Patholgoy Of Neurologic Metabolic Diseases

Question 1

what are examples of major neuronal storage diseases?

Answer 1

Tay-Sachs

Niemann-pick

Gaucher

Mucopolysaccharidoses

if cortical neuronal involvement is present, will always show cognitive function and seizures

Question 2

What is the main component of primary storage lysosomal storage diseases?

Answer 2

When an inherited lack of a lysosomal enzyme causes build up of insoluble metabolites within lysosomes

This generates free radicals and induces apoptosis of cells

Question 3

Tay-Sachs disease (GM2-gangliosidosis)

Answer 3

Deficiency in hexosaminidase (a) subunit
- leads to accumulation of gangliosidoses

Is the most common gangliosidoses and is caused by a loss-o-function mutation.

• is highly common in ashkenazi Jews (1:30 are carriers)
• can detect carriers by serum concentrations of hexosaminidase or DNA sequencing

Tissues most affected

• CNS and autonomic nervous tissues
• retina
• heart/liver/spleen

Accumulation of GM2 leads to foamy swollen CNS and PNS cells. Also may appear onionskined and whorled shaped.

Symptoms:
- neurologic impairment
- motor weakness 
- blindness 
**possess cherry red macula 
(Usually die within 2-3 yrs of birth)

Question 4

What is the hypothesis behind enzyme dysfunctional in lysosomal storage disorders

Answer 4

Mutant enzyme proteins undergo an “unfolded protein” response called proteasomal degradation if they are not stabilized by chaperone proteins.

Question 5

Niemann-Pick disease

Answer 5

Involves primary deficiency in acid sphingomyelinases and the defects are on chromosome 11p15.4

*very common in ashkenazi Jews

Affects CNS/PNS/spleen/live/bone marrow/lungs and lymph nodes usually.

Neurons appear enlarged and vacuolated if it affects the nervous system

3 major types
A) severe deficiency of sphingomyelinase levels and accumulates in phagocytic cells and neurons
- harsher effects are seen with massive organomegaly and neurologic symptoms
- death occurs within 3 years

B) less serious deficency of sphingomyelinase
- organomegaly is still apparent, but NO

C) defect is in lipid transport specifically

• most common type
• mutations in NPC1/2 genes
• shows ataxia, vertical gaze parlays, dysarthria and dystonia.
• doesn’t kill

neurologic symptoms

Question 6

Gaucher disease

Answer 6

Deficency in the enzyme glucocerebrosidase
- abundance of glucocerebroside

There are 3 autosomal recessive variants

Shows huge gaucher cells that appear “wrinkled tissue paper appearance”

Types:

1) chronic non neuropathic form (99% of cases)
- shows bone lesion involvement in almost all cases
- absence of CNS involvement
- hepatosplenomegaly
- does not shorten life span by itself

2 & 3) acute infantile neuropathic form and infantile neuropathic form (1%)

• both are roughly the same and incomparable with life (some 3 can survive but in poor condition)
• difference is that 2 starts immediately after birth and is more severe, whereas 3 starts usually in childhood

Question 7

Mucopolysaccharidoses (MPSs/GAGs)

Answer 7

Defective degradation of mucopolysaccharides from the extracellular matrix

• includes the following
• dermatan sulfate
• heparan sulfate
• keratan sulfate
• chondroitin sulfate

Symptoms:

• hepatosplenomegaly
• skeletal deformities
• lesions of heart valves
• subendothelial arterial depositis
• lesions in brain
• possible MI
• clouding of cornea
• joint stiffness
• mental retardation

*All are autosomal recessive except hunter syndrome (X-linked recessive)

Question 8

Hurler vs hunter syndrome

Answer 8

Both are mucopolysaccharidoses

Hurler (MPS1):

• deficiency in (a)L-iduronidase
• 6-10 yr life expectancy
• usually die from cardiac issues
• produces corneal clouding
• accumulation of dermatan and heparan sulfate is most common

Hunter (MPS2):

• deficiency in iduronate 2-sulfatase
• NO corneal clouding
• more mild and patients usually live
• accumulation of dermatan and heparan sulfate is most common

Question 9

Thiamine deficency (beriberi)

Answer 9

Vitamin B1 deficiency most common seen in alcoholics, gastric patients or in third world areas

May lead to Wernicke encephalopathy which has the Symptoms:

• Abrupt on set of confusion
• abnormalities of the eyes
• ataxia

treatment is thiamine IV dose however if delayed treatment, becomes korsakoff syndrome and that is irreversible memory loss and confabulation

Question 10

Vitamin B12 deficiency

Answer 10

Leads to anemia and subacute combined degeneration of the spinal cord
- affects both descending and ascending tracts

Symptoms:

• ataxia
• numbness and tingling of the lower extremities
• paraplegia

*Treatment = vitamin B12 IV, however if the patient is experiencing paraplegia, treatment doesnt always work

Question 11

Hyperglycemia in the brain

Answer 11

Most common setting of inadequately controlled diabetes

Symptoms

• confusion
• stupor
• coma (eventually due to intracellular dehydration)

Treatment: slow flushing of excess glucose (too fast and will causes cerebral edema)