Updated: 4/6/2019

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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Questions (16)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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(M1.BC.1) A deficiency in which of the following lysosomal enzymes is inherited in a pattern similar to a deficiency of iduronate sulfatase (Hunter syndrome)? Review Topic

QID: 106276
1

Glucocerebrosidase

0%

(0/16)

2

Sphingomyelinase

6%

(1/16)

3

Alpha-galactosidase A

62%

(10/16)

4

Galactocerebrosidase

6%

(1/16)

5

Alpha-L-iduronidase

25%

(4/16)

M1

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PREFERRED RESPONSE 3

(M1.BC.49) A 17-year-old female 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? Review Topic

QID: 100114
1

Cherry red spots on macula

18%

(50/276)

2

Histiocytes with a wrinkled tissue paper appearance

15%

(41/276)

3

Gargoyle-like facies

5%

(13/276)

4

Corneal clouding

11%

(29/276)

5

Angiokeratomas

49%

(135/276)

M1

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PREFERRED RESPONSE 5

(M1.BC.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? Review Topic

QID: 109299
1

Failure of mannose phosphorylation

49%

(50/102)

2

Inappropriate degradation of lysosomal enzymes

21%

(21/102)

3

Congenital lack of lysosomal formation

11%

(11/102)

4

Inappropriate protein targeting to endoplasmic reticulum

8%

(8/102)

5

Misfolding of nuclear proteins

6%

(6/102)

M1

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PREFERRED RESPONSE 1
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(M1.BC.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? Review Topic

QID: 107082
FIGURES:
1

Iduronate sulfatase

1%

(1/77)

2

Alpha-L-iduronidase

6%

(5/77)

3

Arylsulftase A

4%

(3/77)

4

Sphingomyelinase

71%

(55/77)

5

Hexosaminidase A

16%

(12/77)

M1

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PREFERRED RESPONSE 4
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(M1.BC.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? Review Topic

QID: 107083
1

von Willebrand disease Type 1

12%

(10/81)

2

Phenylketonuria

49%

(40/81)

3

Menke's disease

10%

(8/81)

4

Alport's syndrome

6%

(5/81)

5

Hemophilia A

19%

(15/81)

M1

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PREFERRED RESPONSE 2

(M1.BC.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? Review Topic

QID: 106619
FIGURES:
1

Sphingomyelin

4%

(9/202)

2

Ceramide trihexose

64%

(130/202)

3

Galactocerebroside

19%

(39/202)

4

Glucocerebroside

3%

(7/202)

5

GM2 ganglioside

6%

(13/202)

M1

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PREFERRED RESPONSE 2

(M1.BC.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? Review Topic

QID: 107006
1

Sphingomyelinase

5%

(1/22)

2

a-galactosidase A

0%

(0/22)

3

ß-galactocerebrosidase

9%

(2/22)

4

Hexosaminidase A

82%

(18/22)

5

a-L-iduronidase

5%

(1/22)

M1

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PREFERRED RESPONSE 4

(M1.BC.27) A mother brings her 1-year-old daughterd who has had several seizures in the past two 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 appears to be 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? Review Topic

QID: 107008
1

Papilledema

0%

(0/16)

2

Arteriovenous nicking

0%

(0/16)

3

Cotton wool spots

0%

(0/16)

4

Hollenhorst plaque

0%

(0/16)

5

Cherry red spot

94%

(15/16)

M1

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PREFERRED RESPONSE 5
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