Mucolipidosis type II alpha/beta, also referred to as Inclusion-cell (I-cell) disease, is part of the lysosomal storage disease family and results from deficiency of several lysosomal enzymes. The coding and translation of the genes for these enzymes is normal, however, they are not normally transported to the lysosomes from the endoplasmic reticulum because they lack a specific targeting signal. Without the proper functioning of N-acetylglucosamine-1-phototransferase, a build up of substances occur when enzymes are unable to travel inside of the lysosome.
Mucolipidosis II alpha/beta is a rare disorder, although its exact prevalence is unknown. It is estimated to occur in about 1 in 100,000 to 400,000 individuals worldwide. This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
Typically, by the age of 6 months, failure to thrive and developmental delay are obvious symptoms of this disorder. Other symptoms include coarse facial features, skeletal problems, and stiff claw-shaped hands. Carpal tunnel syndrome pain and loss of sensation in the fingertips are common. Hernias, enlarged liver and spleen, a thickening and weakening of the heart muscle, chronic ear infections, and corneal clouding are also present. Additional symptoms are poorly and late formed teeth, as well as a dental condition called gingival hyperplasia, in which the gums are very prominent.
Mutations in the GNPTAB gene cause mucolipidosis II alpha/beta. This gene provides instructions for making part of an enzyme called GlcNAc-1-phosphotransferase. This enzyme helps prepare certain newly made enzymes for transport to lysosomes. Lysosomes are compartments within the cell that use digestive enzymes to break down large molecules into smaller ones that can be reused by cells. GlcNAc-1-phosphotransferase is involved in the process of attaching a molecule called mannose-6-phosphate (M6P) to specific digestive enzymes. Just as luggage is tagged at the airport to direct it to the correct destination, enzymes are often "tagged" after they are made so they get to where they are needed in the cell. M6P acts as a tag that indicates a digestive enzyme should be transported to the lysosome.
Mutations in the GNPTAB gene that cause mucolipidosis II alpha/beta prevent the production of any functional GlcNAc-1-phosphotransferase. Without this enzyme, digestive enzymes cannot be tagged with M6P and transported to lysosomes. Instead, they end up outside the cell and have increased digestive activity. The lack of digestive enzymes within lysosomes causes large molecules to accumulate there. Conditions that cause molecules to build up inside lysosomes, including mucolipidosis II alpha/beta, are called lysosomal storage disorders. The signs and symptoms of mucolipidosis II alpha/beta are most likely caused by the lack of digestive enzymes within lysosomes and the effects these enzymes have outside the cell.
Mutations in the GNPTAB gene can also cause a similar but milder disorder called mucolipidosis III alpha/beta. Instead of preventing the production of any enzyme, these mutations reduce the activity of GlcNAc-1-phosphotransferase. Mucolipidosis III alpha/beta and mucolipidosis II alpha/beta represent two ends of a spectrum of disease severity.
An enzyme assay which measures the amount of N-acetylglucosamine-1-phototransferase typically confirms a diagnosis. White blood cells are examined to measure the amount of this enzyme. If they are low in comparison to normal standards for N-acetylglucosamine-1-phototransferase, a diagnosis of this disorder can be made. A skin biopsy can also be performed which measures the same enzyme in a cultured tissue sample. Low levels of N-acetylglucosamine-1-phototransferase found in comparison to normal standards confirm a diagnosis. The gene responsible for this disorder has been identified, rendering accurate diagnosis, prenatal diagnosis, and carrier testing to be possible.
A unique finding in mucolipidosis type II is the presence of numerous intracytoplasmic inclusions in cells of mesenchymal origin that are observed on electron microscopy. These inclusions are membrane-bound vacuoles filled with fibrillogranular material.
ML II is a particularly severe form of ML. Affected children often fail to grow and develop in the first months of life. Death from pneumonia or congestive heart failure usually occurs within the first decade of life.
No cure or specific therapies for ML currently exists. Therapies are generally geared toward treating symptoms and providing supportive care to the child. For individuals with corneal clouding, surgery to remove the thin layer over the eye has been shown to reduce the cloudiness in the eye. However, this improvement may be only temporary. Physical and occupational therapy may help children with motor delays. Children with language delays may benefit from speech therapy. Respiratory infections should be treated immediately and fully with antibiotics.