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MMD1045: Module 2 > Biochemical Genetics > Flashcards

Biochemical Genetics Flashcards

1
Q

What is Phénylcétonurie (PCU)

A

Phenylalanine is a precursor to tyrosine

PCU is an issue in the** enzyme phénylalanine hydroxylase (PAH) ** leading to buildup of l’acide aminé phénylalanine

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2
Q

Transmission mode of PCU?

A

transmission autosomique récessive

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3
Q

PCU Different tissues present the enzyme at different levels. What is the main targer?

A

prédominance hépatique

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4
Q

Origine de la phénylalanine?

A

Body proteins

Mainly from diet!!!

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5
Q

Décrit les niveaux normaux de phé chez l’adulte?

A

Need to know that there is a **distribution across people **

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6
Q

Le signe le plus important de la PCU

A

déficience intellectuelle

note that there is a gamma of phenotypes:
Certains patients ont seulement un léger retard tandis que la déficience est sévère chez d’autres

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7
Q

Vrai ou faux? Il n’y a pas de dépistage néonatal pour le PCU.

A

Faux

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8
Q

Comment fait-on le dépistage de la PCU?

A

On collecte du sang du bébé sur un papier buvard

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9
Q

Est-ce que le prélèvement de la PCU diffère entre les hôpitaux?

A

Non
NEED TO BE Standardisé due to the already varient phenytupes

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10
Q

Explain Test de Guthrie:

A

Plant patient blood on a paper with bacteria that require phénylalanine in order to grow.

If the bacteria grows -> patient blood does not have the proper enzyme (PAH)

This shows hyperphenylalanine due to déficience de l’enzyme phénylalanine hydroxylase (PAH)

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11
Q

What is the advantage of Spectrométrie de masse en tandem:

A

possibilité de mesurer plusieurs métabolites simultanément.

tests automatisés qui permettent le dosage simultanée de la phénylalanine et d’autres métabolites

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12
Q

Vrai ou faux? Différents tissus expriment l’enzyme PAH de façon différente.

A

Vrai

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13
Q

Pourquoi le niveau de [phé] augmente-t-il au cours des premiers jours?

A

The baby’s nutrition in the placenta comes from the mother and clearance is done properly.
When the baby is outside and starts eating a normal diet, due to the lack of the enzyme the levels of Phe increase.

This is why you need to know when to test the Phe levels

la mère fournissait les nutriments et épurait le sang du bébé via le cordon

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14
Q

Nomme 3 maladies dépistés de façon néonatal au Québec.

A

Phénylcétonurie
Tyrosinémie du type I
MCADD

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15
Q

What would you use for diagnosis of PCU?

A

Chromatographie of amino acids

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16
Q

How to treat PCU and what is the issue with this approach?

A

Le traitement est la diète:

Because the primary source of phenylalanine is diet proteins, on donne un apport restreint en phénylalanine

Body proteins are a source too but those are degraded proteins that make a small proportion of where protein comes from → diet.

The problem is that you cannot restrict everything as the baby needs to grow. Especially milk from the mother.

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17
Q

What is the solution to poor diets that were used as PCU treatment?

A

Aliments thérapeutiques où la phé est réduite ou absente mais qui sont riches
en les autres acides aminés et les autres nutriments.

By knowing what specifically we need to target, we can have more personalized diets.

On peut quantifier, calculer et prescrire les apports de nutriments.

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18
Q

Qu’est-ce que la tolérance chez les atteints de PCU?

A

La quantité maximale de phénylalanine diététique qui permet un taux sanguin acceptable

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19
Q

Si un enfant PCU attrape le rhume, que dois-tu faire?

A

Important concept here is that the diet might vary based on the status of the patient. If they are sick, going growth etc.

Patient PCU manque la capacité d’ajuster la dégradation selon les quantités disponibles

In this case:\
The body is fighting a virus so it will break down proteins (catabolism)
Baisser son apport en phé, car plus de catabolisme que d’anabolisme

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20
Q

True or False

Le pool d’acides aminés circulantes est plus grand que ceux de tissus.

A

False
quantity that we measure in the blood is also a SMALL proportion

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21
Q

L’impact de l’hyperphénylalaninémie sur le développement psychomoteur est au plus important pendant les ________________________.

A

2 premières années de vie

In the first two years of life, the development of the brain is at a critical period:

Principe: la toxicité dépend du stade du développement du cerveau. Worse in babies not as bad in adults.

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22
Q

De quoi dépend la toxicité de la PCU

A

Du stade de développement du cerveau

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23
Q

What is Hyperphénylalaninémie

A

Minor form of PCU with lower levels

Phenylpyruvate is excreted in the urine..

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24
Q

Décrit le taux d’oxidation de phé en fonction de l’enzyme et ce que cela représente.

A

Point here is that the** relation of plasma levels to enzyme activity is not linear**.

