Lysosomal storage diseases

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

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

Lysosomal storage diseases are inherited disorders that are developed in autosomal resistive condition only, which means both parents of the infant must carry the abnormal gene that inhibit the body from making functional enzymes or proteins.

About some of the major lysosomal disorders, symptoms and their defective genes have been described below.


Key points

  1. Every eukaryotic cell has two types of proteolytic mechanisms such as autophagy and lysosomal degradation.
  2. Autophagy mechanism removes specific cell organells, which are marked as unwanted or aged factors such as Mitochondria, ER, peroxysomes, and GC.
  3. Lysosomes popular as suicidal bags of the cell and also referred as recycle bin of the cell.
  4. Lysosomes utilizes their enzymes to degrade the accumulated cellular unwanted or misfolded proteins.
  5. Lack of lysosomal enzymes in the lysosomes leads to emerging of lysosomal storage disease.
  6. On the basis of specific enzyme deficiency, the lysosomal storage diseases have been described as different disorders.
  7. Deficiency of specific enzyme is due to loss of function of specific gene with in the genome.
  8. Lysosomal storage diseases are developed in autosomal recessive manner, which means both parents of the individual should provide baby with function-less gene.
The major lysosomal storage diseases
1. Tay-sachs disease

Tay-sachs is a dangerous genetic disorder inherits from parents. Tay-sachs is autosomal recessive condition that continuously damage the nerve cells in both spinal card and brain. The Tay-Sachs disease (Lysosomal storage disease) caused due to lack of functional lysosomal enzyme, beta-hexosaminidase A, which located in the lysosomes and plays a pivotal role in brain and spinal cord. Generally, within the lysosomes, beta-hexosaminidase-A involved in the breakdown of fatty substance called ganglioside-GM2.

The lack of functional enzyme results into 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 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 the parents. This lysosomal storage disease affects variety of body organs and tissues. Base on disease characteristic features Gaucher disease has been separated into several types. Beta-glucocerebrosidase is very important enzyme found in lysosomes.

In physiological conditions the enzyme beta-glucocerebrosidase breakdown the substrate, glucocerebroside into a sugar (glucose) and a simpler fat molecule (ceramide). Actually, this enzyme translated from the gene called GBA. Any mutations in GBA gene associate to production of abnormal or non-functional (protein) enzyme that results in accumulation of glucocerebrosides. Reduced or eliminated activity of beta-glucocerebrosidase makes the cells to excess accumulation of respective substrate, that can build up higher toxic levels within cells. Due to these toxic levels, various body organs may damage.

a. Type-1 Gaucher disease

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

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, this may sometimes be causing life-threatening conditions. Hence, types 2 and 3 Gaucher disease are called as neuronopathic diseases. The major disorders of these disease types are difficult eye movements, seizures, and brain damage.

c. Perinatal lethal Gaucher disease

This type of Gaucher diseases causes before birth or in early developmental stages of baby in the womb (in infancy). This is 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 baby may die after birth or in some cases before birth.

d. Cardiovascular type Gaucher disease

This is other type of Gaucher diseases that affects the heart, by making heart valves to harden (calcify). The people who are suffering from 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 also called as Mucopolysaccharidosis type II (MPS II) is lysosomal storage disease, that affects various body parts and appears especially in males. This disease is referred as progressively debilitating disorder, in which the rate of progression will be different among affected individuals.

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

This disease appears particularly between the age of 2 and 4, in these ages individual develops large lips, large rounded cheeks, a broad nose, and an enlarged tongue (macroglossia).


4. Pompe disease 

The other names of this disease are acid maltase deficiency, acid maltase deficiency disease, alpha-1,4-glucosidase deficiency, 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 genetical autosomal recessive disorder in which excessive aggregation of a complex sugar molecules called glycogen takes place in cells of the body. Glycogen accumulation in the organs or tissues, particularly muscles causes abnormalities in muscular functions. The lysosomal enzyme, acid alpha-glucosidase (also known as acid maltase) provided from the gene GAA. Any mutation in this gene related to deficiency of enzyme or production of inactive form of enzyme that leads to excessive accumulation of glycogen. In lysosomes, this enzyme plays a pivotal role in breakdown of glycogen into the accessible energy source glucose.

Researcher findings have described Pompe disease in to three forms, they differ in severity and the age at which they appear. Those three types are a) infantile-onset, b) non-classic infantile-onset, and c) late-onset.

a. Infantile-onset

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

b. Non-classic infantile-onset

The symptoms of non-classic form of infantile-onset Pompe disease generally appears 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 affected person usually will not face any problem 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 (only early childhood).

c. late-onset

The late-onset Pompe disease will appear after childhood or adulthood. However, potentiality 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 results 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 organ systems.  Niemann Pick disease shows significant severity in persons who are suffering with this disease. The acid sphingomyelinase is a lysosomal enzyme involved in the breakdown of excessively accumulated sphingomyelin in the lysosomes. The functional sphingomyelinase enzyme required for the breakdown of large lipid, sphingomyelin into another type of small lipid called ceramide.

The gene, SMPD1 is responsible for the production of functional sphingomyelinase enzyme, however, any mutations in this gene lead to accumulation of this large molecule within the lysosome. This large fat molecule accumulation makes cells to malfunction and eventually die. As a disorder progress, the cell completely loss its function 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 and they include type A, type B, type C1, and type C2.

