ISMRD - Mucolipidosis III

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Introduction

Mucolipidosis type III is also known as pseudo-Hurler polydystrophy and is a recessively inherited Lysosomal Storage disorder.

ML III was described in 1966 by Dr. Maroteaux and Dr Lamy from France. They called it Pseudo-Hurler Polydystrophy as it resembled a mild form of Hurler disease, one of the Mucopolysaccharide diseases. “Polydystrophy” means that many organs are abnormal.

The information provided here is based on the experiences of ML III parents and is a guide to the many symptoms your child could have over time, we also cover how to manage the complications of ML III. The Clinical descriptions have been provided by Gretchen Oswald Genetic Councillor.

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What causes Mucolipidosis type III?

Pseudo-Hurler Polydystrophy, Mucolipidosis type III (ML III). 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 Pseudo-Hurler Polydystrophy (ML III), 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.

Pseudo-Hurler Polydystrophy (ML III), is closely related to I-Cell disease (Mucolipidosis II). Both disorders are “targeting “defects. Pseudo-Hurler Polydystrophy 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 Pseudo-Hurler Polydystrophy and I-Cell disease is N-acetylglucosamine-1-phototransferase.

The build up of molecules that is caused by the targeting defect is gradual and interferes with the correct function of the cell. It eventually leads to the clinical features of ML III.

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What testing is available to determine if my child or I have Pseudo-Hurler Polydystrophy (ML III)?

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 III, a blood test should 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 should be performed is to have a skin biopsy this is grown to fibroblast level where the activity of N-acetylglucosamine-1-phototransferase can be measured. The skin sample should show decreased activity of this enzyme. This test will give you an accurate diagnosis.

For families who have had a child diagnosed with ML III, prenatal diagnosis is available in future pregnancies by looking at enzyme activity through Chorionic Villus Sampling (CVS) or amniocentesis.

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How common is ML III?

Accurate figures are hard to predict as the disease is so rare and there is no central registry. We are reliant on organizations such as the various MPS Societies around the world that record instances based on membership.

The United Kingdom booklet on ML2 and ML3 states - Data collected in the UK between 1980 and 1990 demonstrates there were 14 babies born with MLIII. This gives a live birth figure of 1:536,000.

Additionally, an Australian study reported a combined incidence of ML II and ML III of 1:325,000. (JAMA, VOL 281 (3):249-254).

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How is Pseudo-Hurler Polydystrophy (ML III) inherited?

ML III is not contagious and cannot be “caught.” It is a genetic condition, which means that it is caused by a change in the instructions 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 III (N-acetylglucosamine-1-phototransferase). One copy is inherited from the mother in the egg, and one from the father in the sperm.

Only when there is a change in the gene code is there a possibility that the disease will occur. For a person to have ML III, they must inherit changes in both of their genes resulting in instructions that do not function properly. This is known as autosomal recessive inheritance.

For a couple to have a child with ML III, 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 III. If two parents are both carriers, they have a 1 in 4 (25%) chance of having a child with ML III in each pregnancy.

The possibilities of gene inheritance, from two carrier parents is depicted below:

Mucolipidosis results from a changed gene found on one of the autosomal chromosomes (that is one of the 22 chromosomes which is not sex linked). If two carriers come together to have children the possible results will be like this.

Each pregnancy is like the roll of a dice.

There is a one in four chance of having a child of either sex, who is unaffected or not a carrier.
There is a two in four chance of having a carrier child of either sex
There is a one in four chance of having an affected child of either sex.

It is recommended that Genetic counselling be sought to review this information and pregnancy options prior to conceiving another pregnancy.

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Is there a Cure?

Unfortunately at the present time, there is no cure for ML III. Many of the complications require symptomatic management that include surgical procedures.

In 2000 there was a major medical break through in the understanding of bone disease in ML III. There are several children, young adults and adults benefiting from the use of Bisphosphonates, in particular IV Pamidronate for Secondary Metabolic bone disease.

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