CNS Toxic & Metabolic Diseases - Lawlor, Scharer Flashcards Preview

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Flashcards in CNS Toxic & Metabolic Diseases - Lawlor, Scharer Deck (41):

The majority of Lysosomal storage diseases  follow what genetic inheritance pattern?

Name two X-linked exceptions to this

Autosomal recessive

Fabry Disease and Hunter Syndrome are X-linked recessive


Why is delayed diagnosis of LSDs especially bad?

Unrecognized or delayed treatment of LSDs can cause irreversible injury to the brain and major organs (or death).


What symptoms should arouse suspicion of metabolic disorder?

Nearly everything (see slide 6 for an unhelpful wall of text)


Describe some suspicious clinical presentations that may indicate metabolic disorder

All of the following are suspicious in the absence of more common etiologies or other explanation

  • Unexplained lethargy, confusion, comnolescence, coma
  • Unexplained metabolic acidosis/alkalosis
  • Excessive lactate or ketosis
  • Persistent or recurrent hypoglycemia
  • Chronic or worsening symptoms
  • Unusual MRI, EEG, or pathology findings
  • Unusual combination of findings indicating more than one etiology (Occam's razor)


For the unresponsive patient with unexplained lethargy, confusion, or coma, what should you do next? Hints:

  • Exam
  • Blood chemistry
  • Who can help?
  • Immediate treatment
  • Metabolic work-up
  • Alternatives


  • Get a good PE and PMI (duh)
  • STAT glucose, ammonia, and blood pH
    • also: check electrolytes, LFTs, lactate, and urinalysis
  • Call a metabolic specialist (too bad this is never an option on boards)
    • store a 'critical sample' for acute reference
  • Start IV glucose ASAP
  • Metabolic work-up: acylcarnitine profile, amino acid profile, urine organic acid profile (look for things that are non-normal in metabolic diseases)
  • Consider alternatives: infection, intoxication, idiopathic)


Name the deficient enzyme in the following diseases:

Tay-Sachs disease

Sandhoff disease

GM2 Gangliosidosis variant AB

Hexosaminidase A

Hexosaminidase B

Activator protein


Are PKU or galactosemia considered lysosomal storage disorders? Why?

Is poisoning considered a lysosomal storage disease?

No - they involve accumulation of active metabolites

No - poisoning involves accumulation of active substrates

LSD accumulations are inert substrates/metabolites. However, silicosis and abestiosis are not considered defects of lysosomal function.


Tay-Sachs Disease:

  • Especially prevalent in which ethnic population?
  • Which chromosome is affected?
  • Diagnostics?
  • Presentation and S/S?
  • Outcome?

  • Ashkenazi Jews
  • Chromosome 15
  • Enzyme assay of serum, WBCs, and cultured fibroblasts
  • Clinically normal at birth -> psychomotor regression/retardation @ 6 months
    • Progress to blindness, incoordination, flaccidity, mental retardation
    • Eventual decerebrate state
    • Cherry red macular spot
  • Death by 2-3 years


Describe the gross, microscopic, and EM findings seen in Tay-Sachs Disease

Gross: large brain (if survival >2 years)

LM: enlarged, ballooned neurons, astrocytes, and microglia filled with PAS+ material (stored gangliosides)

EM: membranous cytoplasmic bodies


What are some treatment options for Tay-Sachs disease?

Mostly experimental:

  • "Chaperone" proteins - help alpha subunit fold normally
  • Enzyme replacement therapy


Krabbe's Disease (Globoid Cell Leukodystrophy)

  • Which part of the nervous system is affected?
  • Which chromosome is affected?
  • Which enzyme is deficient? How does this cause disease?
  • Diagnostic approach?

  • CNS and PNS
  • Chromosome 14
  • galactocerebroside-B-galactosidase
    • Causes accumulation of psychosine that injures oligodendrocytes
    • Galactocerebroside (myelin component) accumulates in "Globoid" cells
  • Dx: enzyme assay of WBCs or cultured fibroblasts


Describe the clinical course of Krabbe's Disease (Globoid Cell Leukodystrophy)

Describe the treatment option(s)

  • Normal early development with onset of symptoms around 3-6 months
    • irritability, halted development
    • deterioration of motor function, including tonic spasms, opisthotonic posture, and myotonic jerking
    • Optic atrophy, blindness
    • Elevated CSF protein
  • Death by approximately 2 years

Rx: umbilical cord blood or bone marrow transplantation. Must begin in pre-symptomatic phase


Describe Krabbe's Disease:

  • Grossly
  • LM
  • EM

  • Gross: atrophic brain with firm, atrophic white matter and preservation of "U" fibers
  • LM
    • Loss of myelin
    • Globoid (giant/macrophage) accumulated around vessels
    • Background of reactive astrocytosis
    • Decreased oligodendrocytes
  • EM: globoid cells contain crystalloid with straigt/tubular profiles


Metachromatic Leukodystrophy

  • Affected chromosome?
  • Deficient enzyme?
  • Accumulated substance? Which organ system(s)?
  • Dx?

