Lysosomes are membrane-bound organelles within cells. They contain enzymes that degrade unwanted proteins, fats and sugars. Lysosomal storage diseases are genetic diseases that result in defective lysosomal enzymes. A mutation in the gene that codes for a particular enzyme results in a dysfunctional enzyme. The enzyme is unable to break down the fat, protein or sugar molecule that it is responsible for. This causes a buildup in the fat, protein or sugar molecules within the lysosome.
The buildup of large molecules within the lysosome causes many problems to the cells and eventually to the organs. Lysosomal storage diseases affect many different organs, such as the liver, the spleen, the brain, the heart, the nerves and the joints. Patients with lysosomal storage diseases are affected at a very young age, and the disease may be fatal at a young age.
Most lysosomal storage diseases are inherited in an autosomal recessive fashion, i.e., both parents must carry the susceptibility gene mutation in order for the child to be afflicted with the disease. Lysosomal storage diseases are diagnosed by biochemical assays testing the activity of the affected enzyme in the blood. Genetic tests of the DNA identify the specific mutations involved in the disease.
Lysosomal storage diseases can be classified into the molecule involved. Mucopolysaccharidoses are lysosomal storage diseases that result in an accumulation of mucopolysaccharides within the lysosome. An example of a mucopolysaccharidosis is Hurler’s syndrome, which is caused by a deficiency of the enzyme alpha-L-iduronidase, a lysosomal enzyme involved in the degradation of glycosaminoglycans. People with Hurler’s syndrome develop mental retardation, bone and joint deformities, blindness, deafness, heart and lung problems, and enlarged liver and spleen. More than 100 mutations in the gene encoding the alpha-L-iduronidase enzyme have been described.
Sphingolipidoses are lysosomal storage diseases that result in the accumulation of sphingolipids within the lysosomes. Examples of sphingolipidoses are Tay-Sachs disease, Fabry disease, Gaucher disease and Niemann-Pick disease. Gaucher disease is the most common lysosomal storage disease. It is due to a deficiency of the glucocerebrosidase, a lysosomal enzyme. This results in an accumulation of glucocerebroside in the lysosomes of cells. People with Gaucher disease develop bone pain, growth retardation, bleeding and blood disorders such as leukemia. More than 300 mutations in the gene for glucocerebrosidase have been identified.
Fabry disease is an X-linked lysosomal storage disorder due to a deficiency in the enzyme alpha-galactosidase A. This results in an accumulation of glycosphingolipids within the lysosome. Being an X-linked disorder, i.e., the gene is located on the X chromosome, virtually all affected people are male. People with Fabry disease experience pain crises – episodes of intense burning pain in the hands and feet. They also develop heart disease, kidney disease, blindness, deafness and stroke. Fabry disease is confirmed by the demonstration of low alpha-galactosidase activity in blood cells. Over 240 mutations in the alpha-galactosidase gene have been identified.
Pompe disease is a lysosomal storage disease due to the deficiency of the enzyme acid alpha-glucosidase. This results in an accumulation of glycogen within the lysosomes. People with Pompe disease suffer from muscle weakness. Muscle weakness may affect the person in infancy and early childhood, resulting in poor feeding due to difficulty chewing and swallowing. The baby or child will also develop difficulty sitting up and walking due to muscle weakness. At later stages, weakness of the muscles involved in breathing results in breathing difficulties and lung infections, which can cause death.
Over 120 mutations in the acid alpha-glucosidase gene have been identified. The effect of the gene mutation on the protein activity determines the level of protein activity. The lower the protein activity of the enzyme, the more severe the accumulation of glycogen within the lysosomes, and the worse the muscle weakness. People who have mutations causing severe deficiencies of the enzyme are affected at a younger age and have more serious clinical symptoms. Those who have mutations that affect the enzyme less severely, so that some enzyme activity is still retained, may become affected by muscle weakness at an older age and have less severe muscle weakness.