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I-cell disease (mucolipidosis II) is a rare inherited metabolic disorder characterized by coarse facial features, skeletal abnormalities and mental retardation. The symptoms of I-cell disease are similar to but more severe than those of Hurler syndrome. The symptoms associated with this disorder typically become obvious during infancy and may include multiple abnormalities of the skull and face and growth delays.
This disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates. Multiple enzyme deficiencies associated with I-cell disease lead to the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body.
I-cell disease is caused by a mutation in the GNPTA gene that leads to a deficiency in the enzyme UDP-N-acetylglucoseamine-1-phosphotransferase. I-cell disease is inherited as an autosomal recessive genetic trait.
Some of the physical features associated with I-cell disease (ML II) may be apparent at birth (congenital), whereas other features may become apparent between the ages of 6 to 10 months. Craniofacial abnormalities may include coarse facial features, a depressed nasal bridge, a long and narrow head, an unusually high and narrow forehead, and/or skin folds on the inner corners of the eyes (epicanthal folds). The skin may appear to be unusually thick and tight in certain areas of the body (e.g., face, arms, and legs). The corneas of the eyes may appear cloudy.
Infants with I-cell disease may also have skeletal malformations including abnormal curvature of the spine from side to side (scoliosis) and/or from front to back (kyphosis), an unusually short neck, dislocation of the hip at birth (congenital), swelling or enlargement of the top portion of the spine (lumbar gibbus), and/or limited mobility of the shoulders. Skeletal abnormalities may also include misaligned bones in the spinal column (vertebral breaking and wedging), wider than normal spaces between ribs, and/or unusual positioning of the fingers (metacarpal pointing). On occasion, infants with I-cell disease may have fingers that are fused together (split hand deformity or ectrodactyly). (For more information on this disorder, choose "split hand" as your search term in the Rare Disease Database.)
Children with I-cell disease typically have severe delays in the development of gross and fine motor skills, hearing loss, lack of muscle tone (hypotonia), and varying degrees of mental retardation. Growth delays usually result in short stature (dwarfism). In some children with this disorder, a portion of the intestines may protrude through an abnormal opening in the abdominal wall in the area of the navel (umbilical hernia) and/or the groin (inguinal hernia). Abnormal enlargement of the liver (hepatomegaly), is often observed in association with a protruding abdomen in infants with I-cell disease.
Other symptoms of I-cell disease may include frequent respiratory infections, constipation and/or diarrhea, overgrowth of gum tissue (gingival hyperplasia), and/or joint stiffness or joints that are "frozen" in place (contractures). Some children with I-cell disease may have abnormalities of the heart such as defects of the heart valves, enlargement of the heart (cardiomegaly), congestive heart failure and/or heart murmurs.
Individuals with I-cell disease often die in childhood, although some patients survive into their teens.
I-cell disease (Mucolipidosis II) is caused by a mutation in the GNPTA gene that is located on the long arm of chromosome 4 (4q21-q23).
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 4q21" refers to band 21 on the long arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The GNPTA gene mutation leads to a deficiency in the enzyme UDP-N-acetylglucoseamine-1-phosphotransferase that is involved in the synthesis of mannose-6-phosphate, resulting in decreased intracellular levels of lysosomal enzymes and increased levels in blood serum and body fluid. The symptoms of I-cell disease develop due to deficiencies of a variety of lysosomal enzymes in the cells of the body causing an abnormal accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body.
I-cell disease is inherited as an autosomal recessive genetic 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.
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% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% 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%. The risk is the same for males and females.
I-Cell Disease is a rare disorder that affects males and females in equal numbers. Siblings of affected infants have a 1 in 4 chance of being affected by this disorder. Approximately 30 cases of I-Cell Disease have been reported in the medical literature. This disease appears to be more common in Japan than in other countries.
Symptoms of the following disorders can be similar to those I-cell disease. Comparisons may be useful for a differential diagnosis:
The mucopolysaccharidoses are a group of inherited lysosomal storage disorders characterized by the accumulation of certain complex carbohydrates (mucopolysaccharides) in many tissues and organs of the body (e.g., eyes, skeleton, arteries, joints, ears, skin, and/or teeth). In general, the symptoms of these disorders are progressive and vary greatly depending on the specific enzyme deficiencies. Symptoms of the mucopolysaccharidoses, which generally affect many systems of the body, may include abnormal enlargement of different organs (e.g., liver and spleen), multiple bone deformities (dysostosis multiplex) and/or unusual facial features. (For more information on these disorders, choose "mucopolysaccharidoses" as your search term in the Rare Disease Database.)
Hurler syndrome (mucopolysaccharidosis type I [MPS I]) is a rare inherited metabolic disorder that appears in 3 forms of varying severity. Infants with Hurler syndrome (MPS 1-H) usually appear normal at birth, although hernias may be present. Onset of symptoms occurs between the ages of 6 months and 2 years and may include coarse facial features, a prominent forehead, an unusually large tongue (macroglossia), misaligned teeth, and/or clouding of the corneas of the eyes. Repeated upper respiratory infections, noisy breathing, and a persistent nasal discharge may also be present. Other symptoms may include growth delays, mental retardation, joint stiffness, deafness, and/or heart disease. Hurler syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "Hurler" as your search term in the Rare Disease Database.)
