CNS Toxic & Metabolic Diseases - Lawlor, Scharer Flashcards

You may prefer our related Brainscape-certified flashcards:
1
Q

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

Name two X-linked exceptions to this

A

Autosomal recessive

Fabry Disease and Hunter Syndrome are X-linked recessive

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Why is delayed diagnosis of LSDs especially bad?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What symptoms should arouse suspicion of metabolic disorder?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Describe some suspicious clinical presentations that may indicate metabolic disorder

A

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)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

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
A
  • 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)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Name the deficient enzyme in the following diseases:

Tay-Sachs disease

Sandhoff disease

GM2 Gangliosidosis variant AB

A

Hexosaminidase A

Hexosaminidase B

Activator protein

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Are PKU or galactosemia considered lysosomal storage disorders? Why?

Is poisoning considered a lysosomal storage disease?

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Tay-Sachs Disease:

  • Especially prevalent in which ethnic population?
  • Which chromosome is affected?
  • Diagnostics?
  • Presentation and S/S?
  • Outcome?
A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

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

A

Gross: large brain (if survival >2 years)

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

EM: membranous cytoplasmic bodies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are some treatment options for Tay-Sachs disease?

A

Mostly experimental:

  • “Chaperone” proteins - help alpha subunit fold normally
  • Enzyme replacement therapy
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

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?
A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

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

Describe the treatment option(s)

A
  • 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Describe Krabbe’s Disease:

  • Grossly
  • LM
  • EM
A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Metachromatic Leukodystrophy

  • Affected chromosome?
  • Deficient enzyme?
  • Accumulated substance? Which organ system(s)?
  • Dx?
A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

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

What is the treatment in either case?

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

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

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Adrenoleukodystrophy:

  • Location of defect in the cell
  • Enzymatic defect
  • Genetic inheritance pattern
A
  • Peroxisome
  • Decreased activity of very long chain fatty acyl-CoA synthetase
  • X-lined recessive
18
Q

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

A
  • 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
19
Q

Describe the brain tissue in adrenoleukodystrophy:

  • Grossly
  • LM
A
  • Gross
    • gray discoloration of white matter with marked firmness
    • U fiber preservation
  • LM
    • Perivascular inflammation
    • PAS positive macrophages
20
Q

Describe the early clinical manifestations of hepatic encephalopathy

Later features?

A

Early: inattentiveness and short term memory impairment

Later: confusion, asterixis, drowsiness, stupor, coma

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

21
Q

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

What other findings?

A

Globus pallidus

subthalamus

midbrain

cortical edema

22
Q

Alzheimer type II astrocytes are characteristically seen in what pathology?

A

Hepatic encephalopathy

23
Q

What areas of the brain are most sensitive to hypoglycemia?

A

Laminae 3, 5, and 6

Putamen

Caudate nucleus

Dentate nucleus

CA1 area of the hippocampus

24
Q

Mitochondrial diseases show what kind of inheritance?

A

Maternal inheritance

25
Q

What about the genetics of mitochondrial disease dramatically complicates diagnosis?

A

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

26
Q

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

A

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
27
Q

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)
A
  • Heteroplasmic point mutations in mt-tRNA_Leu
  • Heteroplasmic point mutations in mt-tRNA_Lys
  • Large single mtDNA mutation
  • Nuclear mutation of mitochondrial genes
28
Q

Leigh’s Disease (Subacute Necrotizing Encephalopathy):

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

29
Q

Describe Leigh’s disease:

  • Grossly
  • LM
A
  • Gross: Destruction of periventricular gray matter, particularly around the cerebral aqueduct and third ventricle
  • LM: spongiform appearance and vascular proliferation
30
Q

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

What might cause this deficiency?

A
  • Wernicke encephalopathy
  • Korsakoff syndrome

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

31
Q

Describe the usual clinical presentation of Wernicke Encephalopathy

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

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

Sensitive areas -> lesions seen in:

  • Mammillary bodies
  • Dorsomedial thalamus
  • 3rd and 4th ventricles
32
Q

Describe the clinical S/S of Korsakoff Psychosis

How does it arise?

What area of the brain is most characteristically damaged?

A
  • 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

33
Q

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?

A

Vitamin B12

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

Both the CNS and PNS are involved

34
Q

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

A

Anterior and lateral corticospinal tracts

Posterior columns

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

35
Q

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

A

Globus pallidus and substantia nigra

These areas have higher iron content

36
Q

Describe the neuro S/S of carbon monoxide poisoning

A

Motor, cognitive, and psychiatric deficits

Parkinsonian signs

37
Q

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

Describe

A

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

38
Q

Describe the clinical and pathological findings of Fetal Alcohol Syndrome

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

A
  • 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

39
Q

Are the effects of radiation toxicity generally immediate or delayed?

Describe the clinical symptoms

A

Delayed

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)

40
Q

Describe the toxicities associated with:

  • Methotrexate
  • Vincristine
  • Phenytoin
  • Cocaine
  • Amphetamine
A
  • 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
41
Q

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

A

Acute ophthalmic artery obstruction (typically unilateral)

GM1 gangliosidosis

Tay-Sachs disease

Sandoff disease

Nieman-Pick disease

Mucolipidosis