I-cell disease

I-cell disease: Description, Causes and Risk Factors:I-cell diseaseI-cell disease is an autosomal recessive disorder that results as a consequence of defective targeting of lysosomal hydrolases to the lysosomes. The disorder is so called because fibroblasts from afflicted patients contain numerous phase-dense inclusion bodies in the cytosol. I-cell disease was first described in 1967 and was originally thought to be a variant of Hurler syndrome. However, I-cell disease patients present with symptoms earlier than do Hurler syndrome patients and in addition, I-cell patients do not exhibit mucopolysacchariduria. The inclusion bodies seen in I-cell disease are also observed in another condition called pseudo-Hurler polydystrophy that presents later and with milder symptoms compared to I-cell disease. The use of the term mucolipidosis for these related disorders is to denote diseases whose combined clinical manifestations are common to both the mucopolysaccharidoses and the sphingolipidoses.The targeting of lysosomal enzymes to lysosomes is mediated by receptors that bind mannose 6-phosphate recognition markers on the enzymes. The recognition marker is synthesized in a two-step reaction in the Golgi complex. The enzyme that catalyzes the first step in this process is UDP-N-acetylglucosamine:lysosomal-enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase). GlcNAc-phosphotransferase is an ?2?2?2 hexameric complex whose protein subunits are encoded by two genes. The phosphotransferase is a low abundance membrane-associated enzyme possessing two activities. One activity is responsible for the recognition of enzymes that need to be targeted to the lysosomal compartment and the other activity is the catalytic component. The ?- and ?-subunits of the phosphotransferase are encoded by the GNPTAB gene and the ?-subunits are encoded by the GNPTG gene. The GNPTAB gene is located on chromosome 12q23.3 and encodes a 1256 amino acid precursor protein. The protein is proteolytically processed generating a 928 amino acid fragment from the N-terminus (the ?-subunit) and a 328 amino acid fragment from the C-terminus (the ?-subunit). Both I-cell disease and pseudo-Hurler polydystrophy result from defects in the GNPTAB gene. A variant disorder called mucolipidosis III ? (ML-III?) results from defects in the GNPTG gene.I-cell disease is not contagious and cannot be “caught.” It is a genetic condition, which means that it is caused by a change in the instruction that direct the way our bodies grow and develop. These instructions are called genes. People typically have two copies of all their genes, including the gene for ML II (called GNPTAB). One copy is inherited from the mother in the egg, and one from the father in the sperm.Only when there are two changes (or mutations) in the gene code is there a possibility that the disease will occur. For a person to have i-cell disease, they must inherit changes in both copies of GNPTAB. This is known as autosomal recessive inheritance.For a couple to have a child with I-cell disease, both parents must have at least one changed copy of the gene which they pass on to their child. Parents do not have control over which genes they pass on to their children.If a person has one changed copy of the gene and one normal copy of the gene they are said to be a “carrier” of the condition and will not show any symptoms of I-cell disease. If both parents are both carriers, they have a 1 in 4 (25%) chance of having a child with I-cell disease in each pregnancy.Symptoms:I-cell disease is characterized by severe psychomotor retardation that rapidly progresses leading to death between 5 and 8 years of age. Although there are similar signs and symptoms, the earlier onset of symptoms and the lack of mucopolysacchariduria distinguish I-cell disease from Hurler syndrome. I-cell patients exhibit coarse facial features, craniofacial abnormalities, and severe skeletal abnormalities. These skeletal abnormalities include kyphoscoliosis (an abnormal curvature of the spine in both the coronal and sagittal planes), widening of the ribs, lumbar gibbus deformity (refers to a hump or swelling or enlargement on one side of a body surface), anterior beaking and wedging of the vertebral bodies, and proximal pointing of the metacarpals. A clinically unique feature seen in I-cell disease patients that allows easy distinction from Hurler syndrome is a striking gingival hyperplasia. Additional clinical symptoms of I-cell disease include hepatomegaly, cardiomegaly, umbilical hernias, and recurrent upper respiratory infections. The disease progresses rapidly with developmental delay and failure to thrive. Psychomotor retardation is evident in almost all patients by 6 months of age.Diagnosis:For the diagnosis of I-cell disease, a blood test will show increased activity of lysosomal enzymes in the serum. A urine spot screen that screens for other lysosomal storage disease such as oligosaccharide and muccopolysaccharide disorders may not be as helpful in detecting Mucolipidosis disorders. Another test that can be performed is to have a skin biopsy and measure activity of N-acetylglucosamine-1-phototransferase, the targeting enzyme that is deficient in I-cell disease. The skin sample will show decreased activity of this enzyme. This test is only available in a few research labs, you will need to discuss this test with your PCP.For families who have had a child diagnosed with I-cell disease, prenatal diagnosis may be available in future pregnancies by looking at enzyme activity, or preferably, by gene mutation analysis, through Chorionic Villus Sampling (CVS) or amniocentesis. Talk to your doctor about prenatal diagnosis techniques that might be available in your area.Treatment:Individuals with I-cell disease have routine follow-up with Genetics, Orthopedics, Cardiology, Ophthalmology, Pulmonary, Physical Therapy, and ENT as needed. Dentistry follow-up is also very important. Currently, there is no cure to stop the progression of symptoms of I-cell disease and treatment is aimed at addressing the individual problems as they arise. Some patients have benefited from treatment with bisphosphonate drugs. These drugs are used in other disease states to increase bone strength.For some lysosomal storage diseases, bone marrow transplant has been trialled as an experimental therapy. Bone marrow transplantation does not appear to alter the course of the disease in individuals with I-cell disease.NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.


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