This means that even a bit of enzyme can be sufficient to reduce phe in plasma by a lot.

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25
Q

What is PCU atypique?

A

Form of PCU where the enzyme PAH works but the co-factor BH4 is not present.

In these people we will still have an increase of phenylalanine but this is due to the lack of co-factor rather than the enzyme.

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26
Q

True or False,

Tout enfant dépisté pour PCU est évalué pour des concentrations des précurseurs de la BH4

A

True

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27
Q

Cause de la PCU maternelle?

A

Mère PCU non traitée
Enfant normal (PAH works), mais exposé à phé élevé

Le foie embryonnaire a peu de capacité à dégrader la phénylalanine

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28
Q

Que fais-tu si ta patient qui essaie d’avoir un enfant est PCU?

A

Chez toute femme PCU il faut contrôler la concentration de phé plasmatique AVANT la conception

Toute femme PCU devrait être suivie au cours de toute sa période de fertilité

On doit contrôler le niveau de phénylalanine AVANT la conception et pendant toute la grossesse, SURTOUT au premier trimestre:

29
Q

Qu’est-ce qui est touché par le PCU maternelle chez le foetus?

A

premier trimestre
morphogénèse, organogénèse touchées

30
Q

Que nous prouve les différentes maladies de la voie métabolique de phé?

A

Enzymatic dependent phenotypes!!

In different steps of the Phenylalanine cascade, at different stages there can be different issues with completely different phenotypes and symptoms.

Grande diversité dans une seule voie métabolique

31
Q

True or False

Est-ce qu’on dose la thyrosine pour le dépistage de la T1?

A

Non, non-spécifique et non-sensible

Instead Succinylacétone

32
Q

Qu’est-ce qu’on dose pour le dépistage de la Tyrosinemia type I?

A

Succinylacétone

33
Q

Describe Concept of L’autonomie cellulaire

A

In T1 le dommage par fumarylacétoacétate paraît dans la même cellule du
foie qui produit le métabolite

FAA -> dommage dans la cellule d’origine -> insuffisance et cancer du foie

34
Q

Treatment of Tyrosinepie Type 1:

A

NTBC est un inhibiteur très spécifique pour l’enzyme prior to the fumarylacétoacétate

As such, you will not have a buildup of Fumarylacetoacetate as you stop the cascade

Concept of taking an inhibitor that blocks ahead of the problematic enzyme to reduce the buildup of the “bad” molecule.

35
Q

Why must NTBC treatment also be followed with dietary restrictions?

A

NTBC has the effect of leading to the build up of Tyrosine from Phe.

As a result, this type of inhibition treatment needs to be followed with a dietetic restriction of Tyrosine and Phe.

36
Q

Métabolisme intermédiaire draw it

Qu’est-ce qu’on peut mesurer pour savoir où est la maladie

A

Amino Acids
NH4
Acide organique
Acylcarnitines
Glucose
Lactate

You do not need a genetic test. You can just look at the different molecules and metabolites involved in metabolism and have a diagnosis based on the different levels

https://www.notion.so/Biochemical-Genetics-9cd438a0603c48beb81998303729bb26?pvs=4#93c470525fcc4bf9b7b937de2b4fac8b

37
Q

Par quoi sont réfétés dans le sang la concentration des acyls-CoA?

A

acylcarnitines

38
Q

What is the principle of : Prélèvement Critique?

A

The idea that the best time to dose molecules is when a patient is symptomatic as that is when you will find the most buildup (or lack) of molecules.

39
Q

Qu’est-ce qu’un anion gap?

A

In our body (and blood) we have the same amount of + and - molecules

Idea here is to take the main molecules responsible for this balance and measure their concentrations

The difference between cations (like Sodium) and anions (like chloride and HCO3-) is what we call anion gap.

40
Q

In what body fluid do we measure Chromatographie des acides aminés
Acylcarnitines

A

Blood

41
Q

Décrit la leucocinose.

A

Maple syrup urine disease, MSUD:
Urines sentent sirop

Leucinose: Increased leucine in the urine

Déficience de BCKADH
Co-facteur: B1 (thiamine)

41
Q

In what body fluid do we do this: Chromatographie des acides organiques

A

Urine

42
Q

Que dégrade BCKADH?

A

Leucine
Isoleucine
Valine
Enzyme qui dégrade alpha-céto acides provenant ce ces aa

co-factor is B1 (thiamine)

43
Q

True or False

toutes les mutations répondent bien à la vitaminothérapie

A

False

44
Q

Vitaminothérapie pour la leucocinose?

A

Supply B1 as it is a co-factor of BCKADH

45
Q

Moyen d’épurer le sang dans le cas de leucinose?

