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Lysosomal Storage Disorder and its Treatment
Lysosomal storage disorder (LSD), the very rare inherited disorder is a condition due to lysosomal dysfunction of the cell. Lysosome, the organelle of a body cell, acts as the recycling centre of the cell by breaking down the waste substances (substrates) generated in the cell into useful product which in turn is utilized by the cell. Also, any foreign body entering the cell is evaded by lysosome. Lysosome also digests dead cells and thus its role in short can be explained as cellular substrate management and cellular digestion.

The history of Lysosomal storage disorder dates back to 1880’s even before the discovery of lysosome in 1960s. About 40 different hydrolytic enzymes (proteins) are essential for proper functioning of the lysosome. Each of these enzymes is responsible for reduction of particular substrate and deficit or absence of any of these enzymes result in substrate accumulation in the cell causing various diseases categorized under LSD. To name a few, they are Tay-Sachs disease, Gaucher disease, pompe disease, Niemann-pick disease, Farber disease, Krabbe disease, Sandhoff disease, Schindller disease, salla disease and Wolman disease. The most affected age group is children, once inherited the disease, they die even before 15 years of age. Various researches on LSD have proved the average ratio of prevalence of this disorder is 1 in 5000 live births.

The various signs and symptoms of LSD depend on the type of enzyme deficient and the particular type of cell (liver cell, brain cell and so on) which is affected due to Lysosomal dysfunction. Some of the symptoms are reduced motor skills, growth retardation, enlarged organs and rare facial features. Based on the symptoms, the adversity of the disorder is diagnosed by various techniques like enzyme assay and mutation analysis.

In enzyme assay technique, the enzyme levels in patients with LSD are assessed and compared to the desirable level. This technique is even applicable to testing fetus suspected to have inherited LSD, where the sample is collected through amniocentesis. Whereas mutation analysis is carried out for patients suspected to have inherited the disease from carriers in their family.

Treating LSD patient is a challenging task due to restriction in treatment methods and also the symptoms of LSD have adverse effects on overall body system. Most of the LSD patients are treated by managing symptoms. The few treatment methods available for specific Lysosomal storage disorder are Bone marrow transplantation, enzyme replacement therapy, substrate reduction therapy, Umbilical cord blood transplant, Gene therapy and chaperone therapy.

Bone marrow transplant involves transplanting stem cells from a healthy donor to the patient to stimulate the production of the deficient enzyme. In enzyme replacement therapy, the genetically engineered copy of the deficient enzyme is given to the patient intravenously. The rate of production of substrate responsible for the disorder is slowed by administering drugs in substrate reduction therapy. Though these methods prove to be considered treatment methods for LSD each of it has its own limitations which led to the development of research in the field of various treatment methods.

As a result the developed methods are enzyme enhancement therapy, substrate synthesis inhibition therapy, gene therapy and chaperone therapy. In enzyme enhancement therapy, the defective enzymes in LSD are stabilized and in substrate synthesis inhibition therapy applies the principle of blocking a step in substrate production thus reducing the accumulation. Gene therapy, as the name indicates the normal copy of gene replaces the mutated gene responsible for deficit enzyme, thus inducing the normal production and function of the enzyme.

Inspite of the availability of various treatment methods and diverse research to derive suitable treatment methods, the success of it depends on the condition of the patient. While treating a patient for LSD, all the other ailments, past history etc has to be taken into consideration. A complete clinical history of the patient has to be maintained and it also involves care from multidisciplinaries to treat a patient for Lysosomal storage disorder because of its complexity.

Thus the cause, symptom, diagnosis and available treatment methods for LSD is discussed. All the available treatment methods are costly and hence the earlier the diagnosis of the disease increases the maximum chances of survival from the available treatment methods. The knowledge on LSD is significant for individual and medical specialist to diagnose the disease early and treat it.
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Lysosomal storage diseases known as LSDs is a series of genetic disorders owing to problems in any aspect of lysosomal biology. In the last two decades different treatments have been introduced to deal with these conditions. And, the most famous among them is enzyme replacement therapy ERT. Yes some of these disorders have been successfully treated with enzyme replacement therapy.

But, it must be understood that this therapy has some limitations like biodistribution of recombinant enzymes and too much financial cost.
Recently a new strategy for the treatment of LSDs has been launched and it is called as pharmacological chaperone therapy PCT. It is based on chaperone molecules which helps the folding of mutated enzymes. Yes, their functionality and lysosomal trafficking are improved through this strategy.

