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eMedicine Journal
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Pediatrics
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Genetics And Metabolic Disease
I-Cell Disease (Mucolipidosis Type II) Synonyms, Key Words, and Related Terms: 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 |
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 | AUTHOR INFORMATION | Section 1 of 11    |
Authored by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine
Coauthored by Grace Y Lee, MD, Assistant Professor of Pediatrics, Department of Pediatrics, Le Bonheur Children's Medical Center; William B Rizzo, MD, Professor, Department of Pediatrics, University of Nebraska Medical Center; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine
Karl S Roth, MD, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research
Edited by Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
| Author's Email: | Karl S Roth, MD |  |
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| Editor's Email: | Edward Kaye, MD |
eMedicine Journal, June 8 2006, VOLUME 7,
Number 6
| INTRODUCTION | Section 2 of 11  |
Background: I-cell disease is an inherited lysosomal storage disorder. It first was described in 1967 by Leroy and DeMars when they reported a patient with clinical and radiographic features similar to Hurler syndrome (mucopolysaccharidoses 1H [MPS 1H]) but with an earlier onset of symptoms and no evidence of mucopolysacchariduria. 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 of the mucopolysaccharidoses and the sphingolipidoses.
Pathophysiology: Early enzymologic studies showed that cultured fibroblasts from patients with I-cell disease were deficient in a number of lysosomal enzymes. Furthermore, these enzymes were found to be present in excess in tissue culture media and in extracellular fluids, such as serum and urine. It was observed subsequently that I-cell disease fibroblasts were able to internalize and use lysosomal enzymes produced by normal cells, whereas normal or other lysosomal disease fibroblasts were incapable of internalizing lysosomal enzymes secreted by the I-cell disease fibroblasts.
The above findings suggested that a biochemical marker signal may be required for proper trafficking of the lysosomal enzyme, from the site of its production in the endoplasmic reticulum to the lysosome itself. This marker was identified later as a mannose-6-phosphate residue on the lysosomal enzyme that interacts with a specific receptor on the lysosomal membrane, which then triggers endocytosis into the lysosome. The biochemical defect in I-cell disease involves the first step in the addition of the mannose-6-phosphate moiety. The enzyme that catalyzes this reaction is uridine diphospho (UDP)-N-acetylglucosamine:N-acetylglucosaminyl-1-phosphotransferase.
Like many of the lysosomal storage diseases, the functional deficiency of lysosomal enzymes results in abnormal cell architecture. In the case of I-cell disease, the characteristic finding is abnormal vacuolization or inclusions that appear in the cytoplasm. These are observed in cells of mesenchymal origin, especially fibroblasts. The most severely affected system is the skeletal system, in which trabeculation of bone and cartilage structures are abnormal. Muscular tissue, including cardiac muscle, is relatively spared; however, significant vacuolization is present in the connective tissue cells that are in the heart valves. This leads to thickening of the valves, which results in clinically significant valvular disease. Other sites where abnormal cell vacuolization occurs include the renal glomerular podocytes and in the fibroblasts of the periportal spaces in the liver. Hepatocytes and Kupffer cells are not affected.
Interestingly, although psychomotor retardation is a major manifestation of this disease, the pathologic findings in CNS tissue are not as striking as in other organs. Among reported findings is the presence of lamellar bodies in spinal ganglia neurons and in anterior horn cells; however, these findings are not consistent in all patients. Vacuolization of peripheral Schwann cells is minimal but not enough to impair normal myelination.
Frequency:
Mortality/Morbidity: Death from pneumonia or congestive heart failure usually occurs within the first decade of life.
Race: No predilection exists.
Sex: I-cell disease is inherited as an autosomal recessive trait. Both sexes are affected equally.
Age: Clinical manifestations can be present at birth or may present in the first few months of life.
| CLINICAL | Section 3 of 11 |
History: Developmental delay and growth failure are common presentations of I-cell disease. Psychomotor deterioration is rapid and progressive. Some physical signs, such as hip dislocations, inguinal hernias, hepatomegaly, joint limitation, and skin changes, may be present at birth. Coarse facial features and skeletal abnormalities become more conspicuous with time. The full clinical picture usually is evident by the first year of life.
Physical:
Causes:
| DIFFERENTIALS | Section 4 of 11 |
GM1 Gangliosidosis
Mucopolysaccharidosis Type IH
Sialidosis (Mucolipidosis I)
| WORKUP | Section 5 of 11 |
Lab Studies:
Imaging Studies:
| TREATMENT | Section 6 of 11 |
Medical Care:
Consultations:
| MEDICATION | Section 7 of 11 |
Drug therapy currently does not exist to correct the lysosomal storage disorder. See Treatment.
| FOLLOW-UP | Section 8 of 11 |
Complications:
Prognosis:
Patient Education:
| MISCELLANEOUS | Section 9 of 11 |
Special Concerns:
| TEST QUESTIONS | Section 10 of 11 |
CME Question 1: Which of the following features does not distinguish I-cell disease from Hurler syndrome (mucopolysaccharidoses 1H [MPS 1H])?
