What are Lysosomal Storage Disorders (LSDs)?

Lysosomal Storage Diseases (LSDs) are a family of 40 inherited disorders which include a group of approximately 50 genetic diseases, sharing common clinical and biochemical characteristics. Individually, each disease is rare, but by considering all LSDs as a common entity (collectively), the prevalence has been estimated 1 in 7,700 to 1 in 10,000. Because enzyme deficiencies vary with these diseases, LSDs can be broken down further into sub-categories based on the type of enzymatic defect and/or stored substrate product. For instance, galactosialidosis, mucolipidosis II and mucolipidosis III are caused by multiple deficiencies of lysosomal enzmes.

People with LSDs are either lacking or in short supply of particular enzymes that are found in the lysosome (A sac-like organelle - a structurally discrete component of a cell) that contains various digestive enzymes as well as acidic materials. Because of this, molecules that are meant to be broken down by the missing enzymes build up within the lysosome, and can prevent the cell from working properly. Most lysosomal storage diseases are progressive and life threatening. Living with a lysosomal storage disease means living with a rare disease that is sometimes not well understood and hard to diagnose.

Most physicians are not looking for LSDs in the first place, either because they are individually rare or because historically there were no treatments available. Most physicians assume that LSDs always present with symptoms that are fairly obvious and that easily raise suspicion. But more often than not patients initially present with symptoms that resemble those of more common disorders. Good examples of this include: Enlarged abdomen in Gaucher disease and Niemann Pick disease, chronic pain and fatigue in Fabry disease, muscle weakness in Pompe disease, development delay or neurocognitive impairment in a number of LSDs, ear infections and runny noses in the MPS disorders and joint stiffness in the MPS disorders.

Some of the more common symptoms of LSDs may include:

• Changes in facial appearance
• Bone deformities, joint stiffness and pain
• Loss of skills such as speech and learning
• Respiratory and cardiac problems
• Behavioral problems and mental retardation
• Sight and hearing difficulties
• Enlargement of spleen and liver

A child may appear normal at birth, but symptoms appear progressively over the first few months of life.

How are LSDs inherited?

Most LSDs have an autosomal recessive inheritance pattern, which means that in order for a person to develop the disease, that person must inherit two copies of the abnormal gene, one from each parent. Gaucher disease, MPS I, Pompe disease, and Niemann-Pick disease are all autosomal recessive. Genetic counseling can help families understand the chance of passing on the disease to children and can help people living with lysosomal storage diseases make informed decisions about family planning.

Understanding the Role of the Lysosome

The cell is the smallest basic unit of life that performs the functions needed to exist:

• Respiration (“breathing” for the cell)
• Consumption of nutrients (“digestion” for the cell)
• Processing of metabolic wastes (“waste removal” from the cell)

The lysosome is a critical compartment within the cell.

The lysosome digests extra materials and food within the cell, breaking down molecules with strong enzymes. These enzymes are so strong and destructive that they are contained in the lysosome, a separate, membrane-bound section of the cell.

The lysosome "digests" molecules taken in by the cell.

The lysosome breaks down molecules that are taken in by the cell in order to give the cell the building blocks it needs to grow and divide. These building blocks are pumped across the lysosome's membrane (outer surface) to the inside of the cell, where they are used to build new structures that allow the cell to function correctly. The process by which the cell takes in and breaks down materials is like the "digestive tract" of the cell.

Specific enzymes break down specific types of molecules.

Each class of molecule taken into the lysosome has a set of lysosomal enzymes that will break the molecules down into the building blocks the cell will use to create new molecules. There is a fine balance between the creation (or synthesis) of one set of molecules and the breakdown (or degradation) of another set of molecules.

Undigested material will build up in the lysosome.

Lysosomes must be very efficient in digesting the full range of materials brought into the cell. Any material that cannot be digested will generally build up in the lysosome and may clog up other cellular processes. Lysosomal storage diseases are caused by a genetic defect that interferes with the breakdown of materials in the lysosomal system, which may cause severe problems for patients.

Included in the LSDs are the following diseases which may be known by other names. An example would be neuronal ceroid lipofuscinosis, type III, also known as Batten Disease or MPS I, which may be called Hurler or Scheie Syndrome.