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What are lysosomal storage diseases?

Definition of lysosomal storage disease

Lysosomal storage diseases are genetic conditions, emerged due to a lack of functional enzymes to control the excessive accumulation of their respective substrates.

Sometimes a lysosomal enzyme may be either defective or completely absent, this leads to aggregation of the corresponding materials, that contribute to lysosomal storage diseases.

Lysosomal storage diseases are inherited disorders that are only developed in autosomal recessive conditions, which means that both parents of the infant must carry an abnormal gene that inhibits the cells from making functional enzymes or proteins.

Some of the major lysosomal disorders, symptoms and the defective genes responsible for lysosomal diseases have been described below.

Key points of Lysosomal storage diseases

  1. Every eukaryotic cell has two types of proteolytic mechanisms including autophagy and lysosomal degradation.
  2. The autophagy mechanism removes specific cell organelle, which is marked as unwanted or aged factors including mitochondria, endoplasmic reticulum (ER), peroxisomes, and Golgi complex.
  3. Lysosomes are popular as suicidal bags of the cell and are also referred to as recycle bins of the cell.
  4. Lysosomes utilize their enzymes to degrade the accumulated and unwanted cellular or misfolded proteins.
  5. Lack of lysosomal enzymes in the lysosomes leads to the development of lysosomal storage disease.
  6. Based on specific enzyme deficiency, the lysosomal storage diseases have been separated into different disorders.
  7. The deficiency of specific enzymes or enzymatic action is due to the loss of function of a specific gene within the genome.
  8. Lysosomal storage diseases are developed in an autosomal recessive manner, which means both parents of the individual have provided a baby with a mutated gene.

The major lysosomal storage diseases

  1. Tay-Sachs disease
  2. Gaucher disease
  3. Hunter syndrome
  4. Pompe disease 
  5.  Niemann Pick disease
  6. Fabry disease
  7. Metachromatic leukodystrophy
  8. Krabbe
  9. Salla disease (free sialic acid storage disease)
  10. Cobalamin C disease
  11. Mucolipidosis II
  12. Sandhoff disease
  13. Cystinosis

1. Tay-Sachs disease

Tay-Sachs is a dangerous genetic disorder inherits from parents. Tay-Sachs is an autosomal recessive condition that continuously damages the nerve cells in both the spinal cord and brain. This disease is caused due to the lack of functional gene HEXA, which provides instructions to synthesize the lysosomal enzyme, beta-hexosaminidase A.  This enzyme is located in the lysosomes and plays a pivotal role in the brain and spinal cord. In general, within the lysosomes, beta-hexosaminidase-A is responsible for the breakdown of a fatty substance called ganglioside-GM2.

The lack of functional enzymes results in the accumulation of ganglioside- GM2. The accumulation of GM2 substance act as a toxic compound, especially in neurons of the brain and spinal cord. This condition is sometimes stated as a GM2-gangliosidosis or a lysosomal storage disorder. Tay-Sachs disease is related to various defects such as paralysis, blindness and hearing loss, intellectual disability, and seizures.

2. Gaucher disease

Gaucher disease is a genetic condition that inherits from both parents. This lysosomal storage disease affects most body organs and tissues. Base on disease characteristics, Gaucher disease has been separated into several types, Type-1 Gaucher disease, Gaucher disease type 2 and 3, Perinatal lethal Gaucher disease, and Cardiovascular type Gaucher disease. Beta-glucocerebrosidase is a very important enzyme found in lysosomes.

In physiological conditions, the enzyme beta-glucocerebrosidase breakdown the substrate, glucocerebroside into sugar (glucose), and a small fat molecule (ceramide). In general, the enzyme is a product of the gene called GBA. Any mutations in the GBA gene associate with the production of the abnormal or non-functional enzyme result in the accumulation of glucocerebrosides. The reduced or eliminated activity of beta-glucocerebrosidase makes the cells to excess accumulation of respective substrate, which can build up higher toxic levels within the cells. Due to these toxic levels, various body organs could be damaged.

a. Type-1 Gaucher disease

Type-1 Gaucher disease will not cause any damage to neurons of the brain and spinal cord (central nervous system); hence, the disease is also called non-neuronopathic Gaucher disease Type-1. Major signs and symptoms of this type of disease include enlargement of both liver and spleen (hepatosplenomegaly), reduction in red blood cells (anemia), easy bruising due to decrease in blood platelets (thrombocytopenia), lung disease, and abnormalities in bone formation.

