Lecture 56

Question 1

sphingolipid structure

Answer 1

• non-glycerol based lipids
• sphingosine backbone, 1st fatty acid makes it ceramide
• ceramide with phosphate group is phosphosphingolipids such as sphinogmyelin
• ceramide with carbohydrate is glycosphingolipids
• glycosphingolipids: cerebrosides (ceramide + sugar, galactosylceramide, glucosylceramide, lactosylceramide), globosides (usually >2 sugars), gangliosides and sulfatides (acidic/(-) charged lipids)

pg 1454

Question 2

all sphingolipid functions

Answer 2

• structural → components of cellular membranes and lipoproteins
• cell signaling → second messengers or precursors of bioactive second messengers

pg 1455

Question 3

glycosphingolipid functions

Answer 3

• regulation of cellular interactions
• growth and development
• tumorigenic properties (transformed cells change their GSL composition)
• antigenic properties (cell surface receptors for cholera and toxin, viruses, microbes)

pg 1455

Question 4

sphingolipid metabolism

Answer 4

pg 1456

Question 5

bioactive sphingolipids (SL)

Answer 5

• ceramide can be converted to sphingosine and vice versa; both are second messengers
• ceramide is most studied and involved in cell death, apoptosis, senescence, autophagy, differentiation
• sphingosine is involved in apoptosis and is precursor of ceramide, as well as product of ceramide degradation
• addition of phosphate group to ceramide or sphingosine changes their properties
• ceramide-1-P → survival, prolifteration, inflammation
• sphingosine-1-P → survival, proliferation, growth, angiogenesis, inflammation

pg 1457

Question 6

targeting SL metabolism in cancer

Answer 6

• tumor cells have more S1P, C1P and less ceramide → faster tumor proliferation, easier migration/invasion, and chemotherapy resistance
• to target sphingolipid metabolism, we want more ceramide and less S1P/C1P → tumor growth inhibition/apoptosis, migration inhibition, improvement of chemotherapy treatments

pg 1458

Question 7

targeting of SLs in cancer therapy

Answer 7

• inducing intracellular ceramide production
• inhibiting S1P production and signaling

pg 1459-1460

Question 8

Fingolimod or FTY 720 (gilenya, novartis)

Answer 8

• pharmacological antagonist of S1P
• structural analog of sphingosine that can be phosphorylated by sphingosine kinases
• S1P receptor modulator → binds to S1PR1 (a GPCR) causing internalization of the receptor and sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction
• approved by FDA as an immunomodulating drug for treating relapsing multiple sclerosis (RMS) → autoimmune condition targeting neuronal tissue

pg 1461

Question 9

sphingolipid storage diseases

Answer 9

• progressive and affect predominantly nervous tissue
• most are autosomal recessive diseases
• depending on severity of mutation, may be fatal or have extensive phenotypic variability
• genetic variability because a given disorder can be caused by any one of a variety of mutations within a single gene
• incidence of sphingolipidoses is low in the general population
• subclass of lysosomal storage disease

pg 1462

Question 10

sphingolipids in the brain

Answer 10

• need to be constantly produced because they cannot pass the blood-brain barrier
• high abundance of SLs in neuronal tissue

pg 1462

Question 11

lysosomal storage diseases

Answer 11

• normal lysosomal degradation results in full degradation of respective molecules
• problem with any enzyme in degradation leads to accumulation of its respective substrate
• primary storage: stored nonmetabolized products that lead to defective fusion of autophagosome with lysosome and defective degradation of intracellular organelles
• secondary storage: accumulation of toxic proteins and aberrant mitochondria lead to induction of cell damage and generation of free radicals which ultimately leads to cell death

pg 1462

Question 12

diagnosis and treatment of sphingolipid storage diseases

Answer 12

• diagnosis: measuring enzyme activity in fibroblasts of perpipheral leukocytes OR DNA analysis/genetic testing; some also have specific tissue histology
• treatment: enzyme replacement therapy, in certain cases could also use bone marrow transplants

pg 1463

Question 13

Gaucher disease

Answer 13

• accumulated substrate: glucosylceramide (a glucocerebroside)
• deficient enzyme: β-glucosidase
• affected step: glucosylceramide to ceramide
• most common lysosomal storage disease
• hepatosplenomegaly
• osteoporosis of long bones
• CNS involvement in rare infantile and juvenile forms
• histology: crumpled blue tissue paper appearance of cytoplasm

pg 1463-1464

Question 14

Gaucher disease: Type I

Answer 14

• non-neuronopathic form (99% of cases)
• storage is limited to mononuclear phagocytes
• patients have low, but detectable enzyme activity
• shortened longevity, but pretty normal life

