The homocystinuria is a relatively rare congenital disorder of amino acid metabolism. The most common cause is an autosomal recessive inherited defect of Zystathionin synthetase. Falls out of this enzyme, the route of synthesis of cysteine from methionine is interrupted, resulting in the accumulation of homocysteine in plasma and homocystine in the urine. Two molecules of homocysteine connect via a disulfide bridge to homocystine. With increased levels of homocysteine in the blood is excreted as homocystine in the urine.
The homocystinuria is a rare disease with a worldwide rate of new cases of approximately 1:300,000. A higher incidence is found in Ireland at a rate of 1:65.000 births. The world's highest distribution has the disease in Qatar with a homozygous case of 1,800 newborns.
The disease is a mutation of the gene on the chromosome CβS 21 are now more than 92 known mutations krankheitsbedingende. Is short for the loss of bases ( deletion ), or the addition of a base ( insertion) in the course of the DNA strand.
Homocysteine occurs in three different forms in the blood. 80-90 % bound in healthy individuals as homocysteine to transport proteins. The free fraction consists of homocysteine combined with cysteine and homocysteine present as a dimer, in which two amino acid homocysteine are connected via a disulphide bridge.
Due to the increased blood concentration of homocysteine leads to damage to the vessel inner wall. The exact mechanism is still unknown. This can be demonstrated in homozygotes already in infancy as a lack of expansion of the vessel at elevated flow. As a result, there is a very early onset of atherosclerosis. In heterozygotes, the mechanism as in healthy individuals is obtained.
The homocystinuria can cause a range of symptoms in different organs. In this case, there are large differences in disease severity: patients who show almost all of the symptoms and complications up to people who show no clinically evident symptoms. After birth, the children are unremarkable except for the characteristic laboratory findings. Before the age of two rare symptoms occur. The most frequent symptom is an incident of the eye lens. This finding is detectable in 70% of untreated ten year concerned. The earliest symptom occurs in the majority of patients had psychomotor retardation already during the first two years of life. This is irreversible. Often he is accompanied by a short-sightedness. Likewise, there is in childhood in half of the patients with osteoporosis. In 30-60% of a characteristic, Marfan's syndrome -like appearance has been described over the long bones and Spinnenfingerigkeit. Approximately half of the patients developed a psychiatric disorder during their lifetime. About one-fifth suffers from epilepsy.
The limiting factor with respect to the life expectancy thromboembolism, peripheral vascular disease, heart attacks and strokes are crucial. These symptoms are due to the damage of the vessels by the increased amino acid levels. Around 30% suffer a thromboembolic event until the age of 20. About half the age of 30.
In addition to the clinical symptoms are to confirm the diagnosis Various laboratory methods available. By chromatographic methods, the urine concentration of homocystine can be determined. The first indications of the increase of this parameter often provides the cyanide - nitroprusside test. The direct detection of the enzyme defect is achieved through the cultivation of fibroblasts or amniotic fluid cells ( prenatal diagnosis ). Another method of early detection of this disease is the determination of the concentration of methionine in the blood, which is also dammed up by the blocked as homocysteine metabolic pathway and, accordingly, increases.
The therapy of this disease is to bypass the metabolic blockade by a methioninarme and cystinreiche diet. To prevent thrombosis are medicines for anticoagulation, such as acetylsalicylic acid, are used. At low reduction in activity of the defective enzyme, substitution therapy with pyridoxine ( vitamin B6 = ) - the cofactor of Zystathionin synthetase - be helpful. The overall prognosis is favorable with early diagnosis and consistent treatment.
History of Medicine
The homocystinuria has been described by two different research groups in 1962 in Northern Ireland and the United States independently for the first time.