b. Gaucher disease type 2 and 3

The other types of disease such as Type 2 and 3 can cause severe damage to the nervous system, which may contribute to life-threatening conditions. Hence, types 2 and 3 Gaucher disease are called neuronopathic diseases. The major disorders of these diseases include difficult eye movements, seizures, and brain damage.

c. Perinatal lethal Gaucher disease

This type of Gaucher disease appears before birth or in the early developmental stages of a baby in the womb (in infancy). This is the most severe type of disease known as Perinatal lethal Gaucher disease. The main characteristic features of the perinatal lethal disease include hydrops fetalis (extensive swelling caused by fluid accumulation before birth), ichthyosis (dry, scaly skin), or other skin problems, hepatosplenomegaly, idiosyncratic facial features, and serious neurological disorders. Due to these severe symptoms, the baby may die after birth or in few cases before birth.

d. Cardiovascular type Gaucher disease

This is another type of Gaucher disease that affects the heart by making heart valves harden (calcify). People who are suffering from a cardiovascular type of Gaucher disease may also face other disorders like abnormalities in vision, bone disease, and mild spleen enlargement (splenomegaly).

3. Hunter syndrome

Hunter syndrome is also called Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disease, that affects various body parts and appears especially in males. This disease is referred to as a progressively debilitating disorder; however, the rate of progression will be different among affected individuals.

The gene IDS encodes the enzyme called iduronate 2-sulfatase, which is found in the lysosomes. This enzyme is required for the breakdown of large sugar molecules called glycosaminoglycans (GAGs). The enzyme, iduronate 2-sulfatase separates the sulfate group from the molecule called sulfated alpha-L-iduronic acid, which is found in two types of glycosaminoglycans called heparan and dermatan sulfates. Mutations in IDS are related to deficiency of the enzyme, iduronate 2-sulfatase, which results in excessive aggregation of glycosaminoglycans in the cell. The high concentration of glycosaminoglycans in the lysosomes increases their size that manifesting into the enlargement of tissues and organs.

The disease appears particularly between the age of 2 and 4, these individuals develop large lips, large rounded cheeks, a broad nose, and an enlarged tongue (macroglossia).

4. Pompe disease 

The other terms of this disease are acid maltase deficiency disease, acid maltase deficiency disease, alpha-1,4-glucosidase deficiency disorder, AMD deficiency of alpha-glucosidase, GAA deficiency, glycogen lysosomal storage disease type II, glycogenosis Type II, GSD II, GSD2, and Pompe’s disease.

Pompe disease is an inherited genetic autosomal recessive disorder, in which excessive aggregation of a complex sugar molecule called glycogen takes place in cells of the body. Glycogen accumulation in the organs or tissues especially, the muscles causes abnormalities in muscular functions. The lysosomal enzyme, acid alpha-glucosidase (also known as acid maltase) product of the gene GAA. Any mutation in this gene related to deficiency of enzyme or production of the inactive form of the enzyme leads to excessive accumulation of glycogen. In lysosomes, this enzyme plays a pivotal role in the breakdown of glycogen into an accessible energy molecule, glucose.

Research findings have described Pompe disease in three forms based on their severity and the age at which they appear, Infantile-onset, Non-classic infantile-onset, and Late-onset.

a. Infantile-onset

This type of Pompe lysosomal storage disease starts within a few months after birth. Infants who are suffering from this type of disease may face the following health problems, heart defects, muscle weakness (myopathy), poor muscle tone (hypotonia), and liver enlargement (hepatomegaly). After the onset of the disease, infants may affect physical conditions like difficulty in gaining weight and growth. Untreated conditions of the disease related to the early death of infants due to heart failure in the first year of life.

b. Non-classic infantile-onset

The symptoms of non-classic infantile-onset Pompe disease generally appear after one year of age. It is associated with disorders like delayed motor skills (such as rolling over and sitting) and severe muscle weakness. The size of the heart becomes large (cardiomegaly), but the affected person usually will not face any problems with heart function. The weakness of muscles in this disorder results in emerging of serious breathing problems, but most children with non-classic infantile-onset Pompe disease survive only for few years.

c. late-onset

The late-onset Pompe disease will appear after childhood or adulthood. However, the effectiveness of the disease is very less compared to infantile-onset and rarely affects heart function. Most people with late-onset Pompe disease may face problems like progressive muscle weakness, particularly in the legs and the trunk. This disease mostly affects lung muscles that result in breathing trouble. A progressive increase of severity related to breathing problems, that can lead to complete respiratory failure.