pg 1464

Question 15

Gaucher disease: Type II

Answer 15

• acute neuronopathic form
• infantile acute cerebral pattern
• no detectable enzyme activity
• progressive CNS disorders and early death

pg 1464

Question 16

Gaucher disease: Type III

Answer 16

• intermediate to type I and type II
• identified in teens and early twenties
• variable pathology

pg 1464

Question 17

Niemann-Pick disease

Answer 17

• accumulated substrate: sphingomyelin
• deficient enzyme: acid sphingomyelinase (ASMase)
• affected step: sphingomyelin to ceramide
• hepatosplenomegaly
• enlarged liver and spleen filled with lipid
• may present with cherry red spot in the macula (more common with type A)
• occur with greater frequency in Ashkenazi Jewish
• histology: foamy-appearing cells containing sphingomyelin

pg 1463, 1465

Question 18

Niemann-Pick disease: Type A

Answer 18

• less than 1% of normal activity remains
• severe infantile form
• rapid, progressive neurodegeneration in newborns due to deposition of sphingomyelin in the CNS
• early death in childhood
• severe intellectual disability

pg 1465

Question 19

Niemann-Pick disease: Type B

Answer 19

• 5% or more of the normal activity remains
• minimal damage to neural tissue
• affect parenchymal tissues (lungs, spleen, liver, bone marrow) resulting in a chronic form
• life expectancy into adulthood

pg 1465

Question 20

GM2 Gangliosidoses: Tay-Sachs and Sandhoff

Answer 20

• regardless of where the gene defect is, the phenotypes are similar as the same enzyme substrate accumulates (G_M2 gangliosides)
• prevalence among Jews, especially those of Eastern European (Ashkenazic) origin with a carrier rate of 1 in 30

pg 1466

Question 21

Tay-Sachs disease

Answer 21

• accumulated substrate: G_M2 gangliosides
• deficient enzyme: β-hexosaminidase A (HEX A,(αβ))
• rapid, progressive, and fatal neurodegeneration
• blindness, seizures
• excessive startle response
• muscle weakness
• cherry-red macula
• deficiency of activator protein in some cases

pg 1463, 1466

Question 22

Sandhoff disease

Answer 22

• accumulated substrate: G_M2 gangliosides
• deficient enzyme: β-hexosaminidase A (HEX A,(ββ))
• accumulation of globosides also
• same neurologic symptoms as Tay-Sachs, but visceral involvement as well

pg 1463, 1466

Question 23

Farber disease

Answer 23

• accumulated substrate: ceramide
• deficient enzyme: acid ceramidase (ACDase)
• affected step: ceramide to sphingosine + fatty acid
• painful and progressive joint deformity
• subcutaneous nodules of lipid-laden cells
• hoarse cry
• tissue granulomas
• cherry-red macula

pg 1463, 1467

Question 24

Fabry disease

Answer 24

• accumulated substrate: globosides
• deficient enzyme: α-galactosidase
• X-linked (all the rest are recessive)
• red-purple skin rash (angiokeratoma)
• kidney and heart failure
• burning pain in lower extremities

pg 1463, 1467

Question 25

metachromatic leukodystrophy (MLD)

Answer 25

• accumulated substrate: sulfatides
• deficient enzyme: arylsulfatase A
• cognitive deterioration
• demyelination
• progressive paralysis and dementia in infantile form
• histology: nerves stain yellow-brown with cresyl violet; loss of normally blue-stained myelin and enlarged macrophages with Kluver-PAS staining of white matter

pg 1463, 1468

Question 26

Krabbe disease (globoid cell leukodystrophy)

Answer 26

• accumulated substrate: galactocerebrosides
• deficient enzyme: β-galactosidase
• mental and motor deterioration
• blindness and deafness
• near-total loss of myelin
• histology: globoid bodies (glycolipid-laden macrophages) in white matter of brain, gross anatomy → loss of myelin (gray/yellowish white matter)

pg 1463, 1468

Question 27

board style question

A 6-month-old boy is brought to the pediatrician for difficulty feeding and poor motor function. He was born at 39 weeks gestation via spontaneous vaginal delivery and is up to date on all vaccines. He met all developmental milestones until 4 months of age when he started having trouble latching onto his bottle. He has also become increasingly lethargic. Physical exam reveals hypotonia in all 4 limbs, areflexia, and hepatosplenomegaly. Ophthalmoscopic exam reveals macular cherry-red spots. Which of the following enzyme activities is most likely deficient in this child?

Answer 27

1. alpha-galactosidase
2. beta-glucosidase
3. hexosaminidase A
4. arylsulfatase A
5. ceramidase
6. neuraminidase
7. sphingomyelinase

7 → sphingomyelinase