Homocystinuria due to CBS deficiency - HCU€¦ · Supported by as a service to metabolic medicine...

Written by Wendel, Burgard & Konstantopoulou

Homocystinuria due to CBS deficiency First information

Written by Wendel, Burgard & Konstantopoulou as a service to metabolic medicine Supported by 2

Homocystinuria Homocystine in urine

Hyperhomocysteinemia homocysteine in blood Too much

HCU

Written by Wendel, Burgard & Konstantopoulou as a service to metabolic medicine Supported by

Food – Components of a normal diet Protein Fat Carbohydrates

Protein consists of chains of amino acids

Natural Food

Protein

Fat

Carbohydrates

Protein

Fat

Protein

Carbohydrates Carbohydrates

Fat

milk, yoghurt, cereals

eg. meat, poultry, fish, eggs, cheese

eg. fruit, vegetables, potatoes

eg. sugar, lemonade eg. oil, lard eg.

Tyrosine Valine Leucine Threonine Methionine

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Enzymes

Enzymes are proteins that facilitate various chemical reactions in the body. They are involved in the biosynthesis (anabolism) and the degradation (catabolism) of all the substances in the body (= metabolism).

Cystathionine beta-Synthase (CBS) is the enzyme which converts the protein component (= amino acid) methionine.

In homocystinuria the activity of the CBS enzyme is deficient.

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Enzymes

Another enzyme important for the metabolism of methionine and homocysteine is Betaine-Homocysteine Methyltransferase (BHMT).

The BHMT enzyme works properly in a person with homocystinuria. It plays an important role in the treatment of homocystinuria.

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Enzymes

Some enzymes cannot work without the help of vitamins in the form of so called cofactors.

Cystathionine beta-Synthase (CBS) is such an enzyme and vitamin B6 is its cofactor.

CBS Vit B6 + = CBS Vit B6

CBS inactive CBS active

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Healthy person: CBS works

Vit B12

Folic acid

(50%)

(50%)

Betaine

Cystathionine

Cysteine

Homocysteine

Methionine

Enzyme

Enzyme

Enzyme

Enzyme

BHMT

CBS Vit B6

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Cysteine

Metabolism in a patient with homocystinuria: CBS deficiency

Vit B12

Folic acid

Betaine

Cystathionine

Methionine

Enzyme

Enzyme

Enzyme

Enzyme

BHMT

CBS Vit B6

Metabolic Block

Homocysteine

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Diagnostic investigations Methionine Homocysteine

Homocystine

Venous blood

Plasma reference ranges: Homocysteine: < 15 µmol/L Methionine: 15-30 µmol/L

Normal

Increased

Normal

Increased

Urine sample

At time of diagnosis: plasma homocysteine is usually > 200µmol/L

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Pathogenesis Newborns have no symptoms. The symptoms develop in following years.

Homocysteine

Skeleton Tall and thin individuals, long extremities, arachnodactyly (“spider fingers”), knock-knees, scoliosis, chest deformities, osteoporosis

Central Nervous System Developmental delay,

intellectual impairment, epilepsy, focal neurological signs,

psychiatric disorders

Eyes Myopia, dislocation of the lenses, “dancing or shimmering” iris, glaucoma, retinal abnormalities

Vascular System Thrombosis, thromboembolism,

vascular occlusion, thrombophlebitis, pulmonary embolism,

ischemic heart disease

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Treatment

The goal of homocystinuria treatment is to decrease the homocysteine

concentration in the blood until it reaches a safe level, at which

homocysteine is no longer harmful

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Cysteine

Treatment elements

Vit B12

Folic acid

Betaine

Cystathionine

Homocysteine

Methionine

Enzyme

Enzyme

Enzyme

Enzyme BHMT

CBS Vit B6

Metabolic Block

Vit B12

Folic acid

Betaine

+

(+)

B6

Betaine 2

Low amounts of methionine 3

Vitamin B6

1

+

Cysteine

3

Cysteine

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Food – Components of a normal diet

Protein Fat Carbohydrates

Protein consists of chains of amino acids

Natural Food

Protein

Fat

Protein

Fat

Protein


Fat

Carbohydrates

milk, yoghurt eg. fruit, vegetables, cereals


Tyrosine Valine Leucine Threonine Methionine

meat, poultry, fish, eggs, cheese

eg.

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Treatment Low protein diet + methionine-free amino acid mixture

Natural Food

milk, yoghurt eg. fruit, vegetables, cereals


Protein

Fat

Protein

Fat

Protein


Fat

Carbohydrates

Natural Protein

+ “synthetic protein“ = methionine-free and cysteine-containing amino acid mixture

Natural Protein

Food

meat, poultry, fish, eggs, cheese

eg.

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Follow-up in homocystinuria

Systematic follow-up is necessary during treatment.

Goal: blood homocysteine < 50 µmol/L

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Chromosomes, Genes, Mutations

A chromosome is comparable to a cookbook.

A gene is comparable to a recipe for cooking.

A mutation is comparable to an error in the recipe or even a complete lack of the recipe.

The enzyme Cystathionine beta Synthase (CBS) has to be produced constantly in the body according to a specific recipe (gene). If the gene contains pathogenic mutations the enzyme cannot be properly produced.


Inheritance

Mother is a carrier of HCU

Autosomal-recessive (carriers of HCU)

Female egg cells

Father is a carrier of HCU

Male sperm cells

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Inheritance Possible combinations

Child is not a carrier of HCU

Child is a carrier of HCU

Child has HCU



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Inheritance Where HCU derives from?



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Only in approximately 10% of patients is it possible to normalise the homocysteine concentration in blood with the use of vitamin B6

In the remaining patients it is not possible despite complex treatment

Prognosis

Effective treatment started in a newborn

• Normal intelligence • Lens dislocation delay

• Avoidance of epilepsy • Avoidance of osteoporosis

• Age-appropriate school education • No thromboembolism

Treatment start – decrease of the homocysteine concentration; the sooner, the better.

Effective treatment started later

• Organ damage already present is not reversible

• However: dangerous and life-threatening thromboembolism can be avoided

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Homocystinuria due to CBS deficiency - HCU€¦ · Supported by as a service to metabolic medicine...

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