This is part of Rare diseases.

Diagnosis: Homocystinuria

Synonyms: --

Date of publication: 2013-01-23
Version: 1.1

ICD 10 code


The disease

The term homocystinuria refers to the fact that abnormally large amounts of homocystine are excreted in the urine. When the term homocystinuria is used to describe a disease, it usually refers to the special condition caused by impaired functioning of the cystathionine-beta-synthase (CBS) enzyme, and this is the form of the disease described in this material. The disease is characterised by symptoms from the eyes, blood vessels, brain and skeleton. The increased excretion of homocystine is also associated with other medical conditions.

Homocystinuria was described for the first time in 1962 by Irish paediatricians Nina Carson and Desmond Neill. In 1964 it was established that the condition was caused by impaired functioning of the CBS enzyme.


It is not known how many people in Sweden have homocystinuria. Information on how common the disease is varies in international medical literature, but it is estimated that one in every 300,000 newborns has homocystinuria. However, estimates from genetic studies in Denmark and other countries indicate that the disease may be considerably more common. The disease is sometimes asymptomatic and symptoms may also be mild or diffuse, which may account for the fact that so few people with the disease have been identified. There are some countries, such as Ireland, where the disease is more common.


Homocystine is formed when two molecules of an amino acid called homocysteine become one. Homocysteine is produced in cells from the sulphur-rich amino acid methionine, a vital substance found in food, when a methyl group is transferred to another compound. This reaction is extremely important in the life cycle of cells.

The resulting homocysteine can then be converted by two different processes. The first involves it uniting with a folic acid compound and, with the help of vitamin B12 and a particular enzyme system, being re-converted into methionine. A methyl group is then transferred from the folic acid compound and joins with homocysteine, which in turn is converted into methionine. The second process involves the conversion of homocysteine into the amino acid cysteine, an important component of various proteins. The change occurs in two stages, the first of which requires the presence of enzyme CBS (cystathionine beta-synthase) and vitamin B6.

If CBS does not function, homocystinuria will result. Homocysteine cannot be converted into cysteine and if it cannot be re-converted into methionine it accumulates in cells. The result is elevated concentrations of both homocysteine and methionine. Homocysteine has a strong tendency to bind to other sulphur-rich compounds, and to other homocysteine molecules.

High concentrations of homocysteine affect supportive tissue in different parts of the body, for example by making fibrillin unstable. One of the functions of fibrillin is to form the structures which hold the lens of the eye in place. The accumulation of homocysteine also affects the skeleton’s supportive tissue, damages the walls of blood vessels and can contribute to the formation of free radicals. In the brain, different receptors on the surface of nerve cells are affected.

The reason that CBS does not function is a mutation in a gene on chromosome 21 (21q22.3). More than 150 genetic mutations of gene CBS are known (2011). Certain mutations result in the non-formation of the CBS enzyme, while others impair its functionality. Half of all people with homocystinuria have a particular mutation which means that a high concentration of vitamin B6 restores a great deal of enzyme functionality. These people are sometimes known as B6 responders.


The inheritance pattern of homocystinuria is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. In each pregnancy there is a 25 per cent risk that the child will inherit double copies of the mutated gene (one from each parent). The child will then have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.


In homocystinuria it is common that the supportive tissue of the eyes, blood vessels, brain and skeleton are affected. People with the disease are often tall and thin. Inguinal hernias, muscle weakness and thin, fragile skin are also indicators of the condition. People with the type of defective enzyme which can be helped or cured through vitamin B6 treatment often have a milder form of the disease, even without treatment.

There are conditions with similar symptoms to homocystinuria where concentrations of homocysteine are normal, for example Marfan syndrome. Separate information on Marfan syndrome is available in the Rare Disease Database of the Swedish Board of Health and Welfare.

The eyes may be affected in different ways. The most common problem is that the lens becomes dislocated (lens luxation), which can negatively affect vision. Extreme short sight can be the first sign of lens displacement. In a few cases, lens luxation may be found in newborns with the condition, but it is more common in childhood and later in life. In those children who can be treated with vitamin B6, lens luxation generally occurs later.

