(PDF) Lysosomal Storage Diseases

1. In general, explain the nature and pathology of Lysosomal Storage Diseases.?
Answer:
Mainly lysosomal storage disease is caused by abnormal build up of various toxic material in our
body cells that results in the deficiency of enzymes. This disease affect our skeleton, brain, skin,
heart and central nervous system. The main function of lysosme is the breakdown of compels
substances into simple ones when this process does not takes place then the substrate begins to
accumulate in the cells that’s why this disease is called “storage disorder” There are nearly 50
types of this disorder so we can say that it’s signs and symptoms vary from disease to disease.
Clinical trials are in progress to identify more types of this disease. They are struggling and there
is no complete treatment has been approved so far.
Reference: https://rarediseases.org/rare-diseases/lysosomal-storage-disorders/
2. How many hydrolases have been conjectured to the possibility of causing a Lysosomal
Storage Disease?
Answer:
The hydrolases conjected to the possibility of causing a lysosomal storage disease is more
than 60. Lysosomal hydrolases are mainly glycoproteins act as acidic PH so they are
synthesized in rough endoplasmic reticulum. Lysosomal hydrolases includes proteases,
lipases, nucleases, glucosidases, phosphatases and sulfatases. They provides nucleic acid,
amino acids, fatty acids and sugars for neutralization in cellular synthesis. There are twelve
mechanisms lead to deficient acid hydrolases activity and abnormal storage of substrate
have been recognized.
Reference: https://www.sciencedirect.com/topics/medicine-and-dentistry/lysosomal-storage-
disease#:~:text=To%20date%2C%2058%20genetically%20determined,of%20intracellular%20a
nd%20extracellular%20macromolecules.

3. What are three classes of proteins that could lead to LSDs? List 2 defective proteins in
each class.
Lysosomal membrane proteins are classified in to several different groups of small metabolites
exporter proteins including
1. Enzyme protecting protein
This type of protein causes galactosialidosis. It is caused by a mutation in the CTSA gene which
leads to a deficiency of enzymes β-galactosidase and neuraminidase. By this lysosomes of cells
inhibit from functioning. Due to this accumulation of toxic matter occur within the cell. Two defect
proteins
Cathepsin A. Its example is Galactosialidosis
2. Soluble nonenzymetic proteins
Niemann–Pick type C (NPC) This associated with mutations
in NPC1 and NPC2 genes. This disease causes the enlargement of liver and spleen.
This responsible for disability and premature death in all cases beyond early childhood.
Two defective protein
GM2-AP
NPC2
3. Transmemrane proteins
Salla disease (SD)
It is an autosomal recessive disease. It is one of 40 Finnish heritage diseases and affects
approximately 130 individuals, mainly from Finland and Sweden. This disease reduced muscle
tone and strength.
Two defective proteins
NPC1
Sialin
Reference
https://en.wikipedia.org/wiki/Lysosomal_storage_disease

4. Propose a mutation that would prevent a hydrolase from entering the lysosome.
Genetic mutation prevent hydrolases from entering the lysosome. Gene mutation mainly affect
hydrolases like missense Gene mutation. In SLDs the normal metabolism of specific
macromolecules blocked which cause physiological effects. Mutations in the genes that encode
these enzymes are responsible for more than 30 different human genetic diseases.
5. What is Batten Disease?
Batten disease is that the common name for a broad category of rare, fatal, familial disorders of
the system conjointly called vegetative cell ceroid lipofuscinoses, or NCLs. In these diseases, a
defect in an exceedingly specific factor triggers a cascade of issues that interferes with a cell’s
ability to recycle bound molecules. The unwelless has many forms that share a number of identical
options and symptoms however vary in severity and age once symptoms initial begin to look.
Every type is caused by a mutation in an exceedingly totally different factor. Though “Batten
disease” originally referred specifically to the juvenile-onset style of NCL, the term Batten
unwellness is progressively wont to describe all varieties of NCL.
Symptoms
 Children suffer from worsening seizure.
 Progressive loss of language, speech, intellectual abilities and motor skills.
 Blind.
 Bedridden.
 Unable to communicate.
Reference
https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Batten-Disease-
Fact-Sheet
6. As it pertains to mutation, transcriptional regulation and/or posttranslational
modification, explain reasons that cause the degree of seriousness in LSDs?
These are mainly cause by inborn error of metabolism which results in the absence of an enzyme
which lead ho inappropriate storage of material in various cells by the body.

They are inherited as autosomal recessive manner. These diseases follow an autosomal recessive
inheritance pattern.
A defective gene that develops throughout foetal (before birth) growth causes lysosomal storage
diseases. Kids will inherit the cistron from one or each oldsters. The defective cistron regulates a
specific accelerator within the organelle, that either is missing or isn’t enough to method the
surplus substances. Once these substances build up to harmful amounts, cells shut down properly
and will die.
Reference
https://childrensnational.org/visit/conditions-and-treatments/genetic-disorders-and-birth-
defects/lysosomal-storage-disorders
7. Why are therapies for LSD hard to develop?
These diseases can be treated or cured by following Methods.
1. Intravenous Enzymes Replacement.
2. Bone marrow transplantation to slow diseases progress.
3. Umbilical cord blood stem cell transplantation to restore missing Enzymes.
1. Intravenous Enzymes Replacement
Minimal or no enzyme delivery to all or any necessary target sites; delayed diagnosing leading to
irreversible substrate buildup and clinical consequences before beginning ERT; inability of the
therapeutic accelerator to succeed in bound sanctuary sites, nor pass blood–brain barrier; and
immune responses abrogating treatment effectiveness.
2. Bone marrow transplantation to slow diseases progress.
Grafts fail when the body does not accept the new stem cells (the graft). The stem cells that were
given do not go into the bone marrow and multiply like they should.
3. Umbilical cord blood stem cell transplantation to restore missing Enzymes
In preparation for a stem cell transplant, you'll need to have chemotherapy to destroy the damaged
or diseased blood cells. These will eventually be replaced by the transplanted stem cells, although
this process can take several weeks or more.
Until your body starts being able to produce healthy blood cells again, you may be at risk of:
anemia, excessive bleeding and infection.

Reference
https://www.researchgate.net/publication/300542419_Challenges_of_Enzyme_Replacement_Th
erapy_Poor_Tissue_Distribution_in_Lysosomal_Diseases_Using_Pompe_Disease_as_a_Model
https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/stem-cell-
transplant/transplant-side-effects.html
8. Explain how a technique could be used to determine if an enzyme was not properly targeted to
the lysosome.
Enzyme replacement Therapy
It is a technique which determine that if an enzyme not properly targeted to the lysosome. This
technique used in fabry disease, which is X-linked lysosomal storage disease caused by the
deficiency of alpha- galactosidase A. Usually, this is done by giving the patient an intravenous
(IV) infusion of a solution containing the enzyme. ERT balances low levels of
glucocerebrosidase (GCase) enzyme with a modified version of the enzyme. ERT does not
correct the underlying genetic defect, but it increases the concentration of the enzyme that the
patient is lacking.
Reference
https://www.semanticscholar.org/paper/Enzyme-replacement-therapy-of-fabry-disease-Clarke-
Iwanochko/233ac437f3dc46d3b74f6b74c6f1677b92fe6ad3