Lysosomes are organelles within the cell that contain hydrolytic enzymes which digest waste material within the cell. They occur in almost all eukaryotic cells. There are more than 40 different enzymes in a lysosome, each critical to the removal of specific waste products. Unfortunately, when there is a malfunction in this system, the undigested or partially digested macromolecules accumulate within the cell, disrupting function and often causing disease. These illnesses are known as lysosomal storage diseases.
They are genetic in nature and are the result of a recessive gene, which means that both parents must carry the gene for the disease. If a patient is diagnosed with a lysosomal storage disease, the rest of the family should be tested as well. Although none of them may be affected, they may be carriers of the gene involved and should be advised about risks of passing it on to their offspring if they choose to have children.
Traditionally, lysosomal storage disorders have been defined as lysosomal hydrolase enzyme deficiencies. More recently, this has been expanded to include deficiencies or defects of proteins required for post-translational modification of lysosomal enzymes, activator proteins or proteins important to correct intracellular movement between the lysosome and other intracellular compartments.
There are over 40 different lysosomal storage diseases that have been described. All together they occur in 1 in 7,700 people but individually they are much rarer. The most commonly occurring one is Gaucher’s disease happens to 1 in 57,000 individuals. The rarest is sialidosis which can be found in 1 in 4.2 million patients. Because of the extreme rarity of these diseases and the fact that many are slow to develop, they can be very difficult to accurately diagnose. Additionally, the symptoms can often resemble more common ailments. Making it even more complicated, age of onset and degree of symptom expression can vary widely within a single disease.
There are some symptoms that should be considered red flags to a physician. Issues which may indicate a lysosomal storage disease include unusual facial features (particularly an enlarged tongue), cloudy eyes, purplish-blue skin rash, distended or protruding abdomen (possibly due to enlarged organs), muscular weakness or loss of motor skill and skeletal deformities. An enzyme assay test is done using blood, urine or skin. Low levels of an enzyme are indicative of lysosomal storage disease.
There are no cures. Treatment is divided into two basic approaches that are not mutually exclusive. One approach is to treat the symptoms as they arise. This usually involves several specialist as multiple organ systems are often affected. These specialists are overseen by a genetic diseases specialist. The second treatment aims to replace the missing enzyme and correct the underlying issue within the patient.
Bone marrow or hematopoietic stem cell transplants involve transplantation of healthy cells into the body in the hope that the new cells will allow the body to produce the deficient enzyme. It has all the normal risks of a transplant and may not be successful even if the patient does not reject the transplanted cells.
Enzyme replacement therapy (ERT) involves intravenous administration of the enzyme allowing the body to process the accumulated waste. This does not address the symptomatic issues or any central nervous system problems. It has been approved for treatment in Europe for patients diagnosed with Gaucher’s disease, Fabry’s disease and mucopolysaccharidosis diseases.
Substrate synthesis inhibition therapy (SSI) involves an oral drug that is aimed at reducing the production and elimination of cellular waste required. This is believed to have some potential for diseases that cause central nervous system problems.
Gaucher’s disease is the most common of the lysosomal storage disorders. There are five types of Gaucher’s; classified as type 1, 2, 3, cardiovascular, and the perinatal lethal form. Type 1 is the most commonly seen variety. It is the non-neuropathic form of the disease and generally involves enlargement of the spleen and liver, anemia, thrombocytopenia, lung disease and bone issues including pain, fractures and arthritis. Types 2 and 3 have neuropathic involvement and exhibit all of the above symptoms as well as seizures, abnormal eye movements and brain damage. Type 2 typically causes life-threatening issues beginning in infancy while type 3 progresses more slowly. The cardiovascular form primarily affects the heart but also causes eye abnormalities, bone disease and mild enlargement of the spleen. The most severe type is the perinatal lethal form which begins causing life-threatening problems in utero. Children born with the perinatal lethal form rarely live more than a few days after birth.
Fabry’s disease causes kidney and heart issues in the patient along with a burning sensation in the hands and feet, difficulty producing sweat (they may not sweat at all) leading to overheating, gastrointestinal issues, headaches, vertigo, cloudy eyes (vision is unaffected) and an increased risk of stroke. Left untreated, people with Fabry’s often have a lifespan of 40 to 50 years.
Tay-Sachs generally appears when the child is three to six months of age. Development typically slows as muscles weaken and motor control is lost. Seizures, vision and hearing loss, paralysis and intellectual disability follow, and affected children often die at a young age.
Pompe disease disables heart and skeletal muscles with often fatal results. There are two forms. In the infantile variety most children die before their first birthday. The late onset type may appear at anywhere from 10 years of age to 60. Over a period of years muscular weakness, respiratory difficulties and eventually respiratory failure occur.
Hurler’s disease is one of the mucopolysaccharidosis (MPS) diseases. It usually begins in children between the ages of three and eight years. Typical symptoms include claw hands, cloudy eyes, deafness, halted growth, abnormal spinal bones, heart valve issues, thick coarse facial features with a low nasal bridge and diminished mental abilities that become progressively worse. ERT can be helpful but most children die young. Bone marrow transplants have also been tried with limited success.
Lysosomal storage diseases are caused by a deficiency or lack of a hydrolytic enzyme in the body. They are genetic in nature and cannot be cured. While current therapies try to ameliorate the lives of patients and treat symptoms, the prognosis is generally bleak and often ends in premature death.