A: Earlier onset and presentation
B: Gingival hypertrophy
C: Deficiency of lysosomal alpha-L-iduronidase in cultured fibroblasts
D: Absence of mucopolysaccharides in the urine
E: Presence of phase-dense inclusions on electron microscopy in cultured fibroblasts
The correct answer is C: I-cell disease has many clinical and radiographic features that are similar to Hurler syndrome (MPS 1H). These include coarse facial features, dysostosis multiplex, joint stiffness, and psychomotor retardation. Distinguishing features include earlier onset of symptoms and the absence of mucopolysacchariduria. The facial features are similar in both diseases; however, patients with I-cell disease have prominent gingival hyperplasia. A unique histologic finding in I-cell disease is the presence of phase-dense inclusions in fibroblasts under electron microscopy. I-cell disease is caused by the deficiency of uridine diphospho (UDP)-N-acetylglucosamine:N-acetylglucosaminyl-1-phosphotransferase. This enzyme is responsible for proper transport of lysosomal enzymes from their site of production in the endoplasmic reticulum to the lysosome itself. Therefore, lysosomal hydrolases are produced in normal amounts but are not transported to their site of action in the cell. This results in the deficiencyof multiple lysosomal enzymes in cultured fibroblasts, including a-L-iduronidase, the enzyme deficient in Hurler syndrome.
CME Question 2: Regarding the genetics of I-cell disease, which of the following is incorrect?
A: I-cell disease is a rare inherited autosomal recessive disorder.
B: A couple with a child with I-cell disease has a 25% chance of having another child with the same disorder.
C: Patients with I-cell disease may have no family history of the disorder.
D: Each parent of a child with I-cell disease has a 25% chance of carrying the gene responsible for this disorder.
E: A healthy sibling of a child with I-cell disease has a two-thirds chance of being a carrier for the gene responsible for this disorder.
The correct answer is D: I-cell disease is a rare inherited inborn error of metabolism. It is inherited as an autosomal recessive trait. Therefore, each parent of a child with I-cell disease is a carrier of this disease. As carriers, the parents have a 25% chance of having another child affected with this disease. Healthy siblings of a child with I-cell disease have a two-thirds chance of being a carrier of this disease and a one-third chance of not carrying the disease gene. No previous family history of I-cell disease may exist, unless a high degree of consanguinity is present, which occurs in some cultures.
Pearl Question 1 (T/F): I-cell disease is caused by a deficiency of iduronate sulfatase.
The correct answer is False: The primary enzyme deficiency in I-cell disease is uridine diphospho (UDP)-N-acetylglucosamine:N-acetylglucosaminyl-1-phosphotransferase. This enzyme is involved in the proper transport of lysosomal enzymes from their site of production (endoplasmic reticulum) to their site of action (lysosome). Therefore, a defect of this enzyme results in a secondary deficiency of multiple lysosomal enzymes, including iduronate sulfatase.
Pearl Question 2 (T/F): I-cell disease should be considered in an infant with coarse facial features and psychomotor retardation.
The correct answer is True: I-cell disease should be in the differential diagnosis of any child with coarse facial features and developmental delay, especially if the urinary mucopolysaccharide levels are normal.
Pearl Question 3 (T/F): The presence of phase-dense intracytoplasmic inclusions in fibroblasts is diagnostic of I-cell disease.
The correct answer is False: Although phase-dense intracytoplasmic inclusions are suggestive of I-cell disease, the diagnosis must be made biochemically by measuring the activity of uridine diphospho (UDP)-N-acetylglucosamine: N-acetylglucosaminyl-1-phosphotransferase in cultured fibroblasts. Alternatively, various lysosomal enzyme activities can be measured in serum and in cultured fibroblasts. These enzymes are deficient in cultured fibroblasts but are 10-20 times normal in serum.
Pearl Question 4 (T/F): Prenatal diagnosis is available for I-cell disease.
The correct answer is True: Prenatal diagnosis of I-cell disease can by made by the measurement of uridine diphospho (UDP)-N-acetylglucosamine: N-acetylglucosaminyl-1-phosphotransferase activity in chorionic villi or cultured amniocytes. Parents of children who have been diagnosed with I-cell disease should be informed of the 25% recurrence risk and the availability of prenatal diagnosis for future pregnancies.
| BIBLIOGRAPHY | Section 11 of 11 |
| NOTE: |
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