ML II (I-cell disease) and ML III (Pseudo-Hurler Polydystrophy) are closely related diseases, first described in the 1960s. The more severe of the two, I-cell disease, was named by Jules Leroy, a Belgian paediatrician and geneticist, for the inclusions he saw in effected individuals’ cells under a microscope. Pseudo-Hurler Polydystrophy was described by the French physicians, Maroteaux and Lamy, who found the disease reminiscent of severe MPS I, though milder in its manifestations. Both diseases were assigned to the class of Mucolipidosis, I-cell disease as Mucolipidosis II and Pseudo-Hurler Polydystrophy as Mucolipidosis III (or simply, ML II and III). Recent molecular studies identified mutations that correlate with the phenotypes (characteristics) seen in the spectrum of Mucolipidosis II and III, leading to revised classification.
|Revised Classification of Mucolipidosis II and III|
|I-cell disease||ML II||ML II alpha/beta|
|Pseudo-Hurler polydystrophy||ML IIIA||ML III alpha/beta|
|ML III variant||ML IIIC||ML III gamma|
Gene Mutations and the link between ML II, ML II/III and ML III
ML II and ML III are related conditions on the same spectrum of severity. Most individuals have definite features of ML II, the more severe disease, or definite features of ML III, the milder disease. Intermediate ML II/III is the descriptive name used for a subset of individuals who show small stature and skeletal findings similar to individuals with ML II but better cognitive function and longer lifespan, similar to individuals with ML III. Knowing the gene changes in GNPTAB further helps classify the severity of illness. People with ML II have two significant mutations, which thoroughly impair the normal activity of the phosphotransferase enzyme. People with ML III have one or two milder mutations, leading to a small amount of normal enzyme activity. People with Intermediate ML II/III have specific gene mutations that lead to the intermediate clinical features. For this reason, knowing the gene changes can lead to a more accurate expectation of prognosis in an affected individual.
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 doesn’t require the signal on the enzymes.
ML II is closely related to Mucolipidosis III (MLIII) also known as Pseudo-Hurler Polydystrophy. Both disorders are “targeting“ defects. ML III presents with much less severe clinical findings. The enzyme that is responsible for putting the targeting signal on the lysosome enzymes that is not working in both ML II and ML III is N-acetylglucosamine-1-phototransferase.
The targeting defect impairs many lysosomal enzymes ability to reach the lysosomes and interferes with the correct function of the cell. It leads to the clinical features of ML II. Features may progress over time.
What are the clinical features of ML II?
Individuals with ML II characteristically have severe psychomotor retardation. Typically, failure to thrive and developmental delay are obvious by the age of 6 months. The degree of mental retardation is variable but is usually severe. Individuals with ML II have the coarse facial findings that can be characteristic of some Lysosomal Storage Diseases and include a high forehead, puffy eyelids, flat nasal bridge, macroglossia (large tongue) and coarsening of facial features. Radiologically, 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), vertebral body anomalies and claw-hand deformities. Individuals with ML II are prone to carpal tunnel syndrome and can experience pain and loss of feeling in their fingertips. Other musculoskeletal problems include hernias and joint contractures and restriction.
Individuals with ML II develop thickening of the heart valves. The heart muscle may enlarge but not pump efficiently. Enlargement of the liver and spleen are less significant in ML II than in other lysosomal diseases. Other medical concerns include recurrent respiratory and ear infections. Corneal clouding may be present but does not impair vision..
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.
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.
For some lysosomal storage diseases, bone marrow transplant has been trialled as an experimental therapy. Bone marrow transplantation does not appear to alter the course of the disease in individuals with ML II.