BCHM 451 LIBERTY UNIVERSITY Week 4 Disease Questions ASSIGNMENT 2020.pdf

Gaucher Disease – A Sphingoliposis

1. What are sphingolipids and why are they physiologically important? Give particular examples...

Glycolipids=glycosphingolipids-sphingolipids are made of carbs and lipid components. They are found mostly

in nerve tissues in the outer leaflet, so they interact with the extracellular environment. They play a role in

regulation of cellular interactions, growth, and development. Membrane glycolipids associate with cholesterol;

they are antigenic and are the source of ABO blood group antigens. There are two different types of

glycosphingolipids: neutral and acidic. Neutral glycosphingolipids include: cerebrosides (simplest) made of

ceramide and a glucose/galactose molecule (glucocerebroside/galactocerebroside) and globosides (ceramide

oligosaccharides) which are a glucocerebroside with an additional monosaccharide. Acidic glycosphingolipids

sends them to the PM where they are used until they need to be degraded in lysosomes.

4. What is the cellular function of lysosomes and what role do they play in the catabolism of sphingolipids? The

sites of lipid degradation are in lysosomes which is where the acid hydrolases are located that breakdown the

sphingolipids. If one of the enzymes is working properly then the lysosomes can be filled with accumulated

lipids which can cause megaly of the organelle and destroy other cells.

5. What is the genetic defect in Gaucher disease and what particular cell types are affected the most in this

disease? What substrate accumulates to significant levels in the disease? (in attached notes)

6. What are the common types of mutations that result in this disease and what are the patterns of inheritance?

What population is most commonly affected? (in attached notes)

7. Describe the histopathological feature of Gaucher disease and explain what accounts for this. Why does it

(in attached notes)

I-Cell Disease (Mucolipidosis Type II)

*Glycoproteins have a wide range of functions. What are glycoproteins, they are proteins with an

oligosaccharide attached to it. There are different types of glycoproteins: Mucins and Erythropoietin (EPO).

Mucins are heavily glycosylated protein produced and released by epithelial cells. They contain a high number

of threonine and serine residues, which means they can form many o-glycosylation linkages. The highly-

glycosylated characteristics of mucins makes them resistant to proteolysis and gives them the ability to absorb

water. Mucins form mucous barriers that lubricate and protect epithelial tissue. Although most mucins are

released into the extra cellular matrix. Some remain attached to the membranes.

radiographic changes in older children with I-cell are nonspecific like in Hurler’s.

3. What explains the difference in the intracellular and extracellular activities of lysosomal enzymes in I-Cell

disease? Biochemically I-cell disease is characterized by excessive secretion of newly synthesized lysosomal

enzymes into bodily fluids and loss of intracellular activity in fibroblasts.

4. Differentiate I-Cell disease from Gaucher disease, also from Pseudo-Hurler disease. Increase lysosomal

levels in serum cannot distinguish between I-cell and pseudo-hurler. Phosphotransferase deficiency in I-cell is

total while in PHD it can have up to 10% efficiency. Enzyme levels: -mannosidase and -glucuronidase are  

higher in PDH than in I-cell but both have high levels compared to controls; -fructosidase,  -glycosaminidase,

and -glucosaminidase levels are higher in I-cell than PHD but both activities are higher than control. Gaucher 

disease is associated with high glucocerebroside in lysosomes, but in I-cell the accumulation of substrates in the

the Golgi. This occurs through phosphotransferase.

6. Describe how lysosomal enzymes are targeted to the lysosomes and identify the functions of

phosphotransferase, M6P, MPRs. RER Golgi binding to MPRs Acidified department lysosome. M6P is  

phosphorylated by phosphotransferase. Once it is attached, the molecule can now attach to MPRs that transfers

the lysosomal enzyme to the acidified compartment. There are two distinct MPRs: a smaller one that is cation-

dependent and a larger one that is cation-independent

7. Describe the implicated molecular pathologies in I-cell disease and how that varies from ML III. In I-cell,

lysosomal enzymes are not modified by the addition of mannose 6-P because M6P is not phosphorylated by

phosphotransferase. Thus, they are not segregated by the MPRs into the appropriate vesicles in the TGN and

instead are carried to the cell surface and secreted (RER Cell Surface).Golgi

possible remedy for I-cell. Bone marrow transplant has improved biochemical and clinical symptoms of I-cell

probably because hematopoietic progenitors can donate lysosomal enzymes to the deficient cells in all tissues of

the host. Gene replacement is another idea as well as peptide targeting systems.

HMG Co-A Lyase Deficiency

1. What is metabolic acidosis? How is it clinically diagnosed and what are the possible causes? Metabolic acidosis is a

disorder that occurs when the body produces excessive amounts of acid, such as ketoacids or lactic acid; the kidneys are

unable to remove enough acid produced from normal metabolism. Individuals with HMG-COA lyase deficiency cannot

tolerate the increased mobilization of leucine from muscle proteins during fasting and will quickly decompensate and

develop metabolic acidosis because proper catabolism of leucine cannot occur, and HMG and its precursors are excreted.

aciduria, but the urinary organic acids create a unique profile for each disease. In HMG-CoA lyase deficiency the urine

organic acids include 3-methylglutaric and HMG acid. Also, in HMG-CoA lyase deficiency hypoglycemia is not

associated with increased ketone bodies because ketogenesis doesn’t make its full effect in this disease.

4. Are patients with HMG-CoA lyase deficiency always symptomatic? What are common precipitants of their symptoms?

Why did this patient have an aversion for oral feeding? No, not all patients are symptomatic because metabolic

decompensation often results after acute illness especially with fever, vomiting, diarrhea, and dehydration. Common

symptoms include metabolic acidosis, organic acidurias, hyperammonemia, hepatomegaly, and hypoglycemia. The patient

had an aversion for oral feeding because of her chronic gastric acidemia, reflux, frequent hospitalizations, hypotonia, and

developmental delay.

5. Explain the process of ketogenesis and why you think leucine is said to be a ketogenic amino acid. Ketogenesis is an

critical in managing patients with HMG-CoA lyase deficiency? The serum carnitine levels decrease in HMG-CoA lyase

also facilitates the removal of xenobiotics.

7. How is HMG-CoA lyase deficiency different from maple syrup urine disease? Maple syrup disease the deficient amino

acids are leucine, isoleucine, and valine.

8. What is the cause of the hyperammonemia, hypoglycemia, hepatomegaly and hypotonia in this patient? No -oxidation

means that there is an increase of lipids in hepatocytes which causes hepatomegaly, which means that there is no ATP

available from -oxidation which impairs urea synthesis and results in hyperammonemia. Since there is no ATP (and A-

COA for OAA syn) available for gluconeogenesis, glycogen storages are depleted causing fasting hypoglycemia.

9. What is the role of ATP in ureagenesis and gluconeogenesis? Why is frequent feeding important to managing patients