Lysosomal Storage Disorder

Lysosomal storage disorders are rare genetic conditions where the body’s cells cannot properly break down fats, sugars, and other substances, leading to a toxic buildup that can damage organs throughout the body.

Table of contents

• What Are Lysosomal Storage Disorders?
• How Enzymes and Lysosomes Work
• Types of Lysosomal Storage Disorders
• Causes and Inheritance
• Who Is Affected
• Symptoms and Affected Organs
• Diagnosis
• Treatment Options
• Outlook and Prognosis

What Are Lysosomal Storage Disorders?

Lysosomal storage disorders (LSDs) are rare genetic conditions that cause a buildup of toxic materials in your body’s cells. People with LSDs lack certain enzymes (proteins that speed up chemical reactions in the body) or a substance that helps the enzyme work properly^[1]. Without functioning enzymes, your body cannot break down fats, sugars, and other substances. When these materials build up in your body, they can cause serious harm^[1].

Researchers have identified more than 70 different types of lysosomal storage diseases, and they continue to discover more^[1][2]. Although each individual disorder is rare, when viewed together as a group, they affect approximately 1 in 5,000 to 1 in 10,000 live births^[3].

How Enzymes and Lysosomes Work

Enzymes help your cells’ lysosomes (small structures inside cells that act like recycling centers) with metabolism (the process of breaking down substances for energy). They cause chemical reactions that help the lysosomes break down carbohydrates (fiber, starches and sugars), lipids (fats), proteins, and older cells^[1].

Lysosomes are like microscopic recycling bins in your cells. They store, break down, and recycle large unwanted molecules by using very specific enzymes^[5]. When these substances build up in your cells instead of being broken down, they become toxic. The buildup causes damage to other cells and organs throughout your body^[1].

Types of Lysosomal Storage Disorders

Lysosomal storage diseases are generally grouped into three main types based on which enzyme is lacking^[1]:

Lipidoses: This type occurs when your body lacks an enzyme to break down fats. Specific conditions include cholesteryl ester storage disease and Wolman disease^[1].

Mucopolysaccharidoses: These happen when your body lacks an enzyme to break down complex sugar molecules called glycosaminoglycans (long chains of sugar molecules). Specific conditions include Hunter syndrome and Hurler’s disease^[1].

Sphingolipidoses: This type results from not having enough of an enzyme to break down fatty substances called sphingolipids (special fats that protect the surface of your cells). Specific conditions include Fabry disease, Gaucher disease, Krabbe disease, metachromatic leukodystrophy, Niemann-Pick disease, Sandhoff disease, and Tay-Sachs disease^[1].

Other types of lysosomal storage disorders include Batten disease, cystinosis, Danon disease, and Pompe disease^[1].

Causes and Inheritance

Lysosomal storage diseases are inherited metabolic disorders (conditions passed down through families that affect how the body processes substances). Most LSDs are autosomal recessive disorders (you must inherit a changed gene from both parents)^[1]. Your parents carry these gene mutations (changes in genes), but they do not have a lysosomal storage disease themselves.

When both of your parents have a mutated gene, you have a 1 in 4 chance of not having the mutated gene (no risk of an LSD), a 1 in 4 chance of developing an LSD, and a 1 in 2 chance of being a carrier who does not develop an LSD^[1].

In some conditions, only one parent may carry this gene mutation. This is called X-linked inheritance (passed through the X chromosome). Three LSDs have X-linked inheritance patterns^[1]. Hunter syndrome and Fabry disease are examples of X-linked lysosomal storage disorders^[3].

The defective genes affect how your body makes enzymes that break down materials in the cells. A defective gene that develops during growth before birth causes lysosomal storage diseases^[4].

Who Is Affected

Anyone can have a lysosomal storage disorder. However, some ethnic groups and geographic areas have more LSDs than others^[1]. For instance, Eastern European Jewish people and people in Finland have a higher incidence of certain lysosomal storage disorders^[1].

Between 1 in 40,000 and 1 in 60,000 people have lysosomal storage diseases^[1]. When considered together as a group, their incidence is about 1 in 5,000 to 1 in 10,000 births^[3].