  • Chromosome 22
  • Aryl sulfatase A
  • Metachromatic lipids (sulfatides) -> brain, peripheral nerves, kidney -> leads to breakdown of myelin
  • Dx: screen urine for metachromatic deposits, demonstrate enzyme deficiency in urine, WBCs, or fibroblasts


Contrast the clinical presentation of metachromatic leukodystrophy in a child to that in an adult.

What is the treatment in either case?

Child: presents with gait disorder and motor symptoms

Adult: usually presents first with psychosis and cognitive impairment with later progression to motor symptoms

Rx: bone marrow stem cell transplantation (before symptoms appear)


describe the gross appearance/consistency of the white matter in metachromatic leukodystrophy

Normal brain surface with marked loss of myelin with preservation of "U" fibers

The white matter is very firm

LM: metachromasia of white matter deposits (brown staining with acidified cresyl violet stain)



  • Location of defect in the cell
  • Enzymatic defect
  • Genetic inheritance pattern

  • Peroxisome
  • Decreased activity of very long chain fatty acyl-CoA synthetase
  • X-lined recessive


Describe the clinical presentation of both the classic and adrenomyeloneuropathy variants of adrenoleukodystrophy

  • Classic
    • Onset: 5-9 years or 11-21 years
    • Dementia, visual/hearing loss, seizures
    • Adrenal insufficiency following onset of neuro S/S
  • Adrenomyeloneuropathy
    • Adults (20-30 years)
    • Slowly progressive motor symptoms (leg stiffness and clumsiness) with eventual spastic paraplegia
    • Adrenal insufficiency may precende S/S


Describe the brain tissue in adrenoleukodystrophy:

  • Grossly
  • LM

  • Gross
    • gray discoloration of white matter with marked firmness
    • U fiber preservation
  • LM
    • Perivascular inflammation
    • PAS positive macrophages


Describe the early clinical manifestations of hepatic encephalopathy

Later features?

Early: inattentiveness and short term memory impairment

Later: confusion, asterixis, drowsiness, stupor, coma

Also possible: foul breath, hyperventilation, gait disturbances, choreoathetosis


In hepatic encephalopathy, increased MRI T1 signaling can be observed where?

What other findings?

Globus pallidus



cortical edema


Alzheimer type II astrocytes are characteristically seen in what pathology?

Hepatic encephalopathy


What areas of the brain are most sensitive to hypoglycemia?

Laminae 3, 5, and 6


Caudate nucleus

Dentate nucleus

CA1 area of the hippocampus


Mitochondrial diseases show what kind of inheritance?

Maternal inheritance


What about the genetics of mitochondrial disease dramatically complicates diagnosis?

Mitochondrial diseases may depend on the mitochondrial genome itself, nuclear genes that contribute to mitochondrial phenotype, or both.


What criteria should be met before considering genetic testing for mitochondrial disease?

The MCW/CHW approach: significant/suggestive findings in at least three of the following

  • Clinical history and imaging
  • Muscle biopsy (LM level) -> ragged red fibers
  • Muscle biopsy (EM level)
  • Electron transport activity testing
  • Mitochondrial DNA content quantification


Describe the genetic defect in each of the following:

  • MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes)
  • MERRF (Myoclonic Epilepsy with Ragged Red Fibers)
  • KSS (Kears-Sayre Syndrome)
  • Leigh's Disease (Subacute Necrotizing Encephalopathy)

  • Heteroplasmic point mutations in mt-tRNA_Leu
  • Heteroplasmic point mutations in mt-tRNA_Lys
  • Large single mtDNA mutation
  • Nuclear mutation of mitochondrial genes


Leigh's Disease (Subacute Necrotizing Encephalopathy):

  • Genetic defect
  • Enzyme deficiency
  • Genetic mode of inheritance
  • Clinical S/S

  • Mutation in nuclear mitochondrial DNA (also mitochondrial DNA sometimes)
  • Enzyme deficiency in pyruvate->ATP pathway (often decreased activity of cytochrome C oxidase)
  • Autosomal recessive
  • S/S
    • lactic acidemia
    • arrested development
    • hypotonia, seizures
    • extraocular palsies

Death occurs between ages 1-2


Describe Leigh's disease:

  • Grossly
  • LM

  • Gross: Destruction of periventricular gray matter, particularly around the cerebral aqueduct and third ventricle
  • LM: spongiform appearance and vascular proliferation


What two pathologies of the CNS are associated with Thiamine (B1) deficiency?

