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Biochem + Metabolism > Lysosomal Storage Disease B&B > Flashcards

Lysosomal Storage Disease B&B Flashcards

1
Q

most lysosomal storage diseases lead to accumulation of _____

A

ceramide derivatives: sphingosine with addition of fatty acid to NH2

modify head group to yield glycosphingolipids, sulfatides, etc

very important structures for nerve tissue (nerve symptoms), lack of breakdown causes accumulation in liver/spleen

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2
Q

What is the cause of Fabry’s Disease?

A

X-linked lysosomal storage disease due to deficiency of alpha-galactosidase A —> accumulation of ceramide trihexoside (globotriaosylceramide, Gb3) - ceramide with 3 sugar head group

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3
Q

X-linked lysosomal storage disease due to deficiency of alpha-galactosidase A —> accumulation of ____

what disease is this?

A

Fabry’s Disease: accumulation of ceramide trihexoside (globotriaosylceramide, Gb3) - ceramide with 3 sugar head group

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4
Q

how does Fabry’s Disease present? (6)

A

X-linked deficiency of alpha-galactosidase A —> accumulation of ceramide trihexoside

slowly progressive (child —> early adulthood)
1. neuropathy (hands/feet)
2. angiokeratomas: small dark raised spots due to dilated surface capillaries
3. decreased sweat
4. renal disease (proteinuria)
5. cardiac disease (LV hypertrophy)
6. early age CNS problems (TIA/stroke)

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5
Q

Child is brought to pediatrician due to slowly progressive pain in their hands and feet. PE shows small, dark, raised spots over several areas of skin. The mother notes the child seems not to sweat, even when it is hot out. Genetic testing reveals an X-linked deficiency. What recombinant therapy can be used to treat this child?

A

Fabry’s Disease: X-linked deficiency of alpha-galactosidase A —> accumulation of ceramide trihexoside

rx: recombinant galactosidase

slowly progressive neuropathy, angiokeratomas, decreased sweat, renal disease, cardiac disease, early TIA/stroke

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6
Q

lysosomal storage disease presents with child with neuropathy of hands and feet + angiokeratomas + lack of sweat = accumulation of what?

A

Fabry’s Disease: X-linked deficiency of alpha-galactosidase A —> accumulation of ceramide trihexoside

slowly progressive neuropathy, angiokeratomas, decreased sweat, renal disease, cardiac disease, early TIA/stroke

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7
Q

what is the cause of Gaucher’s Disease?

A

most common lysosomal storage disease - AR deficiency of glucocerebrosidase —> accumulation of glucocerebroside (ceramide + glucose head group) within macrophages

causes splenomegaly, anemia/thrombocytopenia (bruising), avascular necrosis

most common among Ashkenazi Jews

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8
Q

AR deficiency of glucocerebrosidase

A

Gaucher’s disease: most common lysosomal storage disease —> accumulation of glucocerebroside (ceramide + glucose head group) within macrophages

causes splenomegaly, anemia/thrombocytopenia (bruising), avascular necrosis

most common among Ashkenazi Jews

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9
Q

how does the most common lysosomal storage disease present? what is the most common initial sign?

A

Gaucher’s disease: AR deficiency of glucocerebrosidase, most common among Ashkenazi Jews

—> splenomegaly is most common initial sign
—> bone marrow issues (anemia, thrombocytopenia —> easy bruising)
—> avascular necrosis (Gaucher macrophages block capillaries)
—> rarely CNS symptoms (Type II/III)

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10
Q

where does glucocerebroside accumulate in Gaucher’s Disease?

A

most common lysosomal storage disease —> AR deficiency of glucocerebrosidase

accumulates within macrophages (Gaucher cells) - large, look like “crinkled paper” on histology

macrophages block capillaries —> bone crisis (intense pain + fever, similar to sickle cell), avascular necrosis, splenomegaly, bone marrow issues

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11
Q

contrast presentation of Type I vs Type II vs Type III Gaucher’s Disease

A

AR deficiency of glucocerebrosidase (lysosomal storage disease)

Type I (most common): presents childhood-adult w/ hepatosplenomegaly, bruising anemia, bone pain - can tx w/ recombinant enzyme

Type II: presents in infancy, marked CNS symptoms, early death (<2)

Type III: childhood onset w/ progressive dementia, shorted lifespan

[remember, most common in Ashkenazi Jewish descent!]