Symptoms and Affected Organs

Lysosomal storage diseases usually appear during pregnancy or soon after birth. More rarely, adults may develop LSDs^[1]. People usually have more severe cases when an LSD starts early and milder cases when an LSD starts later^[1].

The damage from lysosomal storage disorders can affect many parts of your body. Common symptoms may include delay in intellectual and physical development, seizures, facial and other bone deformities, and joint stiffness and pain^[4].

• Brain
• Central nervous system
• Heart
• Skeletal system
• Skin
• Spleen
• Liver
• Bones
• Muscles
• Kidneys

The excess substances built up in cells can cause a wide range of problems throughout the body. Because many different systems can be affected, patients often need care from multiple specialists^[4].

Infants and children suffer more severely compared to adults. The clinical features can be different in children and adults for the same disease. For example, a child’s developing brain is more susceptible to damage and shows symptoms of dysfunction, while this may be milder or absent in adults^[2].

Diagnosis

Providers usually diagnose LSDs during pregnancy or infancy^[1]. Early diagnosis can result in better outcomes and disease management^[6].

Diagnosis includes blood and urine tests^[1]. Doctors typically diagnose lysosomal storage diseases by testing for enzyme deficiencies, prenatal genetic testing, and genetic screening^[4]. Enzyme testing is usually the initial diagnostic test, but genetic analysis of the gene mutations adds precision^[2].

After reviewing your family’s medical history, a diagnosis may be obtained through genetic testing and, when appropriate, prenatal testing^[6]. Some specific screening tests used include elevated total and fractionated urinary glycosaminoglycans for mucopolysaccharidoses^[6].

It can be difficult for physicians to diagnose LSDs because symptoms vary among the different types and individual LSDs are rare. Physicians can usually confirm a diagnosis when they recognize a pattern of symptoms, but this process may take years while doctors rule out other conditions^[8].

Treatment Options

There are no cures for lysosomal storage diseases. However, treatments can help you manage your symptoms and lessen damage to organs and tissues^[1]. When applied early before organ damage sets in, these therapies have the potential to prevent or delay damage, improve quality of life, and increase lifespan^[2].

Several treatment options are available for patients with lysosomal storage disorders:

Enzyme Replacement Therapy: This involves providing the normal enzyme through intravenous (IV) infusions. Enzyme replacement therapy may be used to treat some lysosomal storage diseases, including Gaucher disease, Fabry disease, Pompe disease, and several of the mucopolysaccharidoses^[6]. This treatment can improve symptoms associated with the condition^[6].

Treatment with enzyme replacement therapy for mucopolysaccharidosis type I using laronidase effectively halts progression and reverses all complications of the disease that do not affect the central nervous system^[6].

Substrate Reduction Therapy: These are oral medicines that remove waste from cells to prevent or reduce symptoms^[6]. This therapy addresses the accumulated substances in cells^[9].

Stem Cell Transplants: Some conditions are treated by bone marrow transplantation or umbilical cord blood stem cell transplantation^[4]. This involves removing damaged cells from the spongy material inside the bone and replacing them with healthy, functioning cells. When performed at an early stage, bone marrow transplant can improve symptoms and prevent damage caused by lysosomal storage disorders^[6].

Gene Therapy: Gene therapy, which involves replacing the altered gene that generates a defective enzyme, is at advanced preclinical stages and, for a few disorders, has already progressed to the clinic^[7].

Medications and Supportive Care: Various medications can help manage symptoms. Supportive and symptomatic treatment deals with the secondary effects of lysosomal enzyme deficiency^[9].

Outlook and Prognosis

Lysosomal storage diseases affect mostly children and they often die at a young age if untreated. Many die within a few months or years of birth^[3]. Lysosomal storage diseases are rare, but can lead to death if untreated^[4].

People with lysosomal storage disorders need lifelong care. While there is no cure, treatments can reduce symptoms and prevent, delay, or manage medical complications^[6]. The last decade has observed tremendous advances in understanding many of these conditions. These advances have shown promise in improving the lifespan and quality of life^[2].

Living with a lysosomal storage disease means closely monitoring your condition. Ongoing monitoring and tracking of developmental milestones allows doctors to diagnose problems early and connect patients with specialists to prevent complications and reduce symptoms as soon as possible^[6].