5. Niemann Pick disease

 Niemann Pick is a lysosomal storage disease that affects various body organs.  Niemann Pick disease shows significant severity in persons who are born with a deficiency of the enzyme, acid sphingomyelinase, which is a lysosomal enzyme involved in the breakdown of excessively accumulated sphingomyelin in the lysosomes. The functional sphingomyelinase enzyme catalyzes the breakdown of larger lipid, sphingomyelin into smaller lipid called ceramide.

The gene, SMPD1 is responsible for the production of functional sphingomyelinase enzyme, however, any mutations in this gene lead to the accumulation of this large molecule within the lysosomes. Aggregation of this lipid molecule makes cells malfunctioning and eventually die. As the disorder progress, the cell completely losses its activity in the tissues and organs, e.g., in the brain, lungs, spleen, and liver.

Niemann Pick disease has been divided into four main types, based on their genetic cause, the signs and symptoms of the condition, severity, and the age at which they appear include type A, type B, type C1, and type C2.

  1. Niemann Pick disease type A and type B are caused due to a lack of a functional enzyme, sphingomyelinase, which breaks down sphingomyelin into ceramide.
  2. Niemann Pick disease types C1 and C2 are caused due to a lack of functional protein, that is involved in the transport of lipids within cells.

6. Fabry disease

Fabry disease is a lysosomal storage disease that affects different organs of the body.  Fabry disease shows apparent severity in the affected people. The enzyme alpha-galactosidase A is found in lysosomes and involved in the breakdown of globotriaosylceramide in the cells.

Mutations in the gene GLA disturb the structure and function of the enzyme. Deficiency of the enzyme is related to the lack of the breaking down process in the cell, which manifests into the accumulation of the harmful substrate throughout the body. This accumulation occurs especially in the cells that are lining the blood vessels in the skin and cells in the kidneys, heart, and nervous system. The more concentration of the substance damages the cells, which emerges various signs and symptoms of Fabry disease.

Fabry disease is also linked to potentially life-threatening problems such as progressive kidney damage, heart failure, or excessive strokes.

Few affected persons will have milder types of the disorder that may appear later in life and affect only kidneys or heart.

7. Metachromatic leukodystrophy

Metachromatic leukodystrophy is a lysosomal storage disease caused due to gene mutation or lack of functional gene, that encodes the enzyme called arylsulfatase A. The enzyme, arylsulfatase A is found in the lysosome. Inside the lysosomes the enzyme arylsulfatase A assists breakdown of sulfatides.

The individuals with metachromatic leukodystrophy possess mutations in their genome. Especially the gene, ARSA encodes this enzyme, which prevents excessive accumulation of substrate, sulfatides. Any alterations in this gene result in a lack of a functional enzyme. Excessive accumulation of sulfatides in the cells especially in nerve cells causes damage to the nerve system.

In general, cells in the nervous system produce myelin substance that insulates and protects nerves. The sulfatide aggregation in myelin-producing cells makes progressive destruction of white matter (leukodystrophy) throughout the nervous system. The neurological problems are the main characteristics of metachromatic leukodystrophy, which are related to loss of sensation in the extremities (peripheral neuropathy), inability to speak, seizures, paralysis, blindness, and hearing loss. Gradually, the affected person may lose awareness of their surroundings and become unresponsive.

8. Krabbe

Krabbe (KRAH-buh) is an inherited autosomal recessive disorder (lysosomal storage disease) that damages the protective coat (myelin) of nerve cells in the brain and throughout the nervous system.  Generally, the Krabbe disease can develop during the childhood, adolescence, or adulthood period (late-onset forms).

The main symptoms of the disorder in the initial periods are vision loss and walking difficulties. However, signs and symptoms may be different among affected persons. At most, the persons with late-onset of Krabbe disease may survive many years after the disorders developed. In the US, about 1 in 100,000 people severely suffer from Krabbe disease. In few cases, it will be 6 in 1000 people.

