Cns Toxic & Metabolic Disorders

Front 1

Mendelian inheritance of Wilson’s(hepatolenticular degeneration) disease?

Back 1

Autosomal recessive disorder

Front 2

Pathogenesis of Wilson’s (hepatolenticular degeneration)disease ?

Back 2

Pathogenesis
a. Gene mutation results in:
(1) Defective hepatocyte transport of copper into bile for excretion
(2) Decreased synthesis of ceruloplasmin (binding protein for copper in blood)
b. Unbound copper eventually accumulates in blood
(1) Loosely attached to albumin
(2) Copper deposits in other tissues causing a toxic effect.

Front 3

Normal functions of ceruloplasmin and effect when decreased in Wilson’s (hepatolenticular degeneration) disease

Back 3

Ceruloplasmin, the binding protein for copper, is secreted into the plasma where it represents 90-95% of the total serum copper concentration. The remaining 5-10% of copper is free copper that is loosely bound to albumin. Ceruloplasmin is eventually taken up and degraded by the liver. The copper that was bound to ceruloplasmin is excreted into the bile. The gene defect in Wilson's disease affects a copper transport system that produces a dual defect decreased synthesis of ceruloplasmin in the liver and decreased excretion of copper into bile. Accumulation of copper in the liver increases the formation of free radicals causing damage to hepatocytes. In a few years, unbound copper is released from the liver into the circulation (increased in blood and urine) where it can cause hemolysis or damage to the brain, kidneys, cornea, and other tissues.

Front 4

Gross findings (be able to recognize)of Wilson’s (hepatolenticular degeneration)disease:

Back 4

-Liver disease progresses from acute hepatitis to cirrhosis
-Kayser-Fleischer ring
-Central nervous system disease

Front 5

Clinical findings (be able to identify Kayser-Fleischer ring and exact site of copper deposition)of Wilson’s (hepatolenticular degeneration) disease.

Back 5

Kayser-Fleischer ring
•Due to free copper deposits in Descemet's membrane in the cornea
Central nervous system disease
(1) Atrophy and cavitation of basal ganglia, particularly the putamen
(2) Copper deposits in the putamen
• Produces a movement disorder resembling parkinsonism
(3) Copper deposits in the subthalamic nucleus
• Produces hemiballismus
(4) Copper is toxic to neurons in the cerebral cortex
• Produces dementia

Front 6

Laboratory findings of Wilson’s (hepatolenticular degeneration) disease:

Back 6

Decreased total serum copper
• Due to decreased ceruloplasmin
e. Decreased serum ceruloplasmin
• Useful in diagnosing Wilson's disease in early stages of the disease
f. Increased serum and urine free copper
• Useful in diagnosing Wilson's disease in later stages of the disease

Front 7

Wilson's (hepatolenticular degeneration) disease:

Back 7

↓ synthesis ceruloplasmin, ↓ excretion of copper in bile

Front 8

Kayser-Fleischer ring:

Back 8

excess copper in Descemet's membrane of cornea

Front 9

Mendelian inheritance of acute intermittent porphyria

Back 9

Autosomal dominant disorder

Front 10

enzyme deficiency and accumulation products in blood and urine in acute intermittent porphyria

Back 10

a. Deficiency of uroporphyrinogen synthase (alias porphobilinogen deaminase)
b. Proximal increase in porphobilinogen (PBG) and δ-aminolevulinic acid (ALA)

Front 11

“window-sill test” for acute intermittent porphyria

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Urine is colorless when first voided.
(1) Exposure to light causes oxidation of PBG to porphobilin producing port-wine color.
(2) Classic "window-sill test"

Front 12

Effect of alcohol on heme in an individual with acute intermittent porphyria

Back 12

Decreasing heme precipitates porphyric attacks by increasing porphyrin synthesis.
• Example: drugs enhancing liver cytochrome P-450 system (e.g., alcohol)

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clinical findings in acute intermittent porphyria

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Neurologic dysfunction
(1)Recurrent bouts of severe abdominal pain simulating acute abdomen
(2) Often mistaken for a surgical abdomen
• Patient has “bellyful of scars”.
b. Psychosis, peripheral neuropathy, dementia

Front 14

pathogenesis of acute intermittent porphyria

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Defect in porphyrin metabolism
a. Deficiency of uroporphyrinogen synthase (alias porphobilinogen deaminase)
b. Proximal increase in porphobilinogen (PBG) and δ-aminolevulinic acid (ALA)
c. Urine is colorless when first voided.

Front 15

Acute intermittent porphyria:

Back 15

“bellyful of scars”

Front 16

what type of anemia is produced in a vitamin B12 deficiency?

Back 16

macrocytic anemia (notes)

megaloblastic anemia (Robbins)

Front 17

sites of degeneration vitamin B12 deficiency

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Subacute combined degeneration of the spinal cord:
-Dorsal column,
-lateral corticospinal tract, -spinocerebellar tract demyelination

Front 18

clinical effects of a vitamin B12 deficiency

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Dementia, peripheral neuropathy

Front 19

Why administering and IV with glucose can precipitate an acute Wernicke’s syndrome and how it can be prevented.

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It may precipitate an acute thymine deficiency in alcoholics (depleted by the pyruvate dehydrognase reaction). Deficiency is manifested by Wernicke-Korsakoff syndrome (RR Biochemistry p.55)

Front 20

Pathogenesis of
Wernicke-Korsakoff syndrome

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Most often due to thiamine deficiency.

Front 21

gross and microscopic findings (be able to identify)
Wernicke-Korsakoff syndrome

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(1)Hemorrhages with hemosiderin deposits; sites
• Mamillary bodies, wall of the third and fourth ventricles
(2)Neuronal loss, gliosis, vessel hemorrhage

Front 22

clinical findings in both parts of the Wernicke-Korsakoff syndrome

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Wernicke’s encephalopathy:
reversible findings include-
• Confusion, ataxia, nystagmus, ophthalmoplegia (eye muscle weakness)

Korsakoff’s psychosis
(1) Advanced irreversible stage of Wernicke’s encephalopathy
•Targets the limbic system
(2)Anterograde amnesia (inability to form new memories)
(3)Retrograde amnesia (inability to recall old memories)