After in-depth studies, pharmacological chaperone therapy is supposed to be translated into clinical applications for dealing with Gaucher, Pompe , and Fabry diseases.

This strategy could only be used on those patients having chaperone responsive mutations.

Recently, a demonstration has been carried to asses whether these kinds of therapies have any negative impacts or not. It has also been determined that whether PCT is worth using in clinical applications.
This demonstration moots the drawbacks and strengths of the above mentioned therapies available for Lysosomal storage diseases and suggests that a research in future should be directed towards the improvement of treatment protocols. Besides, it has also been proposed that combination of different available therapies should also be investigated for determining the outsome of Lsds patients.

It goes without saying that this enzyme replacement therapy had been suggested by De Dude in the early years of 1960s. He said that these Lsds diseases could be diagnosed with the advent of genetic molecular technique. On the contrary, in the early years of 1980s, Hobbs proposed that Bone marrow transplantation could also be used for combating against Lysosomal storage diseases.
Sasa Milosevic
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Well, LSDs are rare, with an estimated combined incidence of 1 in 1,500 to 7,000 live births. Some 50 different LSDs have been identified...
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Lysosomal Storage Diseases

Tay-Sachs disease

This disease is caused by mutations on HEXA gene on our chromosome 15. HEXA gene encodes for one part of lysosomal enzyme beta-N-acetylhexosaminidase A. There are more than 100 mutations identified which can alter this protein. Due to this, it is also known as hexosaminidase A deficiency, but also as GM2 gangliosidosis because this enzyme is responsible for degradation of gangliosides (fatty acid derivatives). When it is mutated, it is unable to degrade them, resulting in the accumulation of gangliosides in nerve cells.

Tay-Sachs disease is autosomal recessive disorder, affecting mental and physical abilities by causing deterioration of nerve cells. Since the enzyme is active during the early age, symptoms usually appear during the first year of life and patients usually die by the age of four.

Gaucher disease

This disease is the most common form of lysosomal storage diseases and it is also characterized by the accumulation of fatty acids. It is also the form of sphingolipidosis because it affects the metabolism of sphingolipids.

The difference is that Gaucher disease is caused by the mutations on chromosome 1, which results in deficiency of the enzyme glucocerebrosidase and the accumulation of glucosylceramides, mostly in white blood cells. They can also accumulate in places like brain, bone marrow, liver, spleen, kidneys and lungs. Due to this, Gaucher disease can cause various problems in the body, starting from fatigue and anemia to severe neurologic complications, swelling of lymph nodes, skeletal disorders, bone lesions, liver malfunction, enlarged spleen and liver, etc.

There are three types of Gaucher disease:

- Type I – the most common form of the disease. It does not affect the brain, which is why it is called non-neuropathic type. Symptoms are usually bone disease, skeletal weakness and enlarged liver and spleen (spleen can even rupture in some occasions and the disease even worse). All of these can cause anemia, thrombocytopenia and leukopenia. Patients can sometimes live well into adulthood.
- Type II – affects the brain and it is much more severe than type I. Symptoms are again enlarged liver and spleen, but also brain damage, seizures, spasticity, eye movement disorders, etc. Patients usually die by the age of two.
- Type III – also affects the brain, but it is less damaging than type II. It doesn’t have to start in the childhood, and patients can sometimes reach their adulthood years. Symptoms are once again enlarged liver and spleen, seizures, eye movement disorders, but also poor coordination, anemia and other blood disorders, respiratory problems, etc.
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Lysosomal Storage Diseases

Glycogen Storage Disease II

This disease is characterized by the deficiency of the lysosomal acid alpha-glucosidase enzyme. It is also known by two other names: Pompe disease (named after the Dutch scientist J.C. Pompe who has discovered it in 1932) and acid maltase deficiency (because of the enzyme which can also degrade maltose). It is caused by mutations in gene on chromosome 17. There are around 200 mutations identified up to now that can cause lysosomal storage disease.

Acid alpha-glucosidase degrades glycogen, maltose and isomaltose. If it is mutated and ineffective, glycogen will accumulate in lysosomes and cytoplasm which can lead to cellular injury and may interrupt functioning of organelles.

Based on the levels of alpha glucosidase, there are two forms of Pompe disease:

- Infantile – usually diagnosed within the first 6 months of life. It is characterized by weak muscles and heart failure later on as well as respiratory weakness, which causes death.
- Late onset form – develops more slowly and causes symptoms usually after 2 years of life (or more). It is also characterized by weak muscles and respiratory failure later one. Heart muscles sometimes become enlarged.

