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Classical Homocystinuria, also known as cystathionine beta synthase deficiency or CBS deficiency, is an inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase. It is an inherited autosomal recessive trait, which means a child needs to inherit a copy of the defective gene from both parents to be affected.
This defect leads to a multisystemic disorder of the connective tissue, muscles, CNS, and cardiovascular system. Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of homocysteine in the serum and an increased excretion of homocysteine in the urine. Infants appear to be normal and early symptoms, if any are present, are vague.
The term homocystinuria describes an increased excretion of the thiol amino acid homocystine in urine (and incidentally, also an increased concentration in plasma). The source of this increase may be one of many metabolic factors, only one of which is CBS deficiency. Others include the re-methylation defects (cobalamin defects, methionine sythase deficiency, MTHFR) and vitamin deficiencies (cobalamin (vitamin B12) deficiency, folate (vitamin B9) deficiency, riboflavin deficiency (vitamin B2), pyridoxal phosphate deficiency (vitamin B6)). In light of this information, a combined approach to laboratory diagnosis is required to reach a differential diagnosis.
CBS deficiency may be diagnosed by routine metabolic biochemistry. In the first instance plasma or urine amino acid analysis will frequently show an elevation of methionine and the presence of homocystine. In fact many neonatal screening programs include methionine as a metabolite. The disorder may be distinguished from the re-methylation defects (e.g. MTHFR, methionine synthase deficiency and the cobalamin defects) in lieu of the elevated methionine concentration. Additionally, organic acid analysis and/or quantitative determination of methylmalonic acid should help to exclude cobalamin (vitamin B12) defects and vitamin B12 deficiency giving a differential diagnosis.
The laboratory analysis of homocystine itself is complicated by the fact that most homocystine (possibly >85%) is bound to other thiol amino acids and proteins in the form of disulphides (e.g. cysteine in cystine-homocystine, homocysteine in homocystine-homocystine) via disulphide bonds. Since as an equilibrium process the proportion of free homocystine is variable a true value of total homocysteine (free + bound) is useful for confirming diagnosis and particularly for monitoring of treatment efficacy. To this end it is prudent to perform total homocyst(e)ine analysis in which all disulphide bonds are subject to reduction prior to analysis, traditionally by HPLC after derivatisation with a fluorescent agent, thus giving a true reflection of the quantity of homocysteine in a plasma sample.
Possible Signs and symptoms
- A family history of homocystinuria
- Flush across the cheeks
- Mental retardation
- Psychiatric disease
- Eye anomalies:
- Vascular disease
The life expectancy of patients with homocystinuria is reduced only if untreated. It is known that before the age of 30, almost one fourth of patients die as a result of thrombotic complications (e.g. heart attack).
No specific cure has been discovered for homocystinuria; however, many people are treated using high doses of vitamin B6 (also known as pyridoxine). Slightly less than 50% respond to this treatment and need to intake supplemental vitamin B6 for the rest of their lives. Those who do not respond require a low methionine diet, and most will need treatment with trimethylglycine. A normal dose of folic acid supplement and occasionally adding cysteine to the diet can be helpful, as glutathione is synthetized from cysteine (so adding cysteine can be important to reduce oxidative stress).
Betaine (N,N,N-trimethylglycine) is used to reduce concentrations of homocysteine by promoting the conversion of homocysteine back to methionine, i.e. increasing flux through the re-methylation pathway independent of folate derivates (which is mainly active in the liver and in the kidneys).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-adenosyl-methionine 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, or cystathione beta synthase deficiency) the plasma methionine usually increases above the normal range of 30 micromoles/L and the concentrations should be monitored as potentially toxic levels (more than 400 micromole/l) may be reached.
Low-protein food is recommended for this disorder, which requires food products low in particular types of amino-acid (e.g. methionine).
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- Homocystinuria Support
- GeneReview/NIH/UW entry on Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency
- Paper and discussion on Homocystinuria due to Cystathionine Beta Synthase deficiency