HOMOCYSTINURIA ( AN INBORN METABOLIC

DISORDER)

SYEDDA FATIMA ABID SHAH

DEFINITION

“Homocystinuria is an inherited disorder of metabolism, leading to an

abnormal accumulation of homocysteine and its metabolites in

blood and urine.”(wikipedia.org)

Homocystinuria is an autosomal recessive inherited disorder of methionine metabolism.

Methionine is an essential, non-polar amino acid. Under normal conditions methionine undergoes

conversion to homocysteine. This in turn undergoes transsulfuration to ultimately

yield amino acid cysteine. This step is catalyzed by enzyme Cystathionine Beta

Synthase (CBS). People suffering from this disease are unable to

synthesize CBS, hence leading to an inability to metabolize methionine.

In re-methylation MTRF and vitamin B12 are not present.

PREVALANCE Worldwide, only 1 in 344,000 people have

homocystinuria, making the condition extremely rare.

The disorder is more common in Ireland (1 in 65,000), Germany (1 in 17,800), Norway (1 in 6,400), and Qatar (1 in 1,800).

In Asia it is reported that only 3% cases of homocystinuria are reported. (NIH 2013).

It is more prevalent in men than in women.

METABOLIC PATHWAY

NORMAL PATHWAY

Homocysteine produced in this pathway is either regenerated into methionine or converted to Cysteine.

The reaction is catalyzed by the enzyme, Cystathionine beta synthase (CBS).

The deficiency of CBS due to inherited defects causes homocystinuria.

Due to absence of CBS enzyme, homocysteine accumulates in the blood serum leading to an increased excretion of homocysteine in the urine.

In process of re-methylation lack of vitamin B12 and MTRF occurs.

DEFECTED PATHWAY

In the absence of enzyme Cystathionine beta synthase amino acid cysteine is not produced and the amount of homocysteine starts to raise in blood plasma and urine. (TRANS-SULFURATION).

In the absence of enzyme Methylene Tetra hydrofolate reductase(MTHFR) and vitamin B12 the amino acid homocysteine is not converted into methionine and thus levels of homocysteine starts to raise in blood and in urine. (RE-METHYLATION).

SYMPTOMS

Homocystinuria is accompanied by a variety of clinical and pathological abnormalities which show major involvment in four organ systems. They are

The eye Skeletal Central nervous system and Vascular system.

THE EYE

Ectopia lentis Luxation of lens Myopia Glaucoma Optic atrophy Retinal detachment Loss of vision

SKELETON

Limbs grow out of proportion. Anterior chest deformities. Most distinguishing feature of

homocystinuria is osteoporosis specially spinal osteoporosis.

Long spindly arms and legs.

VASCULAR SYSTEM

Thromboembolism Abnormal blood clots Intravascular thrombosis Heart strokes

CENTRAL NERVOUS SYSTEM

Mental retardation Low IQ Episodic depression Behavioral disorders Schizophrenia

If both parents carry the faulty gene, for each child, there is a:

25% chance the child will be born with the disorder

50% chance the child will be a carrier of the faulty gene

25% chance the child will neither have disorder nor would be the carrier.

DIAGNOSIS

It is present at the time of birth but its symptoms are often remain un noticed in new born babies.

New born babies are tested for homocystinuria before they leave the hospital.

if a child is not tested at the time of birth, a doctor may later discover the disorder based on symptoms. At that point the following be done:

Blood tests to confirm the diagnosis x-rays to look for bone problems An eye exam to look for eye

problems

TREATMENT No specific cure has been discovered for

homocystinuria; however many people are treated using high doses of vitamin B6 ie. Pyridoxine.

Slightly less than 50% respond to this treatment and need to intake supplemental vitamin B6 and for the rest of their lives.

Those who do not respond require a low methionine diet .

Most will need treatment with trimethylglycine. A normal dose of folic acid supplement and

occasionally adding cysteine to the diet.

BETAINE ( TRIMETHYLEGLYCINE)

It is used to reduce the concentration of homocysteine by promoting the conversion of homocysteine back to methionine.

The re-formed methionine is then gradually removed by incorporation into body protein.

The methionine that is not converted into protein is converted to S- adenosylmethionine which goes on to form homocysteine again.

Betaine is therefore only effective if the quantity of methionine to be removed is small. Hence treatment includes both betaine and a diet low in methionine.

In classical homocystinuria (CBS deficiency) the plasma methionine usually increases above the normal and the concentration should be monitored as potentially toxic levels may be reached.

PREVENTION IS BETTER THAN CURE

Genetic counseling is recommended for prospective parents with a family history of homocystinuria

Prenatal diagnosis of homocystinuria is available and is made by culturing amniotic cells or chronic villi to test for the presence or absence of Cystathionine synthase ( the enzyme that is missing in homocystinuria).

If the diagnosis is made while a patient is young, a low methionine diet started promptly and strictly adhered to can spare some mental retardation and other complications of this disease.

COMPLICATIONS

Blood clot Damaged vision Intellectual disability. Coronary artery disease -

e.g., myocardial infarction osteoporosis Fatty infiltration of liver Blood clotting which could lead to

heart strokes.

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