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Sphingolipids: Active Recall Q&A

Basic Structure & Composition

1. What are sphingolipids?

   • Sphingolipids are 18-carbon dihydric alcohols with an amino group at C17 and two hydroxyl groups.

2. What is the backbone of sphingolipids?

   • Sphingosine serves as the backbone of sphingolipids.

3. What is ceramide, and how is it formed?

   • Ceramide is formed by attaching a fatty acid to the amino group at C17 of sphingosine.

Classification & Modifications

1. What happens when a hydrogen is attached at C18 in ceramide?

   • The molecule remains as ceramide.

2. What molecule is formed when ceramide is esterified with phosphocholine?

   • Sphingomyelin.

3. What is formed when ceramide is linked to a single sugar residue?

   • Cerebroside.

4. What is the difference between globosides and gangliosides?

   • Globosides contain two or more sugars.

   • Gangliosides contain N-acetylneuraminic acid (NANA).

5. What modification leads to sulfatides?

   • The addition of a sulfate group to a galactosylceramide.

6. What are the two types of glycosphingolipids?

   • Neutral glycosphingolipids and acidic glycosphingolipids.

Biosynthesis Pathway

1. What two molecules are needed to begin sphingolipid biosynthesis?

• Palmitoyl-CoA and serine.

1. What cofactors are required for the condensation of palmitoyl-CoA and serine?

• Pyridoxal phosphate (PLP) and NADPH.

1. What is the first intermediate formed in sphingolipid synthesis?

• Ketosphinganine.

1. How is dihydroceramide formed?

• Sphinganine is acylated at C17 to form dihydroceramide.

1. What step is required to convert dihydroceramide to ceramide?

• Desaturation of the fatty acid.

Degradation Pathway & Inborn Errors

1. What happens during sphingolipid degradation?

• Sphingolipids are hydrolyzed back to ceramide, which is then broken down into sphingosine and a fatty acid.

1. Which enzyme deficiency leads to the accumulation of sphingomyelin?

• Sphingomyelinase deficiency (causing Niemann-Pick disease).

1. Which enzyme deficiency leads to the accumulation of glucosylceramide?

• Glucocerebrosidase deficiency (causing Gaucher’s disease).

1. Which enzyme deficiency leads to the accumulation of galactosylceramide?

• Galactocerebrosidase deficiency (causing Krabbe disease).

1. What enzyme deficiency leads to the accumulation of gangliosides?

• Hexosaminidase A deficiency (causing Tay-Sachs disease).

1. Why are sphingolipids important in the nervous system?

• They are crucial for nerve conduction, antigenic properties, and membrane structure.

This covers all the major points without repetition while keeping it concise for active recall. Would you like any modifications or additional questions? 😊

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General Questions on Sphingolipidoses

1. What are the important sphingolipidoses that you need to know?

   • Gaucher’s disease, Niemann-Pick disease, Krabbe disease, Metachromatic Leukodystrophy, Fabry’s disease, Tay-Sachs disease, and Farber disease.

2. What three things must you know about each sphingolipidosis?

   • The deficient enzyme, the accumulating lipid, and the other molecule released when the lipid is cleaved.

3. What is a common clinical feature of sphingolipidoses, particularly when they affect the liver and spleen?

   • Hepatosplenomegaly (enlargement of the liver and spleen).

4. Why do many sphingolipidoses involve neurological symptoms?

   • Sphingolipids are important in the nervous system, so their accumulation leads to neurodegeneration.

5. Which three sphingolipidoses occur more frequently, particularly among Ashkenazi Jews?

   • Gaucher’s disease, Tay-Sachs disease, and Niemann-Pick disease.

Enzyme Deficiencies & Accumulating Lipids

1. What enzyme is deficient in Niemann-Pick disease, and what lipid accumulates?

   • Sphingomyelinase is deficient, leading to an accumulation of sphingomyelin.

2. What is the deficient enzyme in Gaucher’s disease, and what lipid accumulates?

   • Glucocerebrosidase (beta-glucosidase) is deficient, leading to an accumulation of glucosylceramide.

3. What enzyme is deficient in Krabbe disease, and what accumulates?

   • Galactocerebrosidase deficiency leads to an accumulation of galactocerebroside.

4. What enzyme deficiency causes metachromatic leukodystrophy, and what accumulates?

   • Aryl sulfatase deficiency leads to an accumulation of sulfatides.

5. What is the enzyme deficiency in Tay-Sachs disease, and what lipid accumulates?

   • Hexosaminidase A deficiency leads to an accumulation of GM2 gangliosides.

6. What is the enzyme deficiency in Fabry’s disease, and what lipid accumulates?

   • Alpha-galactosidase A deficiency leads to an accumulation of ceramide trihexoside.

Biochemical Breakdown of Lipids

1. When sphingomyelin is cleaved, what two molecules are produced?

   • Ceramide and phosphatidylcholine.

2. What two molecules are produced when glucocerebroside is cleaved?

   • Ceramide and glucose.

3. What happens when galactosylceramide is sulfated, and what disease results if it cannot be broken down?

   • It forms a sulfatide, and failure to break it down due to aryl sulfatase deficiency results in metachromatic leukodystrophy.

Clinical Features & Disease Subtypes

1. What major organ systems are affected in Niemann-Pick disease, and what is a key histological feature?

   • The liver, spleen, and nervous system are affected; Zebra bodies are a key histological feature.

2. What are the two major types of Niemann-Pick disease, and how do they differ?

   • Type A affects neurons, causing neurodegeneration, while Type B primarily affects organs like the liver, lung, spleen, and bone marrow with little to no neuronal damage.

3. What are the three types of Gaucher’s disease, and which is most severe?

   • Type 1 (non-neuropathic, most common), Type 2 (infantile, severe, life-threatening), and Type 3 (slowly progressive neurological involvement).

4. What are the hematological consequences of Gaucher’s disease?

   • Anemia (low RBC count) and thrombocytopenia (low platelet count).

5. What is the inheritance pattern of most sphingolipidoses, and which disease is an exception?

   • Most are autosomal recessive, except Fabry’s disease, which is X-linked recessive.