Homocystinuria: Symptoms, Treatment and Management

Homocystinuria is an inherited metabolic condition caused by the reduced activity of the enzyme cystathionine beta-synthase, also known as CBS. Patients with this condition are unable to properly process and convert the amino acid methionine into cysteine. As a result, excess homocysteine is present within the body, specifically in the urine. This can potentially cause many issues and symptoms within the body such as failure to thrive, abnormal blood clotting, brittle bones, nearsightedness, and intellectual disability. Patients with this condition are usually deficient in the B vitamins and folic acid. Signs and symptoms vary depending on severity. There are very mild signs of the disorder, but some are very severe and can cause life threatening or fatal complications. In this paper, I will discuss the various symptoms, the molecular mechanisms, nutritional deficiencies, treatment, and nutritional management for this disease.

Signs and Symptoms

Symptoms associated with homocystinuria vary depending on the severity of the case. Both males and females are equally affected by the condition, with one in three-hundred thousand individuals being affected.In European countries, homocystinuria may be more prevalent, with about one in six-thousand individuals being affected.1 Infants born with the disease often appear healthy at first, as symptoms are not obvious. As the child reaches around the age of three years old, signs and symptoms begin to become more noticeable.1,2 Developmental delays, failure to thrive, and poor vision are some of the first signs that the condition is present and often times lead to diagnosis of the disease.Other signs and symptoms include abnormally long limbs, chest deformities, a high arch on the foot, mental disorders, and abnormal curvature of the spine.2 Progressive mental retardation may be apparent in some children, and many may even develop psychiatric disturbances and seizures. The reason this occurs is due to impaired blood supply to the brain due to the accumulation of homocysteine, which damages the blood vessel walls.2,3

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High concentrations of homocysteine also affects the supportive tissues within the body, which makes fibrillin extremely unstable.2 Patients with the condition will find that they may have vision problems. The lens of the eyes may become dislocated due to the negative impact to the supportive eye tissue. Because excess homocysteine damages the blood vessel walls, patients may experience abnormal blood clotting which negatively affects the arteries and veins.2 This abnormal blood clotting is the main cause of early death in individuals affected by homocystinuria. Each of these signs and symptoms are used to diagnose and treat homocystinuria. In order for confirmation of diagnoses of homocystinuria, clinicians will measure CBS activity in fibroblasts and lymphocytes.2 It is important that patients get diagnosed with homocystinuria as early as possible.

Mechanisms of Homocystinuria

Clinical manifestations of homocystinuria are due to elevated plasma homocysteine levels.It occurs due to a deficient or reduced activity of the cystathionine synthase (CBS) which is responsible for catalyzing the conversion of homocysteine to cystathionine.Homocysteine will be produced in the third step of the metabolic pathway where the conversion of methionine to cystathionine is supposed to take place by the combination of homocysteine and serine.1 However, when the CBS is not present or if it’s activity is reduced, cystathionine cannot properly be formed and the second pathway will not take place. This leads to homocysteine accumulation in the blood serum and urine.

Nutritional Deficiencies of Homocystinuria

A deficiency in vitamin B-12 is a main occurrence in homocystinuria. Reduced activity or deficiency of the enzyme CBS can result in a defect in 5,10-methylene tetrahydrofolate reductase activity, which can be a direct cause of a vitamin B-12 defiency.1,2 Deficiency of trans cobalamin, a carrier protein that binds cobalamin, can also cause vitamin B-12 deficiency due to defective cellular uptake1,2. Since vitamin B-12 is required for methylation of homocysteine to methionine, this seems to be a direct cause of homocystinuria.

There have been several studies to prove this direct cause. For example, one cross sectional study concluded that increased homocysteine levels as well as reduced concentrations of folic acid and vitamin B-12 were found in the blood of patients with homocystinuria.6 The study included thirty patients with the condition due to CBS deficiency, as well as a control group. Each patient as well as the control group were asked to refrain from usual treatment, including drugs or vitamins before the start of the study.6 Blood concentrations to measure homocysteine, folic acid, and vitamin B-12 were taken the morning after the subjects had fasted overnight6. Results determined that significantly increased levels of homocysteine as well as reduced levels of folic acid and vitamin B-12 were present in those with the condition compared to the control group.6 Results also concluded that patients with homocystinuria most likely need higher doses of folic acid and vitamin B-12.6 It is important for patients to monitor their B-12 levels through blood tests and frequently checking amino acid levels.