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12
Q

Child is brought to pediatrician with concern of bruising easily. PE is notable for splenomegaly, and blood labs reveal anemia. Child is of Ashkenazi Jewish descent, and genetic testing reveals…

A

Gaucher’s disease: AR deficiency of glucocerebrosidase, glucocerebroside accumulates within macrophages

—> splenomegaly is most common initial sign
—> bone marrow issues (anemia, thrombocytopenia —> easy bruising)
—> avascular necrosis (Gaucher macrophages block capillaries)
—> rarely CNS symptoms (Type II/III)

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13
Q

Child is brought to ED due to severe bone pain and fever. PE reveals splenomegaly and labs show anemia and thrombocytopenia. Child is of Ashkenazi Jewish descent. What is the cause of this child’s bone crisis?

A

Gaucher’s disease: AR deficiency of glucocerebrosidase, glucocerebroside accumulates within macrophages

—> splenomegaly is most common initial sign
—> bone marrow issues (anemia, thrombocytopenia —> easy bruising)
—> avascular necrosis (Gaucher macrophages block capillaries) + bone crisis
—> rarely CNS symptoms (Type II/III)

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14
Q

what is the cause/pathology of Niemann-Pick disease?

A

AR deficiency of acid sphingomyelinase (ASM) —> accumulation of sphingomyelin (ceramide + phosphate-nitrogen head group) within macrophages (“foam cells”)

—> splenomegaly + neuro deficits + cherry red spot (fundoscopy)

more common among Ashkenazi Jews

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15
Q

AR deficiency of acid sphingomyelinase (ASM)

A

Niemann-Pick Disease: lysosomal storage disease, accumulation of sphingomyelin within macrophages (“foam cells”)

—> splenomegaly + neuro deficits + cherry red spot (fundoscopy)

more common among Ashkenazi Jews

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16
Q

how does a deficiency of acid sphingomyelinase present? (3)

A

Niemann-Pick Disease: accumulation of sphingomyelin, more common among Ashkenazi Jews

—> hepatosplenomegaly (+ secondary thrombocytopenia)
—> progressive neuro deficits (child that loses motor skills)
—> cherry red spot due to central retinal artery occlusion

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17
Q

where does sphingomyelin accumulate in Niemann-Pick Disease?

A

AR deficiency of acid sphingomyelinase (ASM) —> accumulation of sphingomyelin within macrophages (“foam cells”)

—> splenomegaly + neuro deficits + cherry red spot (central retinal artery occlusion)

more common among Ashkenazi Jews

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18
Q

what is the cause of a cherry red spot on fundoscopy, and in which 2 lysosomal storage diseases can it be seen? how do their presentations differ?

A

cherry red spot caused by central retinal artery occlusion (retina appears pale, with red spot in middle)

seen in:
1. Niemann-Pick: neuro deficits + hepatosplenomegaly
2. Tay-Sachs: neuro deficits, NO hepatosplenomegaly

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19
Q

A previously healthy child is brought to the pediatrician due to concerns that they are no longer walking or able to hold objects. On PE, the child is weak, and there is enlargement of the spleen and liver. On neuro exam, a cherry red spot is noted. The child is of Ashkenazi Jewish descent, and genetic testing reveals a deficiency of…

A

Niemann-Pick Disease: AR deficiency of acid sphingomyelinase (ASM)

—> hepatosplenomegaly (+ secondary thrombocytopenia)
—> progressive neuro deficits (child that loses motor skills)
—> cherry red spot due to central retinal artery occlusion

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20
Q

child with loss of motor skills + hepatosplenomegaly + bone marrow biopsy which shows foam cells =

A

Niemann-Pick Disease: AR deficiency of acid sphingomyelinase (ASM), more common among Ashkenazi Jews

sphingomyelin accumulates in macrophages (“foam cells”)

—> hepatosplenomegaly (+ secondary thrombocytopenia)
—> progressive neuro deficits (child that loses motor skills)
—> cherry red spot due to central retinal artery occlusion

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21
Q

what is the cause of Krabbe’s Disease?

A

lysosomal storage disease, AR deficiency of galactocerebrosidase —> accumulation of galactocerebroside (ceramide + galactose head group) - major component of myelin!!

bc of this, symptoms are only neuro - early progressive weakness, early death

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22
Q

what is the consequence of a deficiency of galactocerebrosidase?

