CNS Toxic & Metabolic Diseases - Lawlor, Scharer

Question 1

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

Name two X-linked exceptions to this

Answer 1

Autosomal recessive

Fabry Disease and Hunter Syndrome are X-linked recessive

Question 2

Why is delayed diagnosis of LSDs especially bad?

Answer 2

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

Question 3

What symptoms should arouse suspicion of metabolic disorder?

Answer 3

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

Question 4

Describe some suspicious clinical presentations that may indicate metabolic disorder

Answer 4

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)

Question 5

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

Answer 5

• 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)

Question 6

Name the deficient enzyme in the following diseases:

Tay-Sachs disease

Sandhoff disease

GM2 Gangliosidosis variant AB

Answer 6

Hexosaminidase A

Hexosaminidase B

Activator protein

Question 7

Are PKU or galactosemia considered lysosomal storage disorders? Why?

Is poisoning considered a lysosomal storage disease?

Answer 7

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.

Question 8

Tay-Sachs Disease:

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

Answer 8

• 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

Question 9

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

Answer 9

Gross: large brain (if survival >2 years)

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

EM: membranous cytoplasmic bodies

Question 10

What are some treatment options for Tay-Sachs disease?

Answer 10

Mostly experimental:

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

Question 11

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?

Answer 11

• 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

Question 12

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

Describe the treatment option(s)

Answer 12

• 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

Question 13

Describe Krabbe’s Disease:

• Grossly
• LM
• EM

Answer 13

• 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

Question 14

Metachromatic Leukodystrophy

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

Answer 14

• 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

Question 15

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

What is the treatment in either case?

Answer 15

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)

Question 16

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

Answer 16

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)

Question 17

Adrenoleukodystrophy:

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

Answer 17

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

Question 18

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

Answer 18

• 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

Question 19

Describe the brain tissue in adrenoleukodystrophy:

• Grossly
• LM

Answer 19

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

Question 20

Describe the early clinical manifestations of hepatic encephalopathy

Later features?

Answer 20

Early: inattentiveness and short term memory impairment

Later: confusion, asterixis, drowsiness, stupor, coma

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

Question 21

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

What other findings?

Answer 21

Globus pallidus

subthalamus

midbrain

cortical edema

Question 22

Alzheimer type II astrocytes are characteristically seen in what pathology?

Answer 22

Hepatic encephalopathy

Question 23

What areas of the brain are most sensitive to hypoglycemia?

Answer 23

Laminae 3, 5, and 6

Putamen

Caudate nucleus

Dentate nucleus

CA1 area of the hippocampus

Question 24

Mitochondrial diseases show what kind of inheritance?

Answer 24

Maternal inheritance

Question 25

What about the genetics of mitochondrial disease dramatically complicates diagnosis?

Answer 25

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

Question 26

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

Answer 26

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

Question 27

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)

Answer 27

* Heteroplasmic point mutations in mt-tRNA\_Leu * Heteroplasmic point mutations in mt-tRNA\_Lys * Large single mtDNA mutation * Nuclear mutation of mitochondrial genes

Question 28

Leigh's Disease (Subacute Necrotizing Encephalopathy): * Genetic defect * Enzyme deficiency * Genetic mode of inheritance * Clinical S/S

Answer 28

* 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

Question 29

Describe Leigh's disease: * Grossly * LM

Answer 29

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

Question 30

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

Answer 30

* Wernicke encephalopathy * Korsakoff syndrome Causes include: starvation diets, hemodialysis, gastric stapling, extensive GI durgery, hyperalimentation without thiamine supplementation

Question 31

Describe the usual clinical presentation of Wernicke Encephalopathy What areas of the brain are especially sensitive (most often lesioned)?

Answer 31

* Ophthalmoplegia, nystagmus * Ataxia * Confusion, disorientation, coma Sensitive areas -\> lesions seen in: * Mammillary bodies * Dorsomedial thalamus * 3rd and 4th ventricles

Question 32

Describe the clinical S/S of Korsakoff Psychosis How does it arise? What area of the brain is most characteristically damaged?

Answer 32

* 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

Question 33

**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?

Answer 33

Vitamin B12 * Presentation * Ataxia * Romberg * Spasticity * Decreased reflexes * Mental status changes Both the CNS and PNS are involved

Question 34

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

Answer 34

Anterior and lateral corticospinal tracts Posterior columns Both show vacuolation and demyelination. Axons may also show secondary degeneration

Question 35

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

Answer 35

Globus pallidus and substantia nigra These areas have higher iron content

Question 36

Describe the neuro S/S of carbon monoxide poisoning

Answer 36

Motor, cognitive, and psychiatric deficits Parkinsonian signs

Question 37

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

Answer 37

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

Question 38

Describe the clinical and pathological findings of **Fetal Alcohol Syndrome** What is the (theorized) mechanism of damage to the fetal brain?

Answer 38

* 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

Question 39

Are the effects of radiation toxicity generally immediate or delayed? Describe the clinical symptoms

Answer 39

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)

Question 40

Describe the toxicities associated with: * Methotrexate * Vincristine * Phenytoin * Cocaine * Amphetamine

Answer 40

* 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

Question 41

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

Answer 41

Acute ophthalmic artery obstruction (typically unilateral) GM1 gangliosidosis Tay-Sachs disease Sandoff disease Nieman-Pick disease Mucolipidosis