Lysosomal Storage Diseases - Etiology, Types, Symptoms, Diagnosis, And Treatment

Introduction

Lysosomal storage diseases (LSDs) consist of more than 70 inherited rare metabolic disorders characterized by the altered function of lysosomes that affect 1 in 5000 live births. Lysosomes play an essential role in breaking macromolecules (lipids, proteins, and nucleic acids), recycling cellular components, and signaling. Any alteration in these functions of lysosomes causes impaired transport of molecules and the accumulation of partially digested or undigested macromolecules resulting in cellular damage. In addition, people with lysosomal storage diseases lack essential enzymes that aid in the effective functioning of lysosomes. Due to the defective functioning of lysosomes, the abnormal build-up of toxic materials occurs in the body's cells. It affects different body parts, including the brain, heart, skeleton, and central nervous system.

What Are Lysosomal Storage Diseases?

Lysosomal storage diseases (LSDs) are metabolic diseases caused by single gene defects. Enzymes defects account for the incidence of nearly 70 percent of lysosomal storage diseases (LSDs), and the rest occur due to defects in proteins or enzyme activators. Lysosomes are found inside the cells, containing hydrolytic enzymes that can digest large molecules into fragments. This unique function of lysosomes requires several enzymes. Therefore, the defective functioning of any of these enzymes results in the accumulation of large molecules within the cell and cell damage. Similar to other genetic disorders, lysosomal storage diseases are inherited from parents to their children. Therefore, it mainly affects children and results in serious complications.

What Are the Etiological Factors Responsible for Lysosomal Storage Diseases?

Genetic mutations involving the genes encoding for lysosomal enzymes are the primary cause of lysosomal storage diseases (LSDs). Mutations produce defective enzymes and result in altered lysosomal functioning and cellular damage. In some individuals, enzyme activation, membrane proteins, and membrane transportation defects can cause lysosomal storage diseases. Most lysosomal storage diseases (LSDs) have an autosomal recessive type of inheritance. Recessive genetic disorders occur when the child inherits the same faulty abnormal gene for the trait from each parent. If the child receives only one abnormal gene, they are considered a disease carrier.

What Are the Different Types of Lysosomal Storage Diseases?

Lysosomal storage diseases (LSDs) are classified based on the accumulated substrates in the body. It can be divided into lipid storage diseases, glycoprotein storage diseases, mucopolysaccharidoses, and mucolipidosis. Lysosomal storage diseases include more than 70 diseases identified and named based on the enzyme defect, substance accumulated, or scientist identified.

It consists of the following.

• Farber disease.

• Fabry disease.

• Tay-Sachs disease.

• Schindler disease.

• Krabbe disease.

• Sphingolipidoses.

• Gaucher disease.

• Lysosomal acid lipase deficiency.

• Niemann-Pick disease.

• Galactosialidosis.

• Salla disease.

• Metachromatic leukodystrophy.

• Hurler syndrome.

• Sanfilippo syndrome.

• Maroteaux - Lamy syndrome.

• Cholesteryl ester storage disease.

• Pompe disease.

• Infantile-free sialic acid storage disease.

• Danon disease.

• Cystinosis.

• Beta-mannosidosis.

• Mucopolysaccharidosis.

• Fucosidosis.

• Pycnodysostosis.

• Wolman disease.

• Sly syndrome.

• Hurler-Scheie syndrome.

• Multiple sulfatase deficiency.

• Sandhoff disease.

• Galactosialidosis.

What Are the Common Symptoms of Lysosomal Storage Diseases?

Signs and symptoms associated with lysosomal storage diseases (LSDs) vary depending on the age of onset, enzyme defect involved, and stage of progression (mild to severe).

The most commonly observed symptoms are the following.

• Developmental delay.

• Seizures.

• Movement disorders.

• Deafness.

• Dementia.

• Cardiac problems.

• Enlarged liver.

• Blindness.

• Pulmonary diseases.

• Enlarged spleens.

• Abnormal bone growth.

• Skin rashes.

• Tiredness.

• Anemia.

• Kidney failure.

• Memory loss.

• Depression.

• Muscle weakness.

• Numbness in hands and feet.

• Heart failure.

• Inability to walk.

• Stiff extremities.

How Can We Diagnose Lysosomal Storage Diseases?

Prenatal diagnostic tests can be done to identify the presence of lysosomal storage diseases (LSDs) in the baby during pregnancy. A definitive diagnosis can be made using an enzyme assay. Apart from specific diagnostic tests, other investigations like X-rays, audiometry, pulmonary function tests, visual assessment tests, magnetic resonance imaging (MRI), echocardiogram, liver function test, hemogram, and renal function tests can be done to identify and evaluate a patient's condition and associated complications.

How Can We Manage Lysosomal Storage Diseases?

There is no specific treatment available for lysosomal storage diseases (LSDs). Furthermore, few therapies have been developed for patients suffering from lysosomal storage diseases to improve their quality of life and increase life expectancy.

It includes the following:

• Bone Marrow Transplantation Therapy - It is effective in preventing the progression of mental retardation in children with Hurler disease. Bone marrow transplantation is done before two years of age. It is considered a standard treatment option for infants with Hurler disease.

• Enzyme Replacement Therapy - It is proven effective for the treatment of Gaucher disease type I. Enzyme replacement therapy improves lung and cardiac function and the patient's overall condition.

• Substrate Reduction Therapy - Some specific substances can be used to reduce the formation of toxic substrates by inhibiting the enzymes responsible for their synthesis. Thus the progression of neuropathic defects associated with lysosomal storage diseases can be slowed.

• Proteostasis Regulators - They help to control different steps involved in the progression of metabolic diseases associated with lysosomal storage diseases.

• Pharmacological Chaperone Therapy (PCT) - Chaperons are small molecules that correct misfolding and improve enzyme function. Pharmacological chaperone therapy (PCT) helps to improve the enzymatic defect associated with lysosomal storage diseases.

• Anti-inflammatory Agents - Immunosuppressive agents, along with anti-inflammatory agents, reduce inflammatory agents responsible for the pathogenesis of lysosomal storage diseases.

• Hematopoietic Stem Cell Transplantation (HSCT) - Stem cells obtained from the umbilical cord or donors can also be used instead of bone marrow tissues to improve the patient's condition and outcomes.

• Small Molecule Assisted Substrate Transportation (SMAST) - In this substrate accumulated in the cells due to lack of transporter mechanism is converted to another compound that can be easily transported.

• Supportive Treatments - Apart from specific therapies directed at improving enzyme function, substrate removal, and stem cell therapy, other individual treatments can also be used to reduce the complication associated with lysosomal storage diseases.

Conclusion

Lysosomal storage disorders (LSDs) are a group of rare genetic metabolic diseases affecting the function of lysosomes. Defective functioning of the lysosomal enzymes results in cellular accumulation of macromolecules and cell damage. The most significant etiology associated with the incidence of lysosomal storage diseases is genetic mutations occurring in the genes responsible for coding lysosomal enzymes. In addition, most patients affected with lysosomal storage diseases show other systemic complications and side effects. Thus, the management of lysosomal storage diseases includes specific therapies to improve enzyme function and other supportive therapeutic agents to improve difficulties.