What might cause this deficiency?

  • Wernicke encephalopathy
  • Korsakoff syndrome

Causes include: starvation diets, hemodialysis, gastric stapling, extensive GI durgery, hyperalimentation without thiamine supplementation


Describe the usual clinical presentation of Wernicke Encephalopathy

What areas of the brain are especially sensitive (most often lesioned)?

  • Ophthalmoplegia, nystagmus
  • Ataxia
  • Confusion, disorientation, coma

Sensitive areas -> lesions seen in:

  • Mammillary bodies
  • Dorsomedial thalamus
  • 3rd and 4th ventricles


Describe the clinical S/S of Korsakoff Psychosis

How does it arise?

What area of the brain is most characteristically damaged?

  • Loss of anterograde episodic memory
  • Confabulation
  • Preserved intelligence and learned behavior

"Hypothesized to arise from repeated episodes of Wernicke's encephalopathy"

Damage to medial dorsal nucleus of the thalamus


Subacute combined degeneration of the spinal cord is caused by what vitamin deficiency?

Describe the clinical presentation

Which division of the nervous system is involved?

Vitamin B12

  • Presentation
    • Ataxia
    • Romberg
    • Spasticity
    • Decreased reflexes
    • Mental status changes

Both the CNS and PNS are involved


Which spinal tract(s) is(are) most affected in Vitamin B12 deficiency?

Anterior and lateral corticospinal tracts

Posterior columns

Both show vacuolation and demyelination. Axons may also show secondary degeneration


Carbon monoxide damage is especially apparent in what two areas of the brain? Why?

Globus pallidus and substantia nigra

These areas have higher iron content


Describe the neuro S/S of carbon monoxide poisoning

Motor, cognitive, and psychiatric deficits

Parkinsonian signs


Chronic ethanol toxicity is particularly damaging to which part of the brain?


Cerebellar degeneration -> leading to truncal ataxia, nystagmus, and limb discoordination.

Characteristic atrophy, especially of the superior vermis

LM: dropout of purkinje cells, internal granular cells, and astrocytosis


Describe the clinical and pathological findings of Fetal Alcohol Syndrome

What is the (theorized) mechanism of damage to the fetal brain?

  • Clinical
    • Growth retardation
    • Facial deformities (short palpebral fissure, epicanthal folds, thin upper lip, growth retardation of the jaw)
    • Cardiac defects (ASD)
    • Delayed development and mental insufficiency
  • Pathological
    • Microcephaly
    • Cerebellar dysgenesis
    • Heterotopic neurons

Acetaldehyde crosses the placenta and damages the fetal brain


Are the effects of radiation toxicity generally immediate or delayed?

Describe the clinical symptoms


S/S: similar to a mass lesion. Includes large areas of coagulative necrosis (primarily white matter), and vessels with markedly thick walls

General induction of neoplasms (present years after treatment)


Describe the toxicities associated with:

  • Methotrexate
  • Vincristine
  • Phenytoin
  • Cocaine
  • Amphetamine

  • MTX - Intrathecal or intraventricular administration, in combination with radiation therapy produces:
    • Disseminated necrotizing leukoencephalopathy (especially ventricles and deep white matter)
    • Coagulative necrosis with axonal loss and mineralization
  • Vincristine
    • PO admin: sensory neuropathy
    • Intrathecal admin: axonal swelling
  • Phenytoin
    • ataxia, nystagmus, slurred speech, and sensory neuropathy
    • Atrophy of cerebellar vermins and loss of purkinje cells and granule cells
  • Cocaine
    • Seizures, stroke, hemorrhage
    • Due to vasospasm, emboli, hypercoagulability, hypotension, and drug contaminants
    • Occasional vasculitis
  • Amphetamine
    • Infarcts and hemorrhage
    • Due to vasculitis and hypertension


What is the differential diagnosis for "cherry red spots" on the retina?

Acute ophthalmic artery obstruction (typically unilateral)

GM1 gangliosidosis

Tay-Sachs disease

Sandoff disease

Nieman-Pick disease