Lysosomal Storage Disease

What is Lysosomal Storage Disease?

Lysosomal storage diseases (LSDs) are a type of disease caused by changes in specific genes. Around seventy percent of these diseases are related to issues with enzymes, proteins that help in many body functions. The remaining LSDs are caused by problems with other substances that control these enzymes. If a gene doesn’t work correctly, it can cause the enzyme it controls to become inactive. Likewise, changes in the genes responsible for these controlling substances can also lead to problems. We currently know of about seventy of these diseases, but more are likely to be discovered. Even though each of these diseases is rare on its own, when we consider them as a group, they are quite common.

LSDs can cause problems in the organs where they build up, and the symptoms a person experiences are determined by which organ is affected. These diseases tend to impact infants and children more severely than adults. The symptoms can vary a lot, even for the same disease. For example, a child’s brain is still developing and is more sensitive to damage, so they may experience more severe symptoms than an adult.

Over the past decade, we’ve made significant progress in understanding many of these diseases. This knowledge has given us hope for extending the lifespan and improving the quality of life for people with LSDs, which was previously quite grim. LSDs are similar to certain degenerative conditions that occur later in life, and studying them might help us understand both types of diseases better.

Tests for enzyme function are usually done first for diagnosis. Genetic testing, which looks for specific gene changes, can improve the accuracy of the diagnosis. Treatments include modern techniques that can prevent or slow down organ damage, improve quality of life, and extend lifespan when started before severe organ damage occurs. This is a summary of the recent advancements in understanding, diagnosing, and treating the more common LSDs, with the goal of improving patient outcomes.

What Causes Lysosomal Storage Disease?

Lysosomal storage diseases (LSDs) are a group of diseases mainly caused by changes or defects in genes that control a type of cell structure known as a lysosome. The lysosome acts like a recycling center in cells, helping to break down and recycle various substances. Each disease relates to a specific gene controlling a special enzyme that works within the lysosome.

Various types of changes or mutations in these genes can cause the related enzyme to not work properly. While these mutations can be unpredictable in their effects, there are some common patterns. In some cases, these mutations are inherited, meaning they can be passed down from parents to their children. That’s why knowing if any family members have one of these diseases can be so important. It can help doctors choose the right genetic tests to diagnose these diseases more precisely.

Most LSDs are inherited in what’s known as an autosomal recessive pattern (meaning both parents must carry the mutated gene to pass the disease to their child). However, for three LSDs (Hunter disease, Fabry disease, and Danon disease), the mutation is found on the X-chromosome, one of the two sex chromosomes that determine a person’s biological sex.

Apart from genetics, inflammation and damage caused by harmful substances known as oxidative stress are also key contributors to LSDs.

LSDs can be grouped various ways, with the most common way being the type of substance that builds up within cells. For example, in Sphingolipidosis, types of fat found in cell membranes called sphingolipids build up. This group includes many diseases such as Tay Sachs disease and Gaucher disease.

Another group is Mucopolysaccharidosis, which involves the build-up of long chains of sugar molecules called mucopolysaccharides or glycosaminoglycans (GAGs). This group includes diseases like Hurler and Hunter syndromes.

In other classifications, substances like lipofuscin (a kind of cellular waste), sialic acid (a type of sugar molecule), and certain proteins build up, leading to different types of diseases such as Neuronal ceroid lipofuscinosis and Sialic acid disorders.

In Mucolipidosis, there is a specific kind of issue that results from an mistake in directing certain enzymes to their proper location within cells.

A comprehensive list of the types of LSDs, the enzymes that are affected, the gene responsible, and the substance that builds up can provide a more detailed understanding of these conditions. It should be noted that a protein (a type of substance made by cells) ending with “ase” is an enzyme. An enzyme helps speed up (catalyze) chemical reactions within the cell. If the protein does not end with “ase”, it is not an enzyme.

Risk Factors and Frequency for Lysosomal Storage Disease

Lysosomal storage diseases (LSDs) are a group of uncommon disorders, with some being extremely scarce, affecting just a handful of patients. These diseases, which include Fabry, Gaucher, Metachromatic leucodystrophy, and Pompe, are found everywhere in the world. Although individual LSDs are rare, when considered collectively, they are much more frequent, with the combined occurrence estimated to be between 1 in 5000 to 1 in 8000 people.

