) by a thorough clinical evaluation, detailed patient history, and a variety of specialized tests. In children with Schindler Disease, Type I, examination of samples of tissue (biopsy) from the rectum's muscular layer (myenteric plexus) may reveal lysosomal accumulation in the extensions of nerve cells (axons). Advanced imaging techniques, such as magnetic resonance imaging (MRI) and computer-assisted tomography (CAT) of the brain may reveal degeneration of the outer layer of the brain (cortex), the cerebellum, and the brain stem. In both forms of the disease, urinary analysis (e.g., oligosaccharide and glycopeptide profiles) may reveal increased levels of certain complex compounds in the urine (e.g., oligosacchariduria and glycopeptiduria). Reduced activity of the alpha-NAGA enzyme may be confirmed by conducting enzyme tests (assays) on cultured white blood cells (leukocytes), blood plasma, and/or certain skin cells (fibroblasts) from affected individuals.
Treatment of both forms of Schindler Disease is symptomatic and supportive. In the infantile-onset form of the disease, physical therapy may be beneficial. Antibiotic therapy may be given to treat the respiratory tract infections that may often occur in affected children.
Laser surgery may be used to remove the skin lesions (angiokeratomas) associated with the adult-onset form of Schindler Disease. Affected adults who are diagnosed with angina pectoris should receive medical counseling concerning appropriate medical intervention, proper behavior modification to lower risk of future episodes, and potential drug therapies.
Genetic counseling is advised for families who have a child with Schindler Disease, Type I. Genetic counseling will also be of benefit to individuals with Schindler Disease, Type II and their families.
Research on inborn errors of metabolism such as Schindler Disease is ongoing. Scientists are studying the causes of these disorders and trying to design enzyme replacement therapies that may return missing and/or deficient enzymes to the body.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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