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

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]  

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.

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 heart’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.

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. A report suggests that there is accumulation of inclusion bodies in B-cells of individuals with I-cell disease, which may imply impairment of the immune system.[7]

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.

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 is usually evident by the first year of life.

Growth failure and failure to thrive are rapidly progressive. Birth weight and length may be decreased. Linear growth decelerates during the first year of life and ceases by age 2 years. Head circumference is usually preserved.

Developmental delay is severe and is often the presenting symptom. Infants smile and follow and grasp objects but are unable to roll over or support their weight with their legs. Generalized hypotonia and poor head control are observed. Motor delay is usually more severe than cognitive delay. The severity of developmental delay widely varies.

Coarse facial features: The characteristic facies is similar to that observed in Hurler syndrome. Gingival hypertrophy is a distinguishing feature.

Radiographic findings are as follows[8, 9] :

• Findings are similar to those observed in Hurler syndrome, a condition with which I-cell disease may be confused.
• In early infancy, periosteal new-bone formation leads to cloaking of the long bones.
• The tubular bones of the upper extremities are short and widened, and the phalanges are bullet-shaped.
• Anterior beaking and wedging of the vertebrae occur. This results in a lumbar gibbus deformity and kyphoscoliosis.
• Widening of the ribs is observed.

Frequent upper respiratory tract infections: These patients experience recurrent bouts of pneumonia, bronchitis, and otitis media.

Physical findings include the following:

• Coarse facial features

  • High, narrow forehead

  • Puffy eyelids, epicanthal folds

  • Flat nasal bridge, anteverted nares

  • Long philtrum

  • Prominent gingival hyperplasia and macroglossia

• Musculoskeletal abnormalities

  • Congenital hip dislocation

  • Joint stiffness and claw hand deformities

  • Lumbar gibbus deformity and kyphoscoliosis

• Abdomen

  • Umbilical and inguinal hernias

  • Diastasis recti

  • Mild hepatomegaly

• Cardiovascular findings: Aortic insufficiency murmur may be present

• Ophthalmologic findings: Corneas may be clear or hazy.

• Neurologic findings: Generalized hypotonia may be observed.

I-cell disease is an autosomal-recessive disorder caused by a deficiency of the enzyme UDP-N -acetylglucosamine: N -acetylglucosaminyl-1-phosphotransferase. Deficiency of this phosphotransferase prevents the addition of the mannose-6-phosphate recognition marker because 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.[10]

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. Various mutations in this gene have been reported in patients with I-cell disease.[11]

Biochemical diagnosis can be made in the following ways:

• N -acetylglucosaminyl-1-phosphotransferase activity can be measured in WBCs or in cultured fibroblasts.
• Various lysosomal enzyme activities can be measured in serum and in cultured fibroblasts. The activities of beta-hexosaminidase, iduronate sulfatase, and arylsulfatase A are deficient in cultured fibroblasts, but their serum levels are 10-20 times the reference range. Assays for lysosomal enzymes in leukocytes are not reliable because of mannose-6-phosphate–independent targeting pathways.
• Dried blood spot screening methodology has been reported. ^[12]

Radiography

The characteristic bone changes are similar to those observed in the mucopolysaccharidoses.[9] There may be fractures, bone rarification, and other findings leading to confusion with rickets.[13]

The classic finding is dysostosis multiplex, with a cloaking appearance of the long tubular bones, anterior beaking and wedging of the vertebral bodies, widening of the ribs, proximal pointing of the metacarpals, and bullet-shaped phalanges.

Brain imaging

Brain imaging is not necessary to diagnose I-cell disease, although it is often performed during evaluation of developmental delay.

MRI and CT scan findings can be variable and nonspecific and may not aid in the diagnosis. Reported MRI and CT scan findings include completely normal scans with normal myelination, occasionally accompanied by cerebral atrophy, and nonspecific white matter changes.

A unique finding in I-cell disease is the presence of numerous intracytoplasmic inclusions in cells of mesenchymal origin(i.e. fibroblasts) that are observed on electron microscopy. These inclusions are membrane-bound vacuoles filled with fibrillogranular material. The contents of these vacuoles have not been well characterized; however, they appear to contain various lipids, mucopolysaccharides, and oligosaccharides.

Available treatment for I-cell disease remains limited.

Bone marrow transplantation has been attempted in a small number of patients. Data are limited; however, lysosomal enzyme levels seemed to normalize after transplant in at least one case.[14] Results from a more recent study suggest that BMT is inadequate for treatment of this disease[15] Although progression of the disease should theoretically cease, preexisting damage is usually irreversible. Seriously consider the risks and benefits of bone marrow transplantation in the medical decision-making process.

Efforts can be made to maximize overall health maintenance.

Because these children have progressive failure to thrive, nutritional supplementation may be beneficial. Promptly treat recurrent respiratory infections with antibiotics.

Consultations include the following:

• Geneticist

  • For initial evaluation and diagnosis

  • To provide genetic counseling for recurrence risks

  • To provide prenatal testing for future offspring

• Neurologist/developmental specialist

  • For initial evaluation of developmental delay

  • To recommend physical interventional services, such as physical therapy, occupational therapy, and speech therapy

• Cardiologist: Baseline and serial evaluations are recommended because patients with I-cell disease eventually develop valvular disease and signs of poor cardiac function.

Because these children have progressive failure to thrive, nutritional supplementation may be beneficial.

Drug therapy is not currently a component of the standard of care in lysosomal storage disorder. 

Respiratory infections, such as pneumonia and otitis media, frequently recur in patients with I-cell disease.

Depending on the extent of neurologic compromise, aspiration pneumonia can also become a recurrent problem.

Congestive heart failure results from chronic valvular insufficiency.

Atlantoaxial instability can develop because of abnormally shaped cervical vertebrae. If this occurs, patients should be monitored and, eventually, surgically stabilized to avoid the risk of spinal cord injury.

Psychomotor retardation is progressive, and patients with cardiopulmonary complications usually die by age 10 years.

Families must be educated about the genetic basis of this disorder, including recurrence risks, identification of carriers, and the availability of prenatal diagnosis for future at-risk pregnancies.