LSDs can vary by ethnicity and geographical location. For example, Gaucher disease is found in 1 out every 40,000 to 60,000 people generally, but its occurrence is much higher, up to 1 in 800, amongst Ashkenazi Jews in Eastern Europe. Similar patterns of higher occurrence are observed with Tay-Sachs disease, Niemann-Pick A, and mucolipidosis IV in this group. In the Finnish population, aspartylglucosaminuria and Salla disease occur more often due to genetic isolation and certain shared ancestry traits.

Recent studies involving newborn screening for the five most common LSDs, has revealed interesting results. Out of roughly 65,000 babies screened, 69 showed initial positive results, with 23 eventually confirmed to have late-onset types of the diseases. Such newborn screening holds the promise of revealing more cases, thereby giving a more accurate measure of the incidence of these rare disorders. As newborn screening becomes more universally available, we will gain a clearer picture of the true frequency of LSDs in the population.

• Lysosomal storage diseases (LSDs) are rare, some are extremely rare.
• These include Fabry, Gaucher, Metachromatic leucodystrophy, and Pompe diseases.
• When combined, the incidence of LSDs is between 1 in 5,000 to 1 in 8,000 people.
• Incidence of some LSDs varies by ethnicity and location, with Gaucher disease being more frequent in Ashkenazi Jews and certain LSDs occurring more often in the Finnish population.
• Recent newborn screening revealed more cases, indicating that the true incidence of LSDs could be higher.

Signs and Symptoms of Lysosomal Storage Disease

Lysosomal storage diseases, also known as LSDs, are a group of conditions that can affect multiple organs in the body. They can be quite varied in how they appear and can start showing symptoms at different times in a person’s life. Some LSDs start causing problems before or just after birth, while others might not become apparent until later in childhood or even adulthood.

The impact of the disease can be much more severe in infants compared to adults and in some cases, certain organs like the central nervous system are more affected during the early years of life. If a baby is known to have an LSD before they are born, doctors can keep a close eye on them after birth and start treatment as soon as symptoms appear.

In some families, if there have been multiple instances of babies or newborns dying, it may signal the need to look for an LSD as a potential reason. On the other hand, some LSDs that show up later in life are found by chance during visits to different types of specialists such as eye doctors, cholesterol experts, and kidney dialysis centers.

Most babies with an LSD seem completely normal right after they are born, but there are a few exceptions. Tables C, D, F, G, H, J, and K outline the symptoms and methods that doctors might use to tell these diseases apart.

Testing for Lysosomal Storage Disease

If your doctor suspects a lysosomal storage disease (LSD), a type of genetic disorder, they will run some screening tests. These disorders can be hard to identify because they often have features similar to other conditions. Depending on the suspected LSD, your doctor might look for changes in your urine or blood tests. For example, high levels of certain sugars in your urine could point to specific LSDs, while elevated levels of certain enzymes in your blood could suggest conditions like Pompe disease or Gaucher disease.

A dried blood spot (DBS) test, which involves analyzing a small sample of your dried blood, can be particularly helpful. This test is simple, cost-effective, and the sample remains stable during transportation to the lab for analysis. However, if the DBS test result is positive, further testing will be needed to confirm the diagnosis.

For LSDs, further tests often involve determining the levels of specific enzymes in your blood or in cells from your blood or skin. Some enzymes in these cells can cause interference in the test, so skin cells, though requiring a biopsy, are often seen as the “gold standard”. Another method is to use cells from your blood which have been prompted to grow and multiply in the lab. However, this isn’t helpful for all LSDs, as some enzymes might be inherently absent from these cells.

The enzyme levels can be measured using tests that use fluorescence or more expensive tests that use liquid chromatography and mass spectrometry (LC-MS/MS). In some cases, a person may have lower-than-normal levels of an enzyme, but won’t experience any symptoms or signs of the corresponding LSD. This condition, known as ‘pseudodeficiency’, is due to their body still having adequate enzyme activity to metabolize the substrates of the enzyme, thereby preventing their accumulation.