A

Krabbe’s Disease: accumulation of galactocerebroside - major component of myelin!!

bc of this, symptoms are only neuro - early progressive weakness (“floppy baby”), absent reflexes, optic atrophy, early death (<2)

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23
Q

describe the presentation of Krabbe’s Disease

A

Krabbe’s Disease: AR deficiency of galactocerebrosidase - abnormal metabolism of galactocerebroside, major component of myelin!!

bc of this, symptoms are only neuro - early (<6 mo) progressive weakness (developmental delay, floppy baby), absent reflexes, optic atrophy, fever without infection, early death (<2)

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24
Q

what does histology of Krabbe’s Disease show?

A

aka globoid cell leukodystrophy: AR deficiency of galactocerebrosidase - abnormal metabolism of galactocerebroside, major component of myelin!! (—> neuro symptoms)

biopsy shows globoid cells in neuronal tissue - cells with bunches of nuclei, look like little brains

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25
Q

brain biopsy of a child shows globe-shaped cells with multiple nuclei - what deficiency do they have?

A

Krabbe’s Disease: AR deficiency of galactocerebrosidase - abnormal metabolism of galactocerebroside, major component of myelin!!

bc of this, symptoms are only neuro - early (<6 mo) progressive weakness (developmental delay, floppy baby), absent reflexes, optic atrophy, fever without infection, early death (<2)

26
Q

3mo baby is brought to pediatrician with concern of missed milestones and progressive “floppiness.” Reflexes are absent on PE and there are signs of vision loss. They also have a fever, but workup shows no evidence of infection. Genetic testing is done, which reveals an AR deficiency of…

A

Krabbe’s Disease: AR deficiency of galactocerebrosidase - abnormal metabolism of galactocerebroside, major component of myelin!!

bc of this, symptoms are only neuro - early (<6 mo) progressive weakness (developmental delay, floppy baby), absent reflexes, optic atrophy, fever without infection, early death (<2)

27
Q

describe the structure of gangliosides

A

(type of sphingolipid) ceramide + sugar sequence + NANA head group

NANA = N-acetylneuraminic acid, aka sialic acid

important molecules in neural tissue —> accumulation (via lysosomal storage diseases) causes neuro symptoms

28
Q

what is the cause of Tay-Sachs Disease?

A

AR deficiency of hexosaminidase A —> accumulation of GM2 ganglioside (contains NANA)

—> neuro symptoms

[more common among Ashkenazi Jewish]

29
Q

what is the consequence of AR deficiency of hexosaminidase A?

A

Tay-Sachs: accumulation of GM2 ganglioside (contains NANA)

—> progressive neurodegeneration (3-6 mo) - weakness, exaggerated startle response, seizures, vision/hearing loss, cherry red spot, paralysis, death in childhood

[more common among Ashkenazi Jewish]

30
Q

how does Tay-Sachs Disease present?

A

deficiency of hexosaminidase A —> accumulation of GM2 ganglioside

—> progressive neurodegeneration (3-6 mo) - weakness, exaggerated startle response, seizures, vision/hearing loss, cherry red spot, paralysis, death in childhood

[more common among Ashkenazi Jewish]

31
Q

what is the classic pathology finding of Tay-Sachs Disease?

A

deficiency of hexosaminidase A —> accumulation of GM2 ganglioside

—> progressive neurodegeneration (3-6 mo)

histology shows lysosomes with onion skinning (many circular layers)

32
Q

Tay-Sachs Disease = deficiency of _______, with consequential accumulation of _______

A

Tay-Sachs Disease = deficiency of hexosaminidase A, with consequential accumulation of GM2 ganglioside —> progressive childhood neurodegeneration

recall ganglioside is a type of sphingolipid that contains NANA (sialic acid)

33
Q

Pt is a 4mo child brought to pediatrician due to concern of new onset seizures. The child also has been missing physical milestones. On PE, there is generalized muscle weakness and an exaggerated startle response. Neuro exam is notable for vision and hearing deficits and a cherry red spot on fundoscopy. A biopsy is done which shows lysosomes with many layers, like an onion. The child is of Ashkenazi Jewish descent, and genetic testing reveals a deficiency causing accumulation of…

A

Tay Sachs: deficiency of hexosaminidase A —> accumulation of GM2 ganglioside

—> progressive neurodegeneration (3-6 mo) - weakness, exaggerated startle response, seizures, vision/hearing loss, cherry red spot, paralysis, death in childhood

[more common among Ashkenazi Jewish]

34
Q

describe the structure of sulfatides - for what biological purpose are they relevant?

