Updated: 12/15/2020

Lysosome

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This is an illustration of the lysosome and it's basic function.
Overview 
  • Function
    • digest endosomal material
      • via digestive enzymes
        • glycosylases
        • lipases
        • proteases
      • all are acid hydrolases which function at low pH
    • found in all cells
      • higher concentrations in phagocytic cells
  • Forms
    • primary lysosomes
      • newly formed from the trans-Golgi
      • waiting to receive endocytosed material
    • secondary lysosomes
      • aka phagolysosome
      • formed when primary lysosomes fuse with endocytic vesicles
Lysosomal Storage Disease (by Deficient Enzymes)

  • Sphingolipidoses
    • Sphingomyelinase   
      • deficient in Niemann-Pick disease
        • sphingomyelin accumulates 
          • histiocytes look "foamy
        • presentation
          • hepatosplenomegaly
          • anemia
          • cherry red spots on macula
          • death < 3 years
          • failure to thrive
          • neurodegeneration
        • inheritance
          • AR
          • risk in Ashkenazi Jews
    • α-galactosidase A
      • deficient in Fabry disease
        • ceramide trihexose accumulates
        • presentation
          • peripheral neuropathy
            • especially in hands and feet
          • angiokeratomas 
            • small purple blemishes on skin
          • impaired sweating, either hypo- or anhidrosis
          • cardiovascular disease
          • renal disease
        • inheritance
          • XR
    • β-galactocerebrosidase
      • deficient in Krabbe disease
        • galactocerebroside accumulates 
        • presentation
          • hyperactive reflexes
          • optic atrophy
          • developmental delay
          • presence of globoid cells
            • large multinucleated cells that contain PAS positive inclusions
        • inheritance
          • AR
    • β-glucocerebrosidase 
      • deficient in Gaucher disease
        • glucocerebroside accumulates in cells of phagocytic cells
          • histiocytes (dendritic cells) look like wrinkled tissue paper
            • called Gaucher's cells 
        • presentation
          • three types
            • type I
              • most common
              • hepatosplenomegaly
              • aseptic necrosis of heads of long bones
              • mild anemia
              • possible to live a normal lifespan
            • type II
              • "infantile Gaucher"
              • CNS involved
              • death < 1 year
            • type III
              • "juvenile Gaucher"
              • severity < type II
        • inheritance
          • AR
          • risk ↑ in Ashkenazi Jews
    • Hexosaminidase A
      • deficient in Tay-Sachs disease 
        • GM2 ganglioside accumulates
        • lysosomes with onion skin
        • presentation
          • CNS degeneration
          • blindness
          • cherry red spot on macula
          • startle reflex
          • death < 4 years
          • similar to Niemann-Pick but without hepatosplenomegaly
        • inheritance
          • AR
          • risk ↑ in Ashkenazi Jews
    • Arylsulfatase A
      • deficient in metachromatic leukodystrophy
        • cerebroside sulfate accumulates
        • presentation
          • demyelination in CNS and PNS
            • resulting in ataxia and dementia
        • inheritance
          • AR
  • Mucopolysaccharides
    • α-L-iduronidase
      • deficient in Hurler syndrome
        • heparan sulfate and dermatan sulfate accumulates in heart and liver
        • presentation
          • gargoyle-like facies
          • corneal clouding
          • progressive mental retardation
        • inheritance
          • AR
    • Iduronate sulfatase
      • deficient in Hunter syndrome 
        • heparan sulfate and dermatan sulfate accumulates
        • presentation
          • severity < than Hurler's
          • aggressive behavior
            • remember: hunter's are aggressive
          • corneal clouding absent
        • inheritance
          • XR
 
Other Lysosomal Disorders
  • I (inclusion)-cell disease  
    • cause
      • proteins marked for localization to lysosomes are post-translationally modified in the Golgi
        • mannose residues are phosphorylated by N-acetylglucosamine-phosphotransferase enzyme
      • defect in N-acetylglucosamine-phosphotransferase causes I-cell disease
        • without mannose-6-phosphate designation, the enzymes are secreted instead of being targeted to the lysosome 
      • cells cannot degrade endocytosed material and inclusion bodies build up intracellularly
    • presentation 
      • high plasma levels of lysosomal enzymes
      • skeletal abnormalities
      • restricted joint movement
      • psychomotor retardation
      • early death
      • coarse facial features
    • no treatment
  • Chédiak–Higashi syndrome
    • cause
      • primary lysosomes of leukocytes cannot fuse with phagosomes
      • due to inability of microtubles to polymerize
      • also affects immune cell chemotaxis
    • presentation
      • ↑ infections
        • especially S. aureus
      • partial albinism
      • peripheral neuropathy
    • inheritance
      • AR

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(M1.BC.17.4799) An 18-month-old girl is brought to the pediatrician’s office for failure to thrive and developmental delay. The patient’s mother says she has not started speaking and is just now starting to pull herself up to standing position. Furthermore, her movement appears to be restricted. Physical examination reveals coarse facial features and restricted joint mobility. Laboratory studies show increased plasma levels of several enzymes. Which of the following is the underlying biochemical defect in this patient?