In normal people, the gene, GALC provides the information to synthesize an enzyme called galactosylceramidase, which is involved in the degradation of galactose-associated fats, especially galactolipids also called galactosylceramides. This lipid molecule is a crucial factor in myelin; the breakdown of galactosylceramide is an essential process as the normal turnover of myelin is required throughout life.

Alterations in the GALC gene prevent the production of functional galactosylceramidase enzyme that leads to accumulation of galactosylceramide in certain cells, e.g., forming globoid cells. The enzyme aggregates spoil the myelin synthesizing cells. Damaged cells no longer synthesize the myelin, which leads to demyelination of the nervous system. Without a myelin sheet, nerve cells of the brain and other parts of the body cannot send signals properly, leading to vision loss and walking difficulties, which are the main signs and symptoms of Krabbe disease.

9. Salla disease (free sialic acid storage disease)

 Salla disease is the mildest form of the free sialic acid lysosomal storage disease, that majorly affects the nervous system. Infants with Salla disease generally start to experience reduced muscle tone (hypotonia) during the first year of life, followed by continuous emerging neurological problems.

Signs and symptoms of the disease include intellectual disability, delay in development, seizures, speech impairment, ataxia, muscle spasticity, and involuntary slow movements of the limbs (athetosis). However, most affected children learn to walk. Mutations in the SLC17A5 gene cause this disease and it is inherited in an autosomal recessive manner (genes of both parents affect the infant). Treatment is typically symptomatic and supportive.

The SLC17A5 gene encodes the protein called sialin that is found mainly on the membrane of the lysosome, a major organelle in the cell that digest and recycle cellular components. Sialin transports the metabolite called free sialic acid, which is generated when certain proteins and fats are digested. In general, free sialic acid should leave the lysosomes and transfer to other parts of the cell.  However, mutations in the gene cause excessive accumulation of free sialic acid in lysosomes, which results in the emerging severe health problems mentioned above.

10. Cobalamin C disease

Cobalamin C disease (also known as methylmalonic aciduria with homocystinuria), is an inherited genetic disorder (lysosomal storage disease). The onset and severity of the disease are various with age progression. Most individuals develop disease symptoms within the first year, which are often prompted by fasting, illness, infection, or consumption of more protein.

The main characteristic symptoms include mental retardation, hypotonia, lethargy, intellectual disability, seizures, and eye problems. The MMACHC gene provides information to synthesize the enzyme, cobalamin reductases that involve in the conversion of vitamin B12 (also called cobalamin) into one of two molecules, adenosylcobalamin (AdoCbl) or methylcobalamin (MeCbl).

Adenosylcobalamin is important for the normal function of an enzyme, methylmalonyl CoA mutase. The enzyme is involved in the breakdown of certain protein building blocks (amino acids), fats (lipids), and cholesterol. Adenosylcobalamin is called a cofactor for methylmalonyl CoA mutase because it helps enzymes carry out their function. Adenosylcobalamin is also a cofactor for methionine synthase. This enzyme converts the homocysteine amino acid to a methionine. The body uses an amino acid, methionine to make proteins, and other important methionine-derived compounds.

The emerging symptoms of this disease are due to mutations in the MMACHC gene, which results in a build-up of these substances and their metabolites in the organs and tissues of the body.

11. Mucolipidosis II

Mucolipidosis II is an inherited lysosomal storage disease that continuously damages various body parts. In more cases, affected persons will not survive long periods. Death may happen at an early stage of an infant’s life. The affected child during the initial life develops symptoms such as muscle tone (hypotonia) and a weak cry. Affected children will lose proper growth after birth and gradually lack the growing condition after the second year of life. The development of body organs will be diminished and the development of motor skills and speech will be impaired.

Generally, affected children develop abnormal rounded upper back (kyphosis), dislocated hips, feet that are abnormally rotated (clubfeet), unusually shaped long bones, and short hands and fingers. The baby with this condition also suffers from joint deformities (contractures) that significantly affect mobility. Most babies cannot walk independently if they develop mucolipidosis II.

The main cause of this disorder is the lack of functional gene, GNPTAB in developing babies, mutations and some other gene modulatory factors change the frequency of the gene that leads to loss of function of the respective gene. Inactivated gene, GNPTAB no longer produces the functional enzyme, GlcNAc-1-phosphotransferase, which transfers certain newly synthesized enzymes to lysosomes. The deficiency of these functional factors in lysosomes leads to the development of certain lysosomal storage diseases.