Glaucoma and cataracts may also occur, as well as changes to the retina.

There may also be damage to the walls of blood vessels. Such changes generally occur later than damage to the eye. These abnormalities can cause blood clots (embolisms), which can affect both veins and arteries. Lung embolisms and clots which affect the blood supply to the brain are especially dangerous. For people with homocystinuria, blood clots are the most common cause of serious complications and early death. In people who can be treated with vitamin B6, blood clots usually occur later.

Because of the increased risk of blood clots, women with the disease should not take medication, including birth control pills, containing oestrogen.

Before operations, preventive measures should be taken to reduce the risk of blood clots. (See under “Treatment.”)

The brain can be affected by impaired blood supply and be subject to damage leading to impaired cognitive function. Individuals with intellectual disability require more time to understand and learn new skills. They may also have difficulties organising new information, adapting to new situations, and have trouble seeing how things or events relate to each other. Expressing their will, thoughts or emotions may take longer. The severity of symptoms is determined by the level of cognitive impairment.

Various types of mental problems can be caused by the disease, including depression and behavioural abnormalities.

Epilepsy and problems with movement, including an unstable gait, may also occur.

The skeleton is affected, impairing normal growth. People with homocystinuria are often tall and slim, their limbs being long and thin in proportion to the rest of their bodies. Osteoporosis (when the skeleton loses calcium and becomes brittle), abnormalities of the rib cage, and changes to the vertebrae causing scoliosis (a crooked back) are all very common. Abnormalities of the knee joints also occur.

Other symptoms

People with homocystinuria have an increased tendency to develop inguinal hernia, where the contents of the abdominal cavity bulge through the groin. Small blood vessels in the skin may also be dilated (telangiectasias). The disease is also associated with light skin and fair, brittle hair.

International medical literature contains accounts of several women with the disease who have experienced normal pregnancies and given birth to healthy children. However, it is important to be aware that, when giving birth, there are increased risks associated with the blood vessels.


The diagnosis is established with the help of certain signs including a long, thin build, lens luxation and elevated levels of homocysteine and methionine in blood plasma. To confirm the diagnosis, CBS activity is measured in samples of immature cells of connective tissue (fibroblasts) taken from the skin, or from white blood cells (lymphocytes). If the patient presents with typical body signs and has a characteristic amino acid profile, enzyme measurements need not be carried out.

It is possible to confirm the diagnosis by a DNA analysis that indicates the mutation or mutations which cause the disease. Prenatal diagnosis is possible if the mutation in the family has been identified.

Since 2010, homocystinuria has been one of the diseases which is diagnosed in the general screening of neonates for inherited metabolic disorders (the PKU test). As yet, there are no indications as to how effective this diagnostic technique is in Sweden. It is likely that certain children with the mutations which cause a mild form of the disease, including those who regain enzyme function through vitamin B6 treatment, will not be identified in this form of screening. For this reason it is important that healthcare professionals in their contact with individuals with characteristic symptoms continue to consider this diagnosis.


Treatment aims to reduce the level of homocysteine in the body and prevent and treat complications. It is extremely important that the disease is discovered at an early stage. If treatment commences very early in life and the level of homocysteine can be reduced to near-normal, current experience indicates that symptoms can be prevented. Once they have manifested they will always be present, but treatment can prevent the appearance of new symptoms.

Preventive treatment takes three forms: vitamins to optimise the conversion of homocysteine into methionine; a special diet to reduce the consumption of methionine and increase the level of cysteine; betaine supplements (the amino acid trimethylglycine) when necessary. With the help of a particular liver enzyme, betaine can convert homocysteine into methionine.

Different specialists collaborate in treatment, which should be managed and coordinated by a team with expertise in metabolic diseases. They should work closely with the affected child and parents, and continue to work with adults with the disease.

Vitamin B6

When planning treatment it is important to first