Niemann-pick disease

This disease is in the group of sphingolipidosis (subgroup of lysosomal storage diseases) because it is caused by the accumulation of sphingomyelin in lysosomes. There are three forms of it: A, B and C. The first two ones, A and B, are caused by mutations in SMPD1 gene which codes for sphingomyelin phosphodiesterase 1. The third form, type C, is caused by mutations in genes NPC1 or NPC2 (Niemann-pick disease, type 1 and type 2, respectively). These mutations are inherited in autosomal recessive manner, meaning that both alleles have to be defective in order for the disease to be expressed.

Niemann-pick disease affects those organs in which sphingomyelin accumulates. Accumulation in spleen and liver makes them enlarged and may result in pain, thrombocytopenia, etc. Accumulation in central nervous system may lead to ataxia, dysarthria, dysphagia, dementia and seizures. Other parts of the body can be affected, like bones, for example.
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Farber disease

Discovered by Sidney Farber, this disease is characterized by mutations in ASAH1 gene coding for an enzyme acid ceramidase which catalyzes the synthesis and degradation of ceramide (waxy lipid, composed out of sphingosine and fatty acid) into sphingosine and fatty acid.

Basically, when the enzyme acid ceramidase is mutated, it cannot catalyze its normal functions which leads to accumulation of lipids that were supposed to be degraded. This can cause a lot of different problems in the central nervous system, liver, throat, joints, heart, kidneys, etc., including vomiting, arthritis, swollen joints, swollen lymph nodes, breathing difficulty and others.

Symptoms usually appear during the first few weeks of life, but they can also occur sometimes later in life. Children with this disease usually die within 2 years of life due to lung disease, or enlarged liver and speen.

Krabbe disease

This disease also falls into the category of sphingolipidosis. It is named after Danish neurologist Knud Krabbe, but it is also known by other names like globoid cell leukodystrophy and galactosylceramide lipidosis.

It is caused by mutations in GALC gene (on chromosome 14). GALC gene encodes for an enzyme galactosylceramidase which removes galactose from galactosylceramides. If the enzyme is mutated, accumulated galactosylceramides affect the myelin sheath of nerve cells which can cause huge problems to nervous system and motor skills. This is why Krabbe disease belongs to the group of leukodystrophy disorders which are characterized by degeneration of white matter in the brain (myelin sheath is a part of white matter).

Krabbe disease is often fatal and pretty common among some population groups. Symptoms like fevers, vomiting, seizures, limb stiffness, feeding difficulties and slow motor and mental development usually appear within first six months of life. Other symptoms include deafness, optic nerve enlargement, blindness, paralysis, spasticity, muscle weakness and others.

There are two forms of this disease: juvenile and adult-onset, with adult-onset having slower progression.
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Schindler disease

Named after Detlev Schindler who discovered it, this disease is also known as Kanzaki disease, named after Japanese scientist Hiro Kanzaki who gave additional details about the disease.

It is caused by mutations in the NAGA gene (chromosome 22) which encodes lysosomal enzyme Alpha-N-acetylgalactosaminidase. Deficiency of this enzyme leads to the accumulation of glycoproteins and glycosphingolipids in human body. There are three types of this disease:

- Type I (infantile form) – symptoms start to appear in infants after one year of life. These include weakness, vision loss, seizures, muscle rigidity and decreased ability to move them, discoloration of skin, widening of blood vessels and others.

- Type II (adult form) – is milder than type I disease. It can appear when the person is in his/her 30s and it is characterized by intellectual deterioration and increased coarsening of facial features.

- Type III – is in between the previous two types. Symptoms may be milder like some behavioral problems or delayed speech, but they can also be severe like mental retardation or seizures.

Salla disease

Also known as sialic acid storage disease, this disease is caused by mutations in human gene on chromosome 6 which codes for sialin – membrane protein which usually transports sialic acid out of lysosomes. Mutated version of sialin is unable to do so which leads to accumulation of sialic acid inside the cells.

Salla disease is not as severe as some other lysosomal storage diseases because patients can live well into their 50s and they usually learn to walk or speak normally, even though their intellectual performance is affected. There are various symptoms connected with it, like hypotonia (reduced muscle tone and strength), nystagmus (involuntary eye movements) or cognitive impairment. The production of myelin sheath can also be slowed down or completely stopped. In some severe cases, patients never actually learn to talk or walk.
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