It’s also possible to detect mutations in the genes linked to the enzymes. These techniques involve looking for differences in gene length, or locating specific mutations which can drastically alter the genetic code. However, the definitive diagnosis of an LSD is made by considering the clinical symptoms, biochemical test, radiological findings and genetic testing results together.

Apart from the diagnostic tests, certain tests needed to serve the dual purpose of detecting potential organ damage caused by the LSD and monitor the effectiveness of ongoing treatment. Depending on the specific LSD and the patient’s condition, this could involve anything from X-rays to MRI scans, EKGs, audiometric assessments, pulmonary (lung) function tests, blood tests and more.

In some cases, where a patient is suspected of having an LSD, but has normal enzyme levels and no mutations, further testing is required. Certain proteins, if missing, render the normal enzyme incapable of doing its job, causing symptoms of LSDs.

For families with previous cases of severe LSDs, prenatal screening can be performed using techniques like amniocentesis or chorionic villus biopsy, which involve testing the fluid or tissues surrounding the fetus in the womb.

Screening newborns for LSDs has become more accepted and includes testing for more types of LSDs as new treatments become available. Lastly, an emerging field called metabolomics, which involves the large-scale study of small molecules, shows promise for improving LSD diagnosis and treatment monitoring in the future.

Treatment Options for Lysosomal Storage Disease

Treating diseases related to lysosomes, which are the tiny units inside our cells that help break down and recycle various materials, is best done at specialized medical facilities that offer a variety of treatments. Here are some of the key treatments that physicians use:

1) Enzyme Replacement Therapy (ERT): This treatment involves using lab-made enzymes that are injected into the bloodstream to boost the metabolism of the accumulated substance in the body that the disease causes. However, this treatment is quite expensive and may not be effective in reaching certain areas of the body, such as the brain or poorly circulated tissues. To improve the effectiveness of ERT, researchers are considering various modifications, such as increasing the therapy’s duration, designing it to target specific receptors, directing it to the affected tissue, and implanting capsules of the enzyme directly into the tissue.

2) Pharmacological Chaperone Therapy (PCT): This treatment uses small molecules, called chaperones, to correct misfolding in the proteins making the enzymes that break down materials within the cells. This method is helpful in some diseases related to lysosomes.

3) Proteostasis Regulators: These treatments don’t bind to the enzymes like PCT does, but still work to preserve the enzymes by controlling various steps in breaking down materials within the cells. Although this treatment sounds promising, it can be harmful and is generally not used.

4) Substrate Reduction Therapy (SRT): This method aims to reduce the formation of the materials that accumulate due to the disease, by inhibiting the enzyme that creates these materials in the first place. Although it works slower than ERT, it has been shown to slow the progression of neurological symptoms.

5) Small Molecule Assisted Substrate Transportation (SMAST): This method transforms the material that accumulates due to lack of transport, into another compound that can be easily moved out of the cells.

6) Anti-Inflammatory Agents: These treatments work by reducing inflammation in the body, which is part of the disease process. They help to lessen the damage to organs.

7) Hematopoietic Stem Cell Transplantation (HSCT): Physicians use stem cells from donors or umbilical cord blood to replace bone marrow tissue. These cells can migrate to various organs, including the brain, and become the cells of that tissue, constantly producing the enzyme that is missing due to the disease. This treatment also helps to reduce inflammation and dilution in tissues.

8) Gene Therapy: This method involves modifying the patient’s own stem cells with the correct version of the gene using viruses. These corrected cells are then reintroduced into the patient. This treatment has shown much positive results in clinical trials.

9) Manipulation of Gene Expression: In some cases, a gene has a premature stop signal that stops the production of the enzyme prematurely. Small molecules can be used to bypass this stop signal, correct the gene defect, and restore the enzyme. This technique has not yet been studied in diseases related to lysosomes, but it holds promise for the future.

10) Ancillary Care: Treatments can also help to manage the complications that occur in the different body systems due to these diseases. They might include medications for seizures, specific learning methods for children with cognitive deficits, heart valve replacements, respiratory support, renal replacement therapy and transplantation, braces and corrective surgeries, and psychological counseling and therapies among others.

Ultimately, the best treatments often involve a combination of these methods, depending on the patient’s specific condition and needs.

What else can Lysosomal Storage Disease be?