Sialidosis (mucolipidosis I, type I and II) is a very rare inherited metabolic disorder characterized by a deficiency of the enzyme alpha-neuraminidase. This disorder belongs to a group of diseases known as lysosomal storage diseases. The symptoms of sialidosis type I, which typically begin during the 2nd decade of life, may include sudden involuntary muscle contractions (myoclonus), other neurological symptoms, and/or the appearance of red spots (cherry-red macules) in the eyes. The symptoms associated with sialidosis yype II may begin during infancy or later. It is characterized by the same visual abnormalities as sialidosis type I as well as other findings such as mildly coarse facial features, skeletal changes, and/or mild mental retardation. Sialidosis is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "sialidosis" as your search term in the Rare Disease Database.)
Mucolipidosis III (pseudo-Hurler polydystrophy [ML III]) is a rare inherited metabolic disorder characterized by the accumulation of certain complex carbohydrates (mucopolysaccharides) and fatty substances (mucolipids) in various tissues of the body. The symptoms of this disorder are less severe than those of I-cell disease (ML II) and may include progressive joint stiffness, curvature of the spine (scoliosis), and/or skeletal deformities of the hands (e.g., claw-hands). Growth delays accompanied by deterioration of the hip joints typically develop in children with mucolipidosis III. Other symptoms may include clouding of the corneas of the eyes, mild to moderate coarseness of facial features, mild mental retardation, easy fatigability, and/or heart disease (e.g., congestive heart failure). Mucolipidosis III is inherited as an autosomal recessive trait. For more information on this disorder, choose "Pseudo-Hurler" as your search term in the Rare Disease Database.)
Galactosialidosis is a rare inherited metabolic disorder characterized by deficiencies of the enzymes neuraminidase and beta-galactosidase. Symptoms may include severe swelling of many soft tissues of the body and abdominal swelling due to the development of fluid-filled sacs (ascites). Cherry red spots in the eyes, skeletal abnormalities, abnormal enlargement of many organs of the body (visceromegaly), and/or mental retardation may also occur. Growth delays, joint stiffness, and/or coarse facial features are also characteristic of this disorder. Galactosialidosis is inherited as an autosomal recessive genetic trait.
Sly syndrome (mucopolysaccharidosis VII), is an extremely rare inherited metabolic disorder characterized by a deficiency of the lysosomal enzyme known as beta-glucuronidase. This deficiency leads to the abnormal accumulation of certain complex carbohydrates (mucopolysaccharides) in many tissues and organs of the body. The symptoms of Sly Syndrome are similar to those of Hurler syndrome (MPS I) and the other mucopolysaccharidoses. Symptoms may include mental retardation, short stature with an unusually short trunk, and/or abnormalities of the intestines, corneas of the eyes, and/or the skeletal system. Sly syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "Sly" as your search term in the Rare Disease Database.)
Hunter syndrome (mucopolysaccharidosis II), is a rare inborn error of metabolism characterized by deficiency of an enzyme known as iduronate sulfatase. Initial symptoms and findings associated with Hunter syndrome usually become apparent between two to four years of age. Such abnormalities may include progressive growth delays, resulting in short stature; joint stiffness, with associated restriction of movements; and coarsening of facial features, including thickening of the lips, tongue, and nostrils. Affected children may also have an abnormally large head (macrocephaly), a short neck and broad chest, delayed tooth eruption, progressive hearing loss, and enlargement of the liver and spleen (hepatosplenomegaly). Hunter syndrome is inherited as an X-linked recessive genetic trait. (For more information on this disorder, choose "Hunter" as your search term in the Rare Disease Database.)
Maroteaux-Lamy syndrome (mucopolysaccharidosis VI) occurs in three types: a classic severe type, an intermediate type, and a mild type. The syndrome is characterized by a deficiency in the enzyme arylsulfatase B (also called N- acetylgalactosamine-4-sulfatase), which leads to an excess of dermatan sulfate in the urine. In general, growth retardation occurs from two to three years of age, with coarsening of facial features and abnormalities in the bones of hands and spine. Joint stiffness also occurs. The intellect is usually normal. Maroteaux-Lamy syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "Maroteaux" as your search term in the Rare Disease Database.)
I-cell disease can be diagnosed before birth (prenatally) utilizing amniocentesis or chorionic villus sampling. Amniocentesis is a procedure in which a small portion of the fluid that surrounds the fetus (amniotic fluid) is removed and cells from the fluid are then tested in the laboratory. Chorionic villus sampling (CVS) is a prenatal diagnostic procedure in which a small sample of tissue is removed from the placenta. Abnormally low levels of UDP-N-acetylglucoseamine-1-phosphotransferase enzyme activity in amniotic fluid cells or chorionic villi suggest the diagnosis of I-cell disease.
The diagnosis of I-cell disease may be confirmed in an infant by a thorough clinical evaluation, patient history, and specialized laboratory testing. UDP-N-acetylglucoseamine-1-phosphotransferase enzyme activity can be measured in white blood cells or in cultured fibroblasts. Lysosomal enzymes are typically elevated in the blood serum and decreased in cultured fibroblasts.
The treatment of I-cell disease is symptomatic and supportive. Antibiotics are often prescribed for respiratory infections and yearly flu shots are important. Physical therapy is encouraged to maintain joint function and mobility as long as possible. Total hip replacement has been most effective when performed after puberty. Other orthopedic complications may be managed as they arise. Hearing aids should be considered. Sleep studies can determine the degree of obstructive sleep apnea and the need for treatment. In some cases, heart problems may be treated surgically.
Genetic counseling is advised for families who have a child with this disorder.
Experimental therapies are aimed at treating I-cell disease as early as possible. Bone marrow replacement transplantation has been attempted for the treatment of this disorder but the benefit was limited.
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FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 252500; Last Update: 5/30/03.
Report last updated: 2007/09/17 00:00:00 GMT+0