Inclusion-Cell (I-Cell) Disease (Mucolipidosis Type II)

Updated: Aug 08, 2017
  • Author: Karl S Roth, MD; Chief Editor: Luis O Rohena, MD, FAAP, FACMG  more...
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Overview

Background

I-cell disease is an inherited lysosomal storage disorder. [1] It first was described in 1967 by Leroy and DeMars when they reported a patient with clinical and radiographic features similar to those of Hurler syndrome (mucopolysaccharidoses 1H [MPS 1H]) but with an earlier onset of symptoms and no evidence of mucopolysacchariduria. [2] 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. [3] See the image below.

Profile view of 3-year-old with I-cell disease. Gr Profile view of 3-year-old with I-cell disease. Growth ceased more than one year earlier. Note small orbits, proptotic eyes, full and prominent mouth caused by gingival hypertrophy, short and broad hands, stiffening of small hand joints, prominent abdomen with umbilical hernia, and limited extension of the hips and knees.
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Pathophysiology

Early enzymologic studies showed that cultured fibroblasts from patients with I-cell disease were deficient in numerous 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. I-cell disease fibroblasts were subsequently discovered to be 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 later identified 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. [4]

As in many of the lysosomal storage diseases, the functional deficiency of lysosomal enzymes results in abnormal cell architecture. In 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. [5] Muscular tissue, including cardiac muscle, is relatively spared; however, significant vacuolization is present in the art’s connective tissue cells of the heart valves. This leads to thickening of the valves, which results in clinically significant valvular disease. Other sites of abnormal cell vacuolization include the renal glomerular podocytes and in the fibroblasts of the liver’s periportal spaces. 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.

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Epidemiology

Frequency

International

I-cell disease is a rare disorder that has no ethnic predilection. Very little population data are available, but a recent study from the Netherlands reported a frequency of approximately 1 in 640,000 live births. [6]

Mortality/Morbidity

Death from pneumonia or congestive heart failure usually occurs within the first decade of life.

Race

I-cell disease has no racial predilection.

Sex

I-cell disease is inherited as an autosomal-recessive trait. Both sexes are equally affected.

Age

Clinical manifestations can be present at birth or may present in the first few months of life.

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