A

sulfatides = galactocerebroside + sulfuric acid

major component of myelin, therefore deficiency of arylsulfatase A —> accumulation of sulfatides —> neuro symptoms (metachromatic leukodystrophy)

35
Q

what is the cause of metachromatic leukodystrophy?

A

AR deficiency of arylsulfatase A —> accumulation of sulfatides, which are major component of myelin

therefore, neuro symptoms in child (~2 yo) - ataxia, hypotonia (speech problems), dementia

36
Q

what is the consequence of AR deficiency of arylsulfatase A?

A

metachromatic leukodystrophy: accumulation of sulfatides, which are major component of myelin

therefore, neuro symptoms in child (~2 yo) - ataxia, hypotonia (speech problems), dementia

[note, named this way bc sulfatides take up stains differently and look colorful]

37
Q

describe the presentation of metachromatic leukodystrophy

A

AR deficiency of arylsulfatase A —> accumulation of sulfatides, which are major component of myelin

therefore, neuro symptoms in child (~2 yo) - ataxia, hypotonia (speech problems), dementia, most do not survive childhood

38
Q

Pt is 2yo child brought to pediatrician with concern of frequent stumbling and falls and speech issues. Unfortunately, the child dies 3 years later. Autopsy biopsy shows colorful aggregations of sulfatides. What was the diagnosis?

A

metachromatic leukodystrophy: AR deficiency of arylsulfatase A —> sulfatide accumulation (major myelin component)

neuro symptoms in child (~2 yo) - ataxia, hypotonia (speech problems), dementia

39
Q

what makes Fabry’s Disease and Gaucher’s Disease different from the other lysosomal storage diseases?

A

do NOT present with weakness, can be treated with enzyme replacement therapy - allowing patients to live into adulthood

Fabry’s = X-linked deficiency of alpha-galactosidase A —> hand/feet pain, decreased sweating, rash

Gaucher’s = AR deficiency of glucocerebrosidase —> splenomegaly, anemia, bone crisis

40
Q

contrast the presentations of Krabbe’s Disease and Tay Sachs Disease

A

both lysosome storage diseases leading to neuro symptoms due to accumulation of myelin components

Krabbe’s = deficiency of galactocerebrosidase, <6 mo progressive weakness, absent reflexes, fever without infection, early death (<2)

Tay Sachs = deficiency of hexosaminidase A —> accumulation of GM2 ganglioside, 3-6 mo weakness, exaggerated startle response, seizures, cherry red spot, paralysis, death in childhood, associated with Ashkenazi Jewish

41
Q

which 4 lysosomal storage diseases present with weakness?

A
  1. metachromatic leukodystrophy = deficiency of arylsulfatase A
  2. Niemann Pick = deficiency of acid sphingomyelinase
  3. Krabbe’s = deficiency of galactocerebrosidase
  4. Tay Sach’s = deficiency of hexosaminidase A —> accumulation of GM2 ganglioside

NOT included are Fabry’s and Gaucher’s

42
Q

divide the following lysosomal storage diseases into those that present in a baby vs an older child:
a. metachromatic leukodystrophy
b. Krabbe’s
c. Tay Sachs
d. Niemann Pick

A

baby:
1. Krabbe’s = deficiency of galactocerebrosidase —> neuro symptoms
2. Tay Sach’s = deficiency of hexosaminidase A, neuro symptoms + cherry red spot

child:
1. metachromatic leukodystrophy = deficiency of arylsulfatase A —> ataxia, ~2 yo
2. Niemann Pick = deficiency of acid sphingomyelinase —> hepatosplenomegaly + cherry red spot, older child

and all present with progressive muscle weakness !

