I-Cell Disease (Mucolipidosis Type II)

Synonyms and related keywords: I-cell disease, mucolipidosis type II, mucolipidosis II, ML2, ML II, N-acetylglucosaminyl-1-phosphotransferase deficiency, GNPTA deficiency, inclusion cell disease, I-cell disease, I cell disease. INTRODUCTION I-cell disease is an inherited lysosomal storage disorder. It first was described in 1967 by Jules Leroy, a Belgian paediatrician and geneticist, for the inclusions he saw in effected individuals cells under a microscope. One unique feature of this disease was the presence of phase-dense intracytoplasmic inclusions in the fibroblasts of patients. These cells were termed inclusion cells, or I-cells; thus, the disease was designated I-cell disease. Spranger and Wiedermann subsequently classified this disease as mucolipidosis type II (ML II) because it had clinical characteristics that included mucopolysaccharidoses and sphingolipidoses What is I-Cell disease? I-Cell disease is also known as Mucolipidosis II (ML II). It is an inherited disorder that is part of a larger group of disorders called Lysosomal Storage Diseases. Lysosomes are membrane-bound compartments found in the cells of the body. These compartments contain enzymes, which are responsible for the breakdown of many large molecules. These molecules are continuously made and broken down in our bodies and this process is necessary for appropriate mental and physical development. Each enzyme in the lysosome is responsible for a certain step in the breakdown of the molecule. Many Lysosomal Storage Diseases are caused by the absence of one specific enzyme that leads to the build-up of molecules in the lysosome. However, in I-Cell disease, many lysosome enzymes are missing. This is because the enzymes are lacking a signal that is necessary for them to get inside the lysosome. Instead of getting into the lysosome and breaking down the molecules found there, the enzymes are found outside the lysosome. This leads to the build-up of molecules inside the lysosome. You may hear this disorder called a targeting defect. This refers to the fact that the enzymes lack the signal that targets them to the lysosome in the cell; thus they end up in a place where they are unable to do their work. Not every enzyme within the lysosome is missing, however. It has been shown that some enzymes are able to enter through a different pathway that doesnt require the signal on the enzymes.
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Causes: * I-cell disease is an autosomal recessive disorder caused by a deficiency of the enzyme UDP-Nacetylglucosamine:N-acetylglucosaminyl-1- phosphotransferase. Deficiency of this phosphotransferase prevents the addition of the mannose-6-phosphate recognition marker as the lysosomal enzymes are modified in the Golgi apparatus before being transported to the lysosome; therefore, lysosomal enzymes cannot be endocytosed into the lysosome for normal processing and use. * The UDP-N-acetylglucosamine:N-acetylglucosaminyl-1- phosphotransferase enzyme is the product of the GNPTA gene, which has been mapped to chromosome band 4q21-q23. A variety of mutations in this gene have been reported in patients with I-cell disease. What are the characteristic of ML II? Most individuals have definite features of ML II, the more severe disease, or definite features of ML III (Pseudo-Hurler polydystrophy), the milder disease.Typically, by the age of 6 months, failure to thrive and developmental delays are obvious symptoms of this disorder. Some physical signs, such as abnormal skeletal development they have dysostosis multiplex (abnormal bone formation in multiple bones of the body). Skeletal problems are typically severe and include kyphosis/scoliosis (curvature of the spine), coarse facial features include a high narrow forehead, puffy eyelids, flat nasal bridge, macroglossia (large tongue), and other musculoskeletal problems include hernias, hip dislocations or lumbar gibbus deformity and joint contractures and restriction, and skin changes may be present at birth. Children with ML II usually have enlargement of certain organs, such as the liver (hepatomegaly) or spleen (splenomegaly), and sometimes even the heart valves. The heart muscle may enlarge but not pump efficiently. Affected children often have stiff claw-shaped hands and fail to grow and develop in the first months of life. Delays in the development of their motor skills are usually more pronounced than delays in their cognitive (mental processing) skills. Children with ML II eventually develop a clouding on the cornea of their eyes and, because of their lack of growth, develop shorttrunk dwarfism (underdeveloped trunk). These young patients are often plagued by recurrent respiratory tract infections, including pneumonia, otitis media (middle ear infections) hearing loss/deafness, bronchitis and carpal tunnel syndrome. Children with ML II generally die before their seventh year of life, often as a result of congestive heart failure or recurrent respiratory tract infections. A specific dental problem associated with ML II is gingival hyperplasia (prominent gums) as well as late and poorly formed teeth. Unfortunately, due to the severity of progression of ML II, individuals with this disorder typically do not live past the first decade. Many pass away within the first 5-6 years of life.

Hernia

Hepatosplenomegaly

Corneal Clouding

How is I-Cell disease (ML II) inherited? ML II 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 ML II, they must inherit changes in both copies of GNPTAB. This is known as autosomal recessive inheritance. For a couple to have a child with ML II, 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 ML II. If both parents are both carriers, they have a 1 in 4 (25%) chance of having a child with ML II in each pregnancy. What testing is available to determine if my child has I-Cell disease (ML II)? Testing for lysosomal storage diseases is typically performed in conjunction with a genetics evaluation. A genetics team takes into account the medical history and clinical features of a patient to determine what type of genetic testing is appropriate. For the diagnosis of ML II, 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 defieicient in ML II and ML III. 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 Dr. DNA analysis of GNPTAB, the gene involved in ML II and ML III, confirms the diagnosis when two disease causing mutations are detected. For families who have had a child diagnosed with ML II, 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. What type of treatment is available for I-Cell Disease (ML II)? Individuals with ML II should 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 ML II 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. Nutrition supplements, particularly iron and vitamin B12, are often recommended for individuals with I-Cell disease. Physical therapy to improve motor delays and speech therapy to improve language acquisition are treatment options. Surgery can remove the thin layer of corneal clouding to temporarily improve the complication. It is possible that bone marrow transplant may be helpful in delaying or correcting the neurological deterioration that occurs with I-Cell disease.