Homocystinuria

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Classification according to ICD-10
E72.1 Homocystinuria
ICD-10 online (WHO version 2019)

The homocystinuria is a relatively rare inborn error of amino acid metabolism . Most common cause is an autosomal - recessive inherited defect in cystathionine β-synthase . If this enzyme fails, the synthesis pathway of cysteine from methionine is interrupted, which leads to the accumulation of homocysteine in the blood plasma and homocystine in the urine .

distribution

Homocystinuria is a rare disease with a worldwide rate of new cases of around 1 in 300,000. An increased incidence is found in Ireland with a rate of 1 in 65,000 births. The disease is most widespread in the world in Qatar, with one homozygous case in 1,800 newborns.

root cause

In most cases, the disease is caused by a defect in cystathionine β synthase (CβS) due to an autosomal recessive mutation of the corresponding gene on chromosome 21 (21q22.3). Other genetic defects affect the synthesis of the MTHFR and, more rarely, the group of the cobalamin genes MTRR (CB1E), MTR (CB1G), MMADHC (CB1D). There are now more than 230 disease-related mutations known. It concerns the loss of bases ( deletion ) or the addition of bases ( insertion ) in the course of the DNA strand.

Disease emergence

Homocysteine ​​occurs in three different forms in the blood. 80–90% of healthy individuals are bound to transport proteins as homocysteine. The free fraction consists of homocysteine ​​linked to cysteine, as well as homocystine, which is present as a dimer and in which two homocysteine ​​amino acids are linked via a disulfide bridge.

The level of homocysteine ​​in the blood and not the sole presence of a gene mutation leads to the clinically relevant manifestation of the disease. The increased blood concentration of homocysteine ​​damages the inner wall of the blood vessels . The exact mechanism is still unknown. In homozygotes, this can already be demonstrated in infancy as a lack of expansion of the vessel with increased flow. As a result, arteriosclerosis begins very early . In heterozygotes the mechanism is preserved as in healthy.

Symptoms

Homocystinuria can cause a number of symptoms in different organs. There are great differences in the severity of the disease: from patients who show almost all symptoms and complications to people who show no clinically detectable symptoms. After the birth, the children are normal except for the characteristic laboratory findings. Symptoms rarely occur before the age of two. The most common symptom is a prolapse of the lens of the eye . This finding can be seen in 70% of untreated ten-year-olds affected. As the earliest symptom, psychomotor retardation occurs in the majority of patients during the first two years of life. This is irreversible. It is often associated with myopia . Likewise, half of the patients have osteoporosis in childhood . A characteristic appearance similar to Marfan's syndrome with elongated tubular bones and spider fingers was described in 30–60% . Around half of the patients develop a psychiatric illness in the course of their life. Around a fifth suffer from epilepsy .

Thrombembolism , peripheral arterial occlusive disease , heart attacks and strokes are decisive in terms of life expectancy . These symptoms are based on the damage to the vessels from the increased amino acid levels. Around 30% suffer a thromboembolic event up to the age of 20. Around half up to the age of 30.

diagnosis

In addition to clinical symptoms, various laboratory procedures are available to confirm the diagnosis, depending on the cause. Primarily the homocysteine ​​in the blood is determined. The urine concentration of homocystine can be determined by chromatographic methods. The cyanide nitroprusside test often provides the first indication of an increase in this parameter . The enzyme defect can be directly detected by culturing fibroblasts or amnion cells ( prenatal diagnosis ). Another method of early detection of this disease is the determination of the concentration of methionine in the blood, which like homocysteine ​​is built up by the blocked metabolic pathway and increases accordingly. The MTHFR mutation can be demonstrated using PCR-based sequencing. An elevated homocysteine ​​blood level can indicate the disease, but it can also be present in people without a mutation due to dietary reasons (diets low in B12 and low folic acid).

therapy

The treatment of the most common form of this disease consists in bypassing the metabolic blockade by a diet low in methionine and high in cystine with the aim of reducing homocysteine ​​and methionine in the blood. If the activity of the defective enzyme is slightly reduced, substitution therapy with vitamin B6 ( pyridoxine ) - the cofactor of cystathionine synthetase - can be helpful. Other patients do not respond well to vitamin B6. The rare forms are often characterized by normal or low levels of methionine in the blood, so that there is no restrictive diet in this regard. In addition to vitamin B6, folic acid, vitamin B12 and betaine can also be used for therapy. Anticoagulant drugs such as acetylsalicylic acid are also used for thrombosis prophylaxis . With early diagnosis and consistent therapy, the prognosis is generally favorable.

Medical history

Homocysteinuria was first described independently by two different research groups in Northern Ireland and the USA in 1962 .

Web links

Individual evidence

  1. ^ Siegfried Zabransky: Screening for congenital endocrine and metabolic disorders: methods, application and evaluation . Springer, Berlin 2013, ISBN 978-3-7091-6252-1 , pp. 260-261 .
  2. ^ A b c S. Yap: Classical homocystinuria: vascular risk and its prevention. In: J Inherit Metab Dis. 2003; 26 (2-3), pp. 259-265. PMID 12889665
  3. J. Zschocke, M. Kebbewar, H. Gan-Schreier, C. Fischer, J. Fang-Hoffmann, J. Wilrich, G. Abdoh, T. Ben-Omran, N. Shahbek, M. Lindner, H. Al Rifai, AL Al Khal, GF Hoffmann: Molecular neonatal screening for homocystinuria in the Qatari population. In: Hum Mutat. 2009 Jun; 30 (6), pp. 1021-1022. PMID 19370759
  4. a b Homocystinuria on the NLM's Genetics Home Reference
  5. DS Celermajer, K. Sorensen, M. Ryalls, J. Robinson, O. Thomas, JV Leonard, JE Deanfield: Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents. In: J Am Coll Cardiol . 1993 Sep; 22 (3), pp. 854-858. PMID 8354824
  6. a b B. Reulecke, J. Denecke: Diagnosis and therapy of homocystinuria. In: Pediatric and Adolescent Medicine. 5/2009, pp. 289-293.
  7. MTHFR polymorphism C677T: Sense and nonsense of diagnostics. In: Dtsch Arztebl. 2004; 101, pp. A 3101-3105 [No. 46].
  8. G.-A. v. Harnack: Therapy of diseases of childhood . Springer, Berlin 2013, ISBN 978-3-662-22537-0 , pp. 68-69 .
  9. ^ S. Yap: Homocystinuria due to cystathionine beta-synthase deficiency in Ireland: 25 years' experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. In: J Inherit Metab Dis. 1998 Oct; 21 (7), pp. 738-747. PMID 9819703