QID: 109299
1

Failure of mannose phosphorylation

49%

(57/117)

2

Inappropriate degradation of lysosomal enzymes

20%

(23/117)

3

Congenital lack of lysosomal formation

11%

(13/117)

4

Inappropriate protein targeting to endoplasmic reticulum

9%

(11/117)

5

Misfolding of nuclear proteins

5%

(6/117)

M 1 C

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(M1.BC.15.74) A 25-year-old male presents to his dermatologist for the appearance of small red papules on his buttocks as seen in Figure A. A careful history reveals that the male has had pain in his extremities for the past several years and recently he is experiencing a constant burning sensation in his extremities. Furthermore, he notes that he occasionally gets fevers when the pain is severe. A blood sample was taken and sent for analysis. Results revealed an alpha-galactosidase A activity of 1.5 nmol/hr*mg (nl = 25-55 nmol/hr*mg). Which of the following is most likely accumulated in the lysosomes of this individual?

QID: 106619
FIGURES:
1

Sphingomyelin

5%

(11/232)

2

Ceramide trihexose

65%

(150/232)

3

Galactocerebroside

19%

(43/232)

4

Glucocerebroside

3%

(8/232)

5

GM2 ganglioside

6%

(15/232)

M 2 D

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(M1.BC.15.0) A 1-year-old Israeli child is brought to the pediatrician by his parents because they noticed that the child can no longer sit up, hold his head up, or recognize them anymore. The child's height and weight are in the 25th percentile for his age. On physical exam, the pediatrician notes the child has hepatosplenomegaly and the following is seen on ophthalmoscopic exam (Figure A). A bone marrow biopsy was performed, and the results shown in Figure B. Which of the following is deficient in this male child?

QID: 107082
FIGURES:
1

Iduronate sulfatase

1%

(1/81)

2

Alpha-L-iduronidase

6%

(5/81)

3

Arylsulftase A

4%

(3/81)

4

Sphingomyelinase

73%

(59/81)

5

Hexosaminidase A

15%

(12/81)

M 2 D

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(M1.BC.15.17) A 6-year-old Hispanic male was admitted to the hospital for pain in his left thigh that has increased in severity over the past several months to the point that he can no longer walk. His mother explained that he had the pain about a year ago that resolved spontaneously. She also explained that he has had nose bleeds frequently for the past 6 months. On physical exam, hepatosplenomegaly was observed and he was noted to have a low-grade fever. A CT with intravenous contrast demonstrated aseptic necrosis of the left femoral head. Based on the clinical presentation, the attending physician ordered an assay showing significantly low levels of beta-glucocerebrosidase in peripheral blood leukocytes. Which of the following diseases shares a similar mode of inheritance as the disease experienced by this patient?

QID: 107083
1

von Willebrand disease Type 1

14%

(13/95)

2

Phenylketonuria

48%

(46/95)

3

Menke's disease

11%

(10/95)

4

Alport's syndrome

6%

(6/95)

5

Hemophilia A

18%

(17/95)

M 1 D

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(M1.BC.15.27) An autopsy was performed on a 2-year-old male child. The clinical report stated that the child's parents were first cousins, and that he had deteriorated physically and mentally over the past year, becoming deaf, unable to eat, and paralyzed. A brain biopsy demonstrated the accumulation of GM2-gangliosides in the neurons. Which of the following enzymes was missing from this child?

QID: 107006
1

Sphingomyelinase

13%

(4/30)

2

a-galactosidase A

3%

(1/30)

3

ß-galactocerebrosidase

10%

(3/30)

4

Hexosaminidase A

70%

(21/30)

5

a-L-iduronidase

3%

(1/30)

M 2 D

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(M1.BC.14.27) A mother brings her 1-year-old daughter who has had several seizures in the past 2 weeks to the pediatrician. The mother explains that the child is unable to crawl, sit, or even hold up her own head. She thinks the weakness is getting worse. The parents of the child are first cousins, and the mother's sister had one child who died before the age of 3 with similar symptoms. Hexosaminidase A activity was assayed in the blood and found to be absent. Which of the following will be found on fundoscopic examination of the child?

QID: 107008
1

Papilledema

0%

(0/23)

2

Arteriovenous nicking

0%

(0/23)

3

Cotton wool spots

0%

(0/23)

4

Hollenhorst plaque

4%

(1/23)

5

Cherry red spot

91%

(21/23)

M 2 D

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(M1.BC.14.1) A deficiency in which of the following lysosomal enzymes is inherited in a pattern similar to a deficiency of iduronate sulfatase (Hunter syndrome)?

QID: 106276
1

Glucocerebrosidase

0%

(0/24)

2

Sphingomyelinase

8%

(2/24)

3

Alpha-galactosidase A

58%

(14/24)

4

Galactocerebrosidase

8%

(2/24)

5

Alpha-L-iduronidase

25%

(6/24)

M 1 D

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(M1.BC.12.49) A 17-year-old high school student is found to have an inherited deficiency of alpha-galactosidase A. Skin biopsy shows accumulation of ceramide trihexose in the tissue. Which of the following abnormalities would be expected in this patient?

QID: 100114
1

Cherry red spots on macula

20%

(62/317)

2

Histiocytes with a wrinkled tissue paper appearance

15%

(46/317)

3

Gargoyle-like facies

5%

(17/317)

4

Corneal clouding

10%

(32/317)

5

Angiokeratomas

48%

(152/317)

M 2 E

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