Medical Treatment for Homocystinuria

While there is no cure for the condition, homocystinuria can be managed by several treatments. These treatments aim to lower homocysteine concentrations in the blood in order to get them back into a normal range. A medication called Betaine is sometimes prescribed to patients with homocystinuria.1,2 This medication works to combine with homocysteine to convert it back to methionine and is then used for other functions. Many patients are also treated with high doses of pyridoxine, also known as vitamin B-6. Patients are usually instructed to take 100 to 500mg daily along with a combination of folic acid and vitamin B-12.1,2,3 When taken in combination, each supplement works to lower plasma homocysteine levels as well as prevent symptoms associated with the condition such as vision issues and psychotic disturbances.2 Vitamin B-6 also works as a co-factor to boost the CBS enzyme’s activity. For those with a mild case of homocystinuria, these medical treatments can work to greatly improve their condition.3.5 However, some patients do not respond to pyridoxine/folic acid and B-12 and must take other measures, such as nutritional intervention.

Nutritional Management for Homocystinuria

Nutritional management is an important aspect in treating homocystinuria. For those who do not respond to treatment with pyridoxine, a low methionine diet is recommended. This means that foods containing high amounts of methionine should be limited.7 Luckily, if homocystinuria is diagnosed at an early age, a low methionine diet can help to reduce complications of the disease.7 These complications include severe mental disability as well as failure to thrive. 1,7 Patients with the condition may have to reduce their protein consumption on a day to day basis. This will keep homocysteine levels as low as possible in order to prevent further build up, since many protein rich foods contain high amounts of methionine.7 Therefore, avoidance of meat, dairy, nuts, and eggs is recommended. Many patients are usually given a daily protein limit, so it is important for them to follow this in order to get adequate nutrition while keeping homocysteine levels in a normal range.

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A formula made with every amino acid besides methionine is also used to treat homocystinuria.7 Protein is such an important part of the human diet and because patients with homocystinuria are sometimes put on a low methionine diet that lacks protein, it can be very hard for them to stay healthy and get the proper nutrition. This amino acid formula can greatly improve patient health all while keeping methionine levels low to once again avoid homocysteine build up in the blood. By monitoring the amount of homocysteine in the patient’s blood levels , physicians can gain a better understanding of which treatment works best for them. Luckily, many symptoms can be managed with proper treatment and many patients can go on to live normal lives.


  1. Picker JD, Levy HL. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. 2004 Jan 15 [Updated 2014 Nov 13]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: //www.ncbi.nlm.nih.gov/books/NBK1524/
  2. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Homocystinuria Due to Cystathionine Beta-Synthase Deficiency. Entry No: 236200. Last Edited October 29, 2010. Available at: //omim.org/entry/236200
  3. Yap S. Classical homocystinuria: vascular risk and its prevention. J Inherit Metab Dis. 2003;26:259-65.
  4. Yap S, Naughten E. 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. J Inherit Metab Dis 1998; 21: 738-747.
  5. Wilcken DE, Wilcken B. The natural history of vascular disease in homocystinuria and the effects of treatment. J Inher Metab Dis 1997; 20: 295-300.
  6. Elsaid, M. F., Bener, A., Lindner, M., Alzyoud, M., Shahbek, N., Abdelrahman, M. O., … & Hoffmann, G. F. (2007). Are heterocygotes for classical homocystinuria at risk of vitamin B12 and folic acid deficiency. Molecular genetics and metabolism92(1), 100-103.
  7. Adam S, Almeida MF, Carbasius Weber E, Champion H, Chan H, Daly A, Dixon M, Dokoupil K, Egli D, Evans S, Eyskens F, Faria A, Ferguson C, Hallam P, Heddrich-Ellerbrok M, Jacobs J, Jankowski C, Lachmann R, Lilje R, Link R, Lowry S, Luyten K, MacDonald A, Maritz C, Martins E, Meyer U, Müller E, Murphy E, Robertson LV, Rocha JC, Saruggia I, Schick P, Stafford J, Stoelen L, Terry A, Thom R, van den Hurk T, van Rijn M, van Teefelen-Heithoff A, Webster D, White FJ, Wildgoose J, Zweers H. Dietary practices in pyridoxine non-responsive homocystinuria: a European survey. Mol Genet Metab. 2013 Dec;110(4):454-9. doi: 10.1016/j.ymgme.2013.10.003. Epub 2013 Oct 10



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