12. Sandhoff disease

Sandhoff is an inherited lysosomal storage disease and that destroys nerve cells (neurons) of the brain and spinal cord by accumulating unwanted substances fats and sugars in the lysosomes. This disease rarely appears in people, however, the most common and severe type of Sandhoff disorder becomes apparent in infancy. The babies who are susceptible to cause this lysosomal storage disease appears normally until 3 to 6 months of age. Once their development starts, the implications will start to appear as lowering the growth and impairing the muscle movement. The affected babies also lose their motor skills, vision, and hearing. The Cherry-red spot is an eye disorder, which can be recognized with an eye test and referred to as a main characteristic feature of this disorder.

The functional gene, HEXB is crucial in living cells that provide the specific protein, which is a part of two important lysosomal enzymes in the nervous cells, beta-hexosaminidase A and beta-hexosaminidase B. Any mutation in the gene, HEXB removes the activity of beta-hexosaminidase A and beta-hexosaminidase B, which inhibits these enzymes from breaking GM2 ganglioside and other molecules. Due to the presence of defective enzymes or deficiency of the enzymes contribute to excessive accumulation of their respective substrates, GM2 ganglioside. This condition accumulates unwanted substrate in toxic levels, especially in nerve cells of the brain and spinal cord. A buildup of GM2 ganglioside results in continuous damage of the nerve cells, which develops many of the signs and symptoms of Sandhoff disease and other lysosomal storage diseases (e.g., gangliosidosis).

13. Cystinosis

Cystinosis is an inherited lysosomal storage disease, in which excessive accumulation of the amino acid cystine within the cells takes place. Toxic levels of cystine damage the cells and often form crystals that can build up and develop problems in various organs and tissues. The kidneys and eyes are particularly more susceptible to the damage; the muscles, pancreas, thyroid, and testes could also be affected. Depending on the severity, there are three different forms of cystinosis such as nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis.

Nephropathic cystinosis is a very severe form and appears in newborn babies, causing poor growth and a few types of kidney problems.  The most possible causative problems include soft bowed bones (hypophosphatemic rickets), increased urination, thirst, dehydration, abnormally acidic blood, photophobia, muscle deterioration, blindness, inability to swallow, diabetes, thyroid, and nervous system problems.

An intermediate cystinosis is a moderate-severe form and in some cases, severity may be high and causes at a later age. Intermediate cystinosis typically becomes apparent in affected persons mostly in adolescence. Faulty kidneys and corneal crystals are the main initial characteristic features of this disorder. Untreated intermediate cystinosis may damage the kidney completely, but usually not until the late teens to mid-twenties.

Non-nephropathic is moderately less severe compared to the other two forms, the individuals with non-nephropathic or ocular cystinosis generally suffer from photophobia due to cystine crystals in the cornea, but usually, do not cause kidney problems or most of the other signs and symptoms of cystinosis. Due to the lack of severe symptoms, the age at which this form of cystinosis is diagnosed distinctly in wide ranges.

These three types of cystinosis are caused by mutations in the gene, CTNS. Any mutations in the gene result in a deficiency of a transporter protein called cystinosis. Within the cells, this seven-transmembrane protein that functions as an active transporter normally moves amino acid, cystine out of the lysosomes, which are compartments in the cell that digest and recycle materials. When cystinosis is deficient or defective, then cystine accumulates in toxic levels and forms crystals in the lysosomes. These cystine aggregates can damage the cells in the kidneys and eyes and may also affect other organs.


Frequently asked questions

1. Which of the following cell can release the enzymes of the lysosome to the outside of the cell to digest the extracellular components?

a) Osteoblast

b) Osteoclast

c) Osteocytes

d) Hepatocytes

Answer: The bone resorptive cell such as osteoclast is involved in extracellular digestion by releasing the enzymes of lysosomes outside the cell.

2. Which of the following lysosomal storage disease causes severe dame to neurons of the brain and spinal cord (central nervous system), which is similar to the conditions and symptoms of Tay-Sachs disease.

a) Gaucher disease Type-1 and 2

b) Gaucher disease Type-2 only

c) Gaucher disease Type-1 and 3

d) Gaucher disease Type-2 and 3

 Answer: Gaucher disease Type-2 and 3



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