Our bodies are made up of billions of cells and each cell contains hundreds of small vesicular structures known as lysosomes. Working together as a group, lysosomes function as the 'recycling centre’ of the cell. They act to breakdown or degrade large complex molecules such as proteins, mucopolysaccharides and glycolipids into smaller, simpler components that can be reused by the cell. Cells are dynamic, with complex molecules continuously being synthesized, used for a while, and then degraded and recycled. The recycling process carried out by lysosomes thus enables the body's cells to function normally.
Problems occur when the process fails and the materials ready for breakdown cannot be recycled. As a result, they accumulate within lysosomes and are stored in cells, this being why these disorders are often referred to as 'storage' diseases. Over time, the amount of material building up in each lysosome causes it to swell and occupy more space in the cell, leading to additional problems for normal function. Cells thus become dysfunctional and may die, resulting in a wide variety of clinical symptoms. Depending on the type of material that the cell is unable to degrade, various tissues and organs can be affected. These include the brain as well as visceral organs like the liver or spleen and other tissues like bone and muscle. This is why the clinical symptoms in storage diseases can be so varied. While there presently are no complete cures for storage diseases, scientists worldwide are working aggressively to develop ways to make the lysosome function normally again.
||Shown here are several abnormal lysosomes as seen in a brain cell in the mucopolysaccharide storage disorder known as Hurler disease. The storage material accumulating in the lysosomes appears striped, hence the name “zebra bodies”.
Symptoms of Lysosomal Storage Disease
Babies with LSD generally appear normal at birth, but symptoms appear progressively over the first few months of life. These may include:
Changes in facial appearance
Bone deformities, joint stiffness and pain
Loss of skills such as speech and learning
Respiratory and cardiac problems
Behavioural problems and mental retardation
Sight and hearing difficulties
Enlargement of spleen and liver
The severity of the individual diseases is variable. In the more extreme forms, life is severely shortened and patients die in their teens or earlier. Some patients survive into adulthood. There are also adult-onset LSDs.
How are Lysosomal Storage Diseases Inherited?
All LSDs are inherited in an autosomal recessive manner except for Fabry Disease, Hunter Syndrome (MPSII), and Danon Disease, which are X-linked disorders.
Autosomal Recessive Inheritance
Almost all the genes in the human body come in pairs, one inherited from each parent. A carrier of a recessive condition has one copy of the gene which is altered (a mutation) but also has a normal copy of the gene (the dominant copy). Most people are unaware that they carry genes for a disease until they have an affected child, as the carriers usually have no clinical features of the disease.
If both parents are carriers of a condition, there is a 1:2 (50%) chance of the child also being a carrier, a 1 in 4 (25%) chance of the child not having the disease or being a carrier and 1:4 (25%) chance of the child having the disease. Males and females are equally likely to be affected.
If only one parent is a carrier, there is no chance of the child having the condition; however, there is a 1:2 chance in each pregnancy that the child will be a carrier.
The sex chromosomes come in two types, X and Y. Females have two X chromosomes (XX) and males an X and a Y chromosome (XY.)
In X-linked inheritance, the abnormal gene is on the X chromosome. These conditions tend to be more common among males because if the affected gene is on the X (female) chromosome there is no dominant allele to 'hide' or counteract it on the Y (male) chromosome. But if the gene is dominant then girls may be affected. For females to inherit an X-linked recessive condition they must inherit two copies of the recessive allele, one from each parent, whereas the boys need only one copy of the recessive gene to develop disease.
For an X-linked condition, for each pregnancy, the inheritance chances are:
affected boy: 1:4 (25%) chance
unaffected boy: 1:4 (25%) chance
female carrier 1:4 (25%) chance
female, non-carrier: 1:4 (25%) chance