LT10 Treatment of Metabolic Disease and the Brain

Question 1

Define metabolic disease

Answer 1

Disease or disorder that disrupts normal metabolism = can occur in any cell type

Metabolic disease affects the ability of hte cell to perform critical biochemical reactions that invovle the processing or tranpsort of protein carbs, or lipids

Question 2

What affects brain function?

Answer 2

How efficiently the brain metabolises glucose

Question 3

What occurs in the brain if blood glucose levels drop?

Answer 3

Poor attention and cognitive function

Question 4

What damage can HYPERglycaemia cause?

Answer 4

Damages functional connectivity
Damaged brain metter integrity

Can caus ebrian to atrophy
Can lead to small-vessel disease
Cognitive difficulties

Vacsular dementia

Question 5

Why does your brain need lipid metabolism?

Answer 5

Complex lipids are needed to maintain and repiar key neuronal structures

Example = myelin sheath for electronical conductivity

Question 6

What are 5 metabolic disorders of the brain?

Answer 6

Mitochondrial dyfcuntion

Lysosomal dysfunction

Peroxisomal dysfunction

Non-organelle based dysfunction

Peripheral metabolic disease influenced by the brain

Question 7

What occurs when mitochondria are damaged and the consequences?

Answer 7

Reduced energy production/supply

ROS is generated

Neurones are very sensitive to these occurances = can result in damage of neurones

Question 8

Name 4 inborn mitochondrial diseases

Answer 8

Leigh disease
MELAS
MERRF
KSS

All reduce cellular ATP with varying severity = which is reflected in the rate of clinical decline

Question 9

What is the mechanism of action of Leigh disease?

Answer 9

Severe neurological disease in newborns to infants

It is a form of subacute necrotizing encephalomyelopathy

This disease results from mutations that affect production of pyruvate dehydrogenase AND cytochrome c oxidase (Complex IV) in electron transport chain

(affects Complex I, II and V to a much lesser extent)

Question 10

What does subacute necrotizing encephalomyelopathy (SNEM) mean?

Answer 10

Rapid loss of neuronal tissue

Question 11

What are the clinical symptoms of Leigh disease?

Answer 11

Psychmotor retardation
Ataxia
Eye movement abnormalities
Seizures
Lactic acidosis

Question 12

What are the pathological features of Leigh disease?

Answer 12

Spongey degeneration of neuropile of basal ganglia, thalamus, brain stem, and spinal cord

Question 13

What is the mechanism of action of MELAS?

Answer 13

Majority of patients have mutation at 3243 site on mtDNA (maternal transmission)

This encodes part of the dihydrouridine loop of the leurcine tRNA

Mutation causes reduced thiomodificaiton = pauses translation

Afects mitochondrial gene translation = reducing all mt encoded proteins

Results in deficits in almonst all protein complexes in the ETC

Some patients have mutatios in NADH dehydrogenase genes

Question 14

How does MELAS differ from Leigh disease

Answer 14

Main difference to Leigh disease later onset = teenage

Longer life expectancy and dementia

Periphal symptoms arem ore cmmon

Question 15

What helps alleviate MELAS symptoms and why?***

Answer 15

Amino acid and co-enzyme supplements can help

These amino acids and coenzymes don’t directly repair the MT-TL1 gene mutation but help optimize mitochondrial function by supporting energy production, reducing oxidative damage, and improving nutrient delivery to tissues. This can help mitigate symptoms like lactic acidosis, stroke-like episodes, and muscle weakness in MELAS patients.

Question 16

What is the mechanism of action of MERRF?

Answer 16

Most cases have mutation in mtDNA at 8344 site

Affects Lysine tRNA function (MELAS is leucine tRNA)

Question 17

Difference of MERRF compared to MELAS?

Answer 17

MERRF has few stroke-like events
Less episodic vomiting

MERRF often has LIPOMATOSIS = multiple lipid abnormal structure on trunk and extremities

MERRF present at any age but usually from teens onwards

Question 18

What is the mechanism of action of KSS?

Answer 18

Most cases = large deletion of mtDNA

Usually increased protein, lactate and pyruvate in the CSF

Question 19

What are symptoms specific to KSS?

Answer 19

Pronounced ptosis
High incidence of cardiac defects
Patient normall short stature

Question 20

Why can Cysteine supplementaiton benefit mt-tRNA mutation diseases?

Answer 20

Cys is required for the 2-thiomodificaiton of mt-tRNAs

So increasing its level can ‘push’ towards higher thiomodification

Question 21

What is the role of lysosomes?

Answer 21

Digestive system of the cell

Degrade foreign material

Contribute to the degradation of obselete components from within the cell itself

Question 22

What happens in lysosomal dysfunctions?

Answer 22

Accumulation fo non-metabolized macromolecules

Promotes defects in variety of aspects of metabolism

Ultimately leads to cell loss, most severe forms = neuronal oss

Question 23

How do you diagnose lysosomal disorders?

Answer 23

Differential diagnosis by clinical symptom

Enzymatic assay

Question 24

Name 4 lysosomal dysfunction diseases

Answer 24

Tay-Sachs disease

Niemann-Pick disease type A

Metachomatic leukodystrophy

Krabbe disease

Question 25

What pathway do the lysosomal disease affect?

Answer 25

GLYCOLIPID BREAKDOWN pathway Ultimately leading to the reduction of ceramide and accumulation of precursors

Question 26

Why is metachromatic leukodystrophy named this?

Answer 26

Metachromatic = comes from staining of white matter

Question 27

What occurs in metachromatic leukodystrophy?

Answer 27

Metachromatic leukodystrophy (MLD) is a rare, inherited lysosomal storage disorder caused by mutations in the ARSA gene, which encodes the enzyme arylsulfatase A. This enzyme is responsible for breaking down sulfatides, a type of lipid found in the myelin sheath that insulates nerve fibers in the central nervous system (CNS). Without sufficient arylsulfatase A activity, sulfatides accumulate in cells, especially in the nervous system, leading to progressive damage to the myelin and other tissues

Question 28

What builds up in Krabbe disease?

Answer 28

Galactoceramide breakdown is part of normal turnover of myeline sheath Psychosine is a toxic byproduct of myelin production and needs to be removed It accumulates in Krabbe disease It may be responsible for the slight variation in clinical phenotype between MLD and Krabbe

Question 29

What is the difference between type A and B Niemann-Pick?

Answer 29

Type B is less severe and fewer CNS problems Type B Niemann-Pick disease is less severe than Type A because it involves a partial deficiency of the enzyme sphingomyelinase, rather than a complete absence of it. This residual enzyme activity allows for some breakdown of sphingomyelin, preventing the rapid and widespread neurological degeneration seen in Type A. As a result, individuals with Type B primarily experience organ involvement like hepatosplenomegaly (enlarged liver and spleen) and lung issues, without the severe neurodegeneration that leads to early death in Type A. The slower progression and the absence of significant central nervous system damage in Type B contribute to a more mild clinical course, with individuals potentially surviving into adulthood.

Question 30

What are the clinical symptoms of Niemann-Pick?

Answer 30

Larger liver and spleen Severe CNS problems due to loss of myelin