Biochem - Metabolism (Lysosomal storage diseases)

Question 1

In general, what causes lysosomal storage diseases? What general effect do they have?

Answer 1

Each is caused by deficiency in one of the many lysosomal enzymes. Results in an accumulation of abnormal metabolic products.

Question 2

What are 2 major categories of lysosomal storage diseases?

Answer 2

(1) Sphingolipodoses (2) Mucopolysaccharidoses

Question 3

Name 6 examples of sphingolipodoses.

Answer 3

(1) Fabry disease (2) Gaucher disease (3) Niemann-Pick disease (4) Tay-Sachs disease (5) Krabbe disease (6) Metachromatic leukodystrophy

Question 4

Name 2 Mucopolysaccharidoses.

Answer 4

(1) Hurler syndrome (2) Hunter syndrome

Question 5

What are 3 clinical findings of Fabry disease?

Answer 5

(1) Peripheral neuropathy of hands/feet, (2) angiokeratomas, (3) cardiovascular/renal disease

Question 6

What are the deficient enzyme and accumulated substrate in Fabry disease?

Answer 6

DEFICIENT ENZYME: alpha-galactosidase A; ACCUMULATED SUBSTRATE: ceramide trihexoside

Question 7

What is the mode of inheritance for Fabry disease?

Answer 7

XR

Question 8

What is the most common lysosomal storage disease?

Answer 8

Gaucher disease

Question 9

What are 5 clinical findings of Gaucher disease?

Answer 9

(1) Hepatosplenomegaly, (2) Pancytopenia, (3) Aseptic necrosis of femur, (4) Bone crises, (5) Gaucher cells (lipid-laden macrophages resembling crumpled tissue paper)

Question 10

What is the treatment for Gaucher disease?

Answer 10

Treatment is recombinant glucocerebrosidase

Question 11

What are Gaucher cells, and how do they appear on histology?

Answer 11

Gaucher cells (lipid-laden macrophages resembling crumpled tissue paper)

Question 12

What are the deficient enzyme and accumulated substrate in Gaucher disease?

Answer 12

DEFICIENT ENZYME: Glucocerebrosidase (Beta-glucosidase); ACCUMUALTED SUBSTRATE: Glucocerebroside

Question 13

What is the mode of inheritance of Gaucher disease?

Answer 13

AR

Question 14

What are 4 clinical findings of Niemann-Pick disease?

Answer 14

(1) Progressive neurodegeneration, (2) Hepatosplenomegaly, (3) “Cherry-red” spot on macula, (4) Foam cells (lipid-laden macrophages)

Question 15

What are the deficient enzyme and accumulated substrate in Niemann-Pick disease?

Answer 15

DEFICIENT ENZYME: Sphingomyelinase; ACCUMULATED SUBSTRATE: Sphingomyelin; Think: “NO MAN PICKS (Niemann-Pick) his nose with his SPHINGer (Sphingomyelinase).”

Question 16

What is the mode of inheritance for Niemann-Pick disease?

Answer 16

AR

Question 17

What are 4 clinical findings of Tay-Sachs disease? What negative clinical finding distinguishes Tay-Sachs from another lysosomal storage disorder, and what is that disorder?

Answer 17

(1) Progressive neurodegeneration, (2) Developmental delay, (3) “cherry-red” spot on macula, (4) lysosomes with onion skin; No hepatomegaly (vs. Niemann-Pick)

Question 18

What are the deficient enzyme and accumulated substrate in Tay-Sachs disease?

Answer 18

DEFICIENT ENZYME: Hexosaminidase A; ACCUMULATED SUBSTRATE: GM2 ganglioside; Think: “Tay-SaX lacks heXosaminidase”

Question 19

What is the mode of inheritance for Tay-Sachs disease?

Answer 19

AR

Question 20

What are 4 clinical findings of Krabbe disease?

Answer 20

(1) Peripheral neuropathy (2) Developmental delay (3) Optic atrophy (3) Globoid cells

Question 21

What are the deficient enzyme and accumulated substrate(s) in Krabbe disease?

Answer 21

DEFICIENT ENZYME: Glactocerebrosidase; ACCUMULATED SUBSTRATE(S): Galactocerebroside, Psychosine

Question 22

What is the mode of inheritance for Krabbe disease?

Answer 22

AR

Question 23

What are 2 clinical findings of Metachromatic leukodystrophy?

Answer 23

(1) Central and peripheral demyelination with ataxia, (2) Dementia

Question 24

What are the deficient enzyme and accumulated substrate in Metachromatic leukodystrophy?

Answer 24

DEFICIENT ENZYME: Arylsulfatase A; ACCUMULATED SUBSTRATE: Cerebroside sulfate

Question 25

What is the mode of inheritance for Metachromatic leukodystrophy?

Answer 25

AR

Question 26

What are 5 clinical findings of Hurler syndrome?

Answer 26

(1) Developmental delay, (2) Gargoylism, (3) Airway obstruction, (4) Corneal clouding, (5) Hepatosplenomegaly

Question 27

What are the deficient enzyme and accumulated substrate

Answer 27

DEFICIENT ENZYME: Alpha-L-iduronidase; ACCUMULATED SUBSTRATE: Heparan sulfate, Dermatan sulfate

Question 28

What is the mode of inheritance of Hurler syndrome?

Answer 28

AR

Question 29

What are 2 clinical findings of Hunter syndrome? What negative clinical finding helps to distinguish it from another lysosomal storage disorder, and what disorder is that?

Answer 29

(1) Mild Hurler (which is characterized clinically by development delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly) + (2) aggressive behavior; No corneal clouding (v. Hurler syndrome); Think: "HUNTERs see clearly (no corneal clouding) and aggressively aim for the X (X-linked recessive)"

Question 30

What are the deficient enzyme and accumulated substrate in Hunter syndrome?

Answer 30

DEFICIENT ENZYME: Iduronate sulfatase; ACCUMULATED SUBSTRATE: Heparan sulfate, Dermatan sulfate

Question 31

What is the mode of inheritance for Hunter syndrome?

Answer 31

XR; Think: "HUNTERS see clearly (no corneal clouding) and aggressively aim for the X (X-linked recessive)."

Question 32

Draw a diagram depicting the metabolic steps blocked by the 6 major sphingolipidoses.

Answer 32

See p. 114 in First Aid 2014 for visual at bottom of page

Question 33

In what patient population do Tay-Sachs, Niemann-Pick, and some forms of Gaucher disease have an increased incidence?

Answer 33

Increased incidence of Tay-Sachs, Niemann-Pick, and some forms of Gaucher disease in Ashkenazi Jews.