Lysosomal storage diseases (LSDs) are a type of inherited metabolic disorders that can often present similar symptoms to other diseases. Therefore, understanding the subtle differences between them is key to making a correct diagnosis.

The differential diagnoses for notable LSDs include the following:

• Niemann-Pick A: GM1 gangliosidosis, Wolman disease, Cholesterol ester storage disease
• Niemann-Pick B: Niemann-Pick A, Gaucher, Other Spingolipidosis
• Niemann-Pick C1 and C2 (perinatal): Alfa 1 antitrypsin deficiency, Tyrosinemia, Idiopathic neonatal cholestasis, Congenital infections, Niemann-Pick A, Gaucher disease
• Niemann-Pick C1 and C2 (Childhood): GM 2 gangliosidosis, Other LSDs, Organic acidemias, Maple syrup urine disease, Mitochondrial disorders, Wilson Disease, ADHD, Dystonias
• Niemann-Pick C1 and C2 (Adult): Progressive supranuclear palsy, Alzheimer disease, Frontotemporal dementia, Other psychiatric disorders
• Tay Sachs Disease: Sandhoff disease, Cerebral Neuronal Lipofuscinosis(CLN), Leigh syndrome, Amyotrophic lateral Sclerosis (ALS)
• Sandhoff Disease: Tay-Sachs, Gaucher, Niemann-Pick, CLN(Juvenile and Adult types), Leigh syndrome
• Gaucher Disease: Niemann-Pick diseases, Pompe disease, Hurler disease(MPS I), Tay Sachs disease
• Fabry Disease: Schindler disease, Gaucher disease, Fucosidosis, Erythromelalgia
• Metachromatic leukodystrophy(MLD): ASA pseudodeficiency, Multiple sulfatase deficiency(MSD), Chronic inflammatory demyelinating polyneuropathy(CIDP), Guillain Barre syndrome(GBS)
• Lysosomal Acid Lipase Deficiency (LALD): Wolman disease, Niemann-Pick diseases, Galactosemia, Fructosemia, Aminoacid metabolism disorder, Chamarin Dorfman syndrome
• Krabbe Disease: Adrenal leukodystrophy(ALD), MLD, Canavan’s leukodystrophy, Alexander disease
• CLN 2 (Late infantile Neuronal Ceroid Lipofuscinosis 2)/[tripeptyl peptidase 1(TPP1) Deficiency]: Doose syndrome, Dravet syndrome, Lennox-Gestault syndrome, Lafora disease, Unverricht-Lundborg disease, Chanelopathies( SCN1A or SCN2A), CLN 5,6,7,8,10 diseases, Sialidosis, Galactosialidosis, Grey matter diseases, White matter disease, Mitochondrial diseases, Infections, Intoxications
• Pompe disease(Glycogen Storage Disease II /GSD 2): Werdnig Hofmann syndrome (Spinal muscular atrophy I), Danon disease, Endomyocardial fibroelastosis, Other GSDs, Fascioscapulohumeral, Becker, and Duchenne muscular dystrophies, McArdle(GSD V), Hers(GSD VI) diseases
• Cystinosis: Conditions causing Fanconi syndrome, Lowe syndrome, Wilson disease, Tyrosinemia type 1, Galactosemia, GSDs, LSDs, Diabetes Insipidus
• MPS IV A (Morquio A): MPS IVb, GM 1 gangliosidosis, Other MPS, Mucolipidosis, Legg Calve-Perthes disease, Spondyloepiphyseal dysplasia
• MPS VI (Maroteaux-Lamy Syndrome): MPS I. II, IVa , and VII, Multiple sulfatase deficiency, Mucolipidosis, Sialidosis
• MPS VII(Sly Syndrome): Other MPS, Mucolipidosis
• MPS I (Hurler (severe), Scheie (mild), Hurler-Scheie (intermediate): MPS II and other MPS, Multiple sulfatase deficiency, I-cell disease
• MPS II (Hunter disease-Neuronopathic and Non-neuronopathic): MPS I, Mucolipidosis, Mannosidosis, Multiple sulfatase deficiency

What to expect with Lysosomal Storage Disease

The expected outcome or prognosis for lysosomal storage diseases (LSDs), which are rare genetic disorders that result from the absence or malfunctioning of certain enzymes in the body, depends on several factors:

* The specific symptoms and characteristics of the disease (known as the phenotype)
* The timeliness of the diagnosis
* The specific treatments applied
* The medical facilities available for diagnosis and treatment

In cases where the disease presents with severe symptoms, unfortunately, the expected outcome can be quite poor. Some types of LSDs can involve severe complications, such as hydrops fetalis (a severe form of prenatal edema or swelling in the fetus), or failure of the heart and lungs within the first year of life. In these instances, counseling during pregnancy can be incredibly beneficial.