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


6. Fabry disease

Fabry disease is a lysosomal storage disease that affects different organ of the body.  Fabry disease shows apparent severity in people, who are suffering from this disease. The enzyme alpha-galactosidase A 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 related to lack of the breaking down process in the cell, that manifesting into accumulation of the substrate throughout the body. This accumulation especially in the cells that 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 emerge various signs and symptoms of Fabry disease.

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

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


7. Metachromatic leukodystrophy

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

The individual with metachromatic leukodystrophy possess mutations in their genome. Especially the gene, ARSA encodes this enzyme, that prevents excessive accumulation of its substrate. Any alterations in this gene results in to lack of functional enzyme. Excessive accumulation of sulfatides in the cells especially in nervous cells cause the damage to nerve system.

Generally, cells in the nervous system produce myelin substance that insulates and protects nerves. This 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, they may lose awareness of their surroundings and become unresponsive.


8. Krabbe

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

The main symptoms of the disorder in initial periods are Vision loss and walking difficulties. However, signs and symptoms may different between affected persons. Most commonly Persons with late-onset of Krabbe disease may survive many years after the disorders developed. In the US, about 1 in 100,000 people develop the Krabbe disease affects. In few cases, it will be 6 in 1000 people.

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

Alterations in the GALC gene prevents 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 synthesized cells. Damaged cells no longer synthesize the myelin that leads to demyelination of nervous system. Without myelin sheet, nerve cells of the brain and other parts of the body cannot send signals properly, leading to the Vision loss and walking difficulties, which are 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 starts to experience reduced muscle tone (hypotonia) during the first year of life, followed by slowly continuous neurological problems.

Signs and symptoms of the disease include intellectual disability and 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 lysosome, major organelle in the cell that digest and recycle cellular components. Sialin transport the metabolite called free sialic acid, which is generated when certain proteins and fats are digested. Generally, free sialic acid should leave the lysosome and transport to other parts of the cell.  However, mutations in the gene cause excessive accumulation of free sialic acid in lysosome, that result in emerging severe health problems mentioned above.


 10. Cobalamin C disease

Cobalamin C diseases (also known as methylmalonic aciduria with homocystinuria), is an inherited genetic disorder (lysosomal storage disease). Onset and severity of the disease is 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 protein that involve in 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. This enzyme involved in breakdown of certain protein building blocks (amino acids), fats (lipids), and cholesterol. Adenosylcobalamin is called as cofactor for methylmalonyl CoA mutase because it helps enzyme carry out its function. Adenosylcobalamin is also a cofactor for methionine synthase. This enzyme converts the homocysteine amino acid to methionine. The body uses amino acid, methionine to make proteins and other important methionine-derived compounds.

The emerging of this diseases symptom are due to mutations in the MMACHC gene, that results in build-up of these substances and their metabolites in the organs and tissues of the body.


11. Mucolipidosis II

Mucolipidosis II is inherited lysosomal storage disease that continuously damages various body parts. More cases affected persons will not survive longer period. Death may happen early age of infant life. The affected child during the initial life develops symptoms such as muscle tone (hypotonia) and weak cry. Affected children will loss proper growth after birth and gradually lack the growing condition after second year of life. Developmental of body is diminished and development of motor skills and speech will be impaired.


Generally, affected children develop abnormally 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 with joint deformities (contractures) that significantly affect mobility. Most babies cannot walk independently if they develop mucolipidosis II.

The main cause of this disorder is 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 respective gene. Inactivated gene, GNPTAB no longer produce the functional enzyme, GlcNAc-1-phosphotransferase, which transfer the certain newly made enzymes for to lysosomes. Deficiency of this functional factors in lysosomes leads to development of certain lysosomal storage disease.


12. Sandhoff disease

Sandhoff is 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 the people, however, the most common and severe type of Sandhoff disorder becomes apparent in infancy (early stage in the development or growth of babies). 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 starts 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 as main characteristic feature of this disorder.


The functional gene, HEXB is crucial in living cells that provides 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, that inhibits these enzymes from breaking down of GM2 ganglioside and other molecules. Due to presence of defective enzymes or deficiency of enzymes contribute to excessive accumulation of their respective substrates, e.g. GM2 ganglioside. This condition buildup unwanted substrate in toxic levels, especially in nerve cells of the brain and spinal cord. A buildup of GM2 ganglioside result in continuous damage of these 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 inherited lysosomal storage disease in which excessive accumulation of the amino acid cystine within the cells takes place. Toxic level of cystine damages cells and often forms 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 may also be affected. Depending on severity there are three different forms of cystinosis such as nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis.

Nephropathic cystinosis is very severe form and starts in new born baby, causing poor growth and a particular type 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.

Intermediate cystinosis is moderate severe form and in some cases, severity may be high and causes at a later age. Intermediate cystinosis typically becomes apparent in affected person 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 other two forms, the individuals with non-nephropathic or ocular cystinosis generally suffer with 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 mutation in the gene results in deficiency of a transporter protein called cystinosin. 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 cystinosin 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.


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

a) Osteoblast

b) Osteoclast

c) Osteocytes

d) Hepatocytes

Answer: The bone resorptive cell, Osteoclast involved extracellular digestion by releasing the enzymes of lysosomes outside of the cell.


2. Which of the following lysosomal storage disease causes severe dame to neurons of brain and spinal card (central nervous system), that is similar to 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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