43
Q

what enzyme is deficient in the following lysosome storage diseases?
1. metachromatic leukodystrophy
2. Niemann Pick
3. Krabbe’s
4. Tay Sach’s
5. Fabry’s
6. Gaucher’s

A
  1. metachromatic leukodystrophy = deficiency of arylsulfatase A
  2. Niemann Pick = deficiency of acid sphingomyelinase
  3. Krabbe’s = deficiency of galactocerebrosidase
  4. Tay Sach’s = deficiency of hexosaminidase A (accumulation of GM2 ganglioside)
  5. Fabry’s = (X-linked) deficiency of alpha-galactosidase A
  6. Gaucher’s = deficiency of glucocerebrosidase
44
Q

what type of molecules accumulate in lysosomal storage diseases?

A

all derivatives of ceramides containing sphingosine and fatty acids

45
Q

describe the structure of glycosaminoglycans

A

aka mucopolysaccharides - long polysaccharides of repeating disaccharide units containing an amino sugar and uronic acid

46
Q

what disaccharide moiety is contained in both heparan sulfate and dermatan sulfate, and why is this relevant?

A

heparan sulfate (NOT heparin) and dermatan sulfate our both glycosaminoglycans that contain L-iduronate

This molecule accumulates in glycosaminoglycans storage diseases (Hurlers and Hunters)

47
Q

what kind of disorders are Hurler’s and Hunter’s? how are they diagnosed?

A

mucopolysaccharidosis (glycosaminoglycans storage disorders) due to inability to break down heparan and dermatan

Hurler’s = Type I; Hunter’s = Type II

dx: mucopolysaccharides in urine

48
Q

what accumulates when there is a deficiency of alpha-L-iduronidase? what is this disease called?

A

Hurler’s Syndrome (Type I mucopolysaccharidosis): AR deficiency of alpha-L-iduronidase —> accumulation of heparan and dermatan sulfate

causes coarse facial features, short stature, intellectual disability, hepatosplenomegaly, infections, corneal clouding in 1st year of life

49
Q

what causes Hurler’s Syndrome?

A

Type I mucopolysaccharidosis - AR deficiency of alpha-L-iduronidase —> accumulation of heparan and dermatan sulfate

causes coarse facial features, short stature, intellectual disability, hepatosplenomegaly, infections, corneal clouding in 1st year of life

50
Q

how does a deficiency of alpha-L-iduronidase present (7)? what is this disease called?

A

Hurler’s Syndrome (AR) —> accumulation of heparan and dermatan sulfate

presents in first year of life with:
1. coarse facial features + short stature
2. dysostosis multiplex (radiographic findings due to bone defects)
3. intellectual disability
4. corneal clouding (abnormal arrangement of collagen)
5. hepatosplenomegaly
6. frequent infections (thick secretions)
7. airway obstruction, sleep apnea (tracheal cartilage abnormalities)

51
Q

what is the cause of Hunter’s Syndrome?

A

Type II mucopolysaccharidosis - X-linked deficiency of iduronate-2-sulfatase (IDS) —> accumulation of heparan and dermatan sulfate

presents 1-2yo w/ bone abnormalities, behavioral problems (aggressive), learning difficulty (can mimic ADHD), hepatosplenomegaly + frequent infections

52
Q

what accumulates when there is a deficiency of iduronate-2-sulfatase (IDS)? what is this disease called?

A

Hunter’s Syndrome (Type II mucopolysaccharidosis): X-linked deficiency of iduronate-2-sulfatase (IDS) —> accumulation of heparan and dermatan sulfate

presents 1-2yo w/ bone abnormalities, behavioral problems (aggressive), learning difficulty (can mimic ADHD), hepatosplenomegaly + frequent infections

53
Q

how does a deficiency of iduronate 2-sulfatase (IDS) present? what is this disease called?

A

Hunter’s Syndrome (X-linked) —> accumulation of heparan and dermatan sulfate

presents 1-2yo with:
1. bone abnormalities
2. behavior problems (aggression) + learning difficulty (mimics ADHD)
3. hepatosplenomegaly
4. frequent infections (thick secretions)

54
Q

contrast Hurler vs Hunter Syndromes … include enzyme deficiency, key clinical features, ages of presentation

A

both mucopolysaccharidosis that cause accumulation of heparan and dermatan sulfate … both cause bone abnormalities, hepatosplenomegaly, frequent infections

Hurler’s (Type I): AR deficiency of alpha-L-iduronidase —> intellectual disability, corneal clouding, first year of life
[“L” looks like “I” for Type 1, also 1 for 1st year of life]

Hunter’s (Type II): X-linked deficiency of iduronate-2-sulfatase —> aggression + learning difficulty (mimics ADHD), ages 1-2yo
[“2” for Type II, also 2 for age]

55
Q

Pt is 7mo child brought to pediatrician due to developmental concerns. On examination, facies are coarse and the liver and spleen are enlarged. They have already had 2 ear infections and a pulmonary infection. There is notable corneal clouding. X-ray reveals an enlarged skull and abnormal rib and spine structure. Urinalysis shows elevated heparan and dermatan. What is the diagnosis?

A

Hurler’s Syndrome: AR deficiency of alpha-L-iduronidase —> accumulation of heparan and dermatan sulfate (mucopolysaccharides)

presents in first year of life with:
1. coarse facial features + short stature
2. dysostosis multiplex (radiographic findings due to bone defects)
3. intellectual disability
4. corneal clouding (abnormal arrangement of collagen)
5. hepatosplenomegaly
6. frequent infections (thick secretions)
7. airway obstruction, sleep apnea (tracheal cartilage abnormalities)

56
Q

Child is brought to pediatrician due to concern of behavioral issues and difficulty in school. The parents state the child has always had aggressive outbursts, and in school they are falling behind due to difficulty concentrating. Their teacher initially mentioned concern of ADHD, but the behavioral psychologist referred the patient to the pediatrician due to concern of frequent sinus and ear infections and coarse facial features. Urinalysis shows elevated mucopolysaccharides. What is the diagnosis?

A

Hunter’s Syndrome: X-linked deficiency of iduronate-2-sulfatase —> accumulation of heparan and dermatan sulfate

presents 1-2yo with:
1. bone abnormalities
2. behavior problems (aggression) + learning difficulty (mimics ADHD)
3. hepatosplenomegaly
4. frequent infections (thick secretions)

57
Q

How does I-cell (Inclusion Cell) Disease present? (5)

A

lysosomal enzymes NOT processed in Golgi due to failure to add mannose-6-phosphate (M6P) —> enzymes secreted outside of cell

presents in first year with:
1. growth failure + coarse facies
2. hypotonia + motor delay
3. frequent infections
4. clouded corneas
5. dysostosis multiplex (abnormal bone findings on X-ray)

58
Q

What is the cause of I-cell (Inclusion) Disease (be exact)? What are the key clinical (lab) findings (4)?

A

lysosomal enzymes synthesized normally but NOT processed in Golgi due to failure to add mannose-6-phosphate, which directs enzymes to lysosome —> enzymes secreted outside of cell

  1. low intracellular lysosomal enzymes
  2. high plasma lysosomal enzymes
  3. multiple abnormal enzymes
  4. intracellular inclusions in lymphocytes and fibroblasts
59
Q

What are the key lab findings of I-cell (Inclusion) Disease (4)?

A
  1. low intracellular lysosomal enzymes
  2. high plasma lysosomal enzymes
  3. multiple abnormal enzymes
  4. intracellular inclusions in lymphocytes and fibroblasts

lysosomal enzymes synthesized normally but NOT processed in Golgi due to failure to add mannose-6-phosphate, which directs enzymes to lysosome —> enzymes secreted outside of cell

60
Q

Child presents to pediatrician due to concern of missed motor milestones. They are 30th percentile for growth, and there is significant motor delay and hypotonia. They have coarse facial features and multiple joint abnormalities. Corneas are clouded. They have had 3 respiratory infections in the past year. Labs show multiple abnormal lysosomal enzymes, which are elevated in the plasma. What is the dx?

A

I-cell (inclusion) Disease: lysosomal enzymes NOT processed in Golgi due to failure to add mannose-6-phosphate (M6P) —> enzymes secreted outside of cell

presents in first year with:
1. growth failure + coarse facies
2. hypotonia + motor delay
3. frequent infections
4. clouded corneas
5. dysostosis multiplex (abnormal bone findings on X-ray)

61
Q

deficiency in acid alpha-glucosidase (aka lysosomal acid maltase) =

A

Pompe’s Disease: glycogen storage disease Type II, also a lysosomal storage disease!

—> accumulation of glycogen in lysosomes, presents in infancy with severe disease and early death

Biochem + Metabolism (18 decks)

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