However, if treatments for LSDs are available and started before damage to the organs occurs, the prognosis improves both in terms of lifespan and quality of life. Even so, it’s important to note that some organ damage can’t be reversed, such as persistent neurological dysfunction (problems with the brain, spinal cord, and nerves) following hematopoietic stem cell transplantation (HSCT, a procedure that transplants healthy cells into a patient’s body) in Hurler disease (a type of MPS I, a form of LSD).

The expected outcome of these diseases is likely to improve as newborn screening becomes more widespread, and as we make further improvements in diagnosis and treatment options.

Possible Complications When Diagnosed with Lysosomal Storage Disease

Lysosomal storage diseases (LSDs) can lead to a variety of complications. Some of these complications are specific to the disease, while others result from treatments associated with these conditions.

Different body systems can be affected by LSDs, each with unique symptoms:

• Nervous System: Symptoms may include seizures, buildup of fluid in the brain, movement disorders, intellectual disability, psychosis, peripheral nerve disorders, carpal tunnel syndrome, and spinal cord compression.
• Cardiovascular: Conditions such as heart enlargement and dilation, irregular heartbeats, heart failure, high blood pressure, heart valve disease, and vascular disease might occur.
• Respiratory: Problems might include lung damage and infection, sleep apnea, breathing failure due to lung damage, and abnormal curvature of the spine.
• Gastrointestinal: Enlarged spleen and spleen disorders, swallowing difficulties, and increased susceptibility to hepatitis C infection might develop.
• Musculoskeletal: Conditions like bone lesions, fractures, deformities, joint contractures, spinal instability, and abnormal curvature of the spine might occur.
• Hematological: A decrease in all types of blood cells might manifest.
• Eyes: Issues might include cloudy corneas and retinal damage leading to visual impairment and blindness.
• ENT (Ear, Nose, and Throat): Enlargement of adenoids and tonsils and related clinical effects, upper respiratory infections, Eustachian tube dysfunction, and mixed hearing loss might occur.

Additionally, various medications used in supportive treatment of LSDs, like sedatives, antiepileptics, antipsychotics, can have side effects and may interact with other drugs.

Patients with LSDs might require surgeries on their nervous system, bones, ENT region, eyes or may require general surgeries. The structure of the neck, jaw, upper airways, and respiratory muscles can create difficulties during anesthesia.

There could also be complications due to treatments like Enzyme Replacement Therapy (ERT) or Hematopoietic Stem Cell Transplant (HSCT). Some patients might develop an immune response against ERT, leading to allergic reactions. In some cases, the treatment needs to be slowed down or stopped, or additional medications are needed. Risk of infection is also present with some forms of ERT.

HSCT can result in complications due to radiation and immunosuppressive therapy, including opportunistic infections and graft versus host disease.

Adeno-associated vectors for gene therapy might also have complications like delayed onset of action, need for repeated administration and the development of anti-vector antibodies.

Lastly, it’s important for healthcare providers to recognize early signs of caregiver burnout and provide the necessary support.

Preventing Lysosomal Storage Disease

Teaching patients is a crucial part of handling lysosomal storage diseases (LSDs). These are a group of rare diseases where the body’s cells can’t break down certain types of molecules, leading to various health problems. Parents of kids with these diseases will need clear, detailed information about their child’s condition. This will help them understand and adjust to the realities of managing a long-term health condition.

Parents should also be encouraged to reach out for help, such as joining support groups or getting in touch with organizations that focus on these diseases. These can be invaluable sources of advice, as well as emotional support. There are also new treatments available for these diseases, and parents will need help to find health centers where these treatments are offered.

Additionally, it could be really helpful for parents to understand how these diseases might be passed down to future generations. This can help ease worries and assist in planning and handling potential complications.