A

Hémodialyse

hemodialysis is quick enough to clear the leucine from the body to save the patient

46
Q

Syndrome?
* Hypoglycémie sévère
* Diarrhée
* Pas de cétose
* Stéatose hépatique
* Coma

A

MCAAD

Medium Chain Acyl Carnitines

47
Q

What are Ketone bodies:

A

alternative energy source for your body, especially for the brain

Substances produced by the liver during a process called ketogenesis, which happens when your body doesn’t have enough glucose (sugar) for energy.

When your body doesn’t have enough glucose for energy, it starts to break down stored fat into fatty acids. **The liver then converts these fatty acids into ketone bodies. **

48
Q

Transporteur des ag dans la mito?

A

Carnitine Navete:

Carnitine is a key transporter to get Acetyl-CoA inside the mitochondria

49
Q

Pourquoi est-ce que le cerveau est affecté chez cet enfant atteint de MCADD?

A

Les réserves internes sont minimes.
Normalement le cerveau consomme le glucose.
En cas d’hypoglycémie, les corps cétoniques
augmentent, et alimentent le cerveau.
Dans l’hypoglycémie sans cétose, les deux sources énergétiques majeures sont absentes.

Patient will have an issue in beta-oxydation of medium chain fatty acids → cannot make ketone bodies when fasting.

The brain does not get any energy (no ketone bodies, no glucose) → coma

Due to the lack of the enzyme, there will be build up of fats in the liver → fatty-liver

50
Q

Treatment of MCADD

A

Give glucose solute, decrease Medium chains in diet

But wait, why does this help the foie-gras?

Because, once there is glucose in circulation, there will not be breakage and transport of fatty acids in the liver as glucose can be used as source of energy!!!!

51
Q

La grande majorité des protéines mitochondriales sont d’origine ________

A

nucléaire

52
Q

Quel est le seul complexe de la chaine respiratoire qui ne dépend pas de l’ADN mito?

A

2

Complex 2 is fully build via nucleic proteins and thus is dependent on nucleic DNA

53
Q

What is acyl-carnitines à chaîne
moyenne (C8)

A

Marqueurs pour le dépistage et pour le
diagnostic of MCADD

54
Q

Describe L’Atrophie optique de Leber (LHON, Leber hereditary optic neuropathy)

A

Mitochondrial Disease

LHON est HOMOPLASMIQUE

55
Q

True of False,

We can look at the amino acids levels to diagnose LHON

A

Perte de la vision centrale d’un œil ou des deux yeux.

Because only eyes are touched, we cannot look for amino acid levels

Diagnosis is purely GENETIC

56
Q

Problème dans les maladies de surcharge?

A

Le substrat ne peux pas sortir de la cellule + déficit enzymatique

57
Q

Problème de la maladie de Gaucher?

A

Pas de dégradation des sphingolipides

Glucocerebrosidase: is an important enzyme that is required in the degradation of sphingolipds

This is of course due to the accumulation of Sphingolipids → maladie de surcharge

58
Q

Que pensez-vous arrivera si on ne peut pas dégrader la glucocérébroside?

A

Accumulation de sphigolipides
Toxicité

maladie de Gaucher

59
Q

Phénotype typique de Gaucher?

A

Sphingolipid accumulation of white blood cells in the spleen

60
Q

Qu’est-ce qu’on dose pour Gaucher?

A

La glucocérébrosidase est dosée dans les globules blancs purifiés d’un prélèvement de sang.

If a deficiency is found on the enzyme → diagnosis of Gaucher’s Disease

61
Q

How to treat maladie de gaucher?

A

Delivery of the enzyme: glucocérébrosidase

→ Enzymatic Replacement

ORRR:

Les cellules transplantées fabriquent l’enzyme.

62
Q

What is Homocystinurie classique:

A

A family history of 2 rare diseases found in 2 siblings:

thrombose cérébrale + une luxation des crystallins

63
Q

Diagnosis of Homocystinurie classique:

A

Dosage of l’homocystine totale. On fait aussi une chromatographie des acides aminés plasmatiques pour doser l’homocystine libre et la méthionine

Remeber the non linear metabolic pathway!!

64
Q

Lack of B12 and methionine?

A

Voie métabolique non-linéaire

If the enzyme in the bottom is affected → if there is enough B12 vitamin then we will make Methionine

If there isn’t enough B12 → buildup of Homocysteine

65
Q

Methionine utility

A

It is a key molecule required for methylation

66
Q

Traitement pour l’homocystinurie?

A

– Diète
– Vitamines (cofacteurs) efficaces pour certaines erreurs innées et certaines mutations. (B6 vitamine, B12 vitamin)

Provide Vitamin B6 (precursor) to increase enzymatic activity and thus homocysteine degradation

Also, reduce methionine from diet.

67
Q

Est-ce que la voie de l’homocystinurie est linéaire?

A

False

68
Q

Dans la LHON, qui a le plus de risque d’être atteint entre les gars et les filles?

A

Gars

MMD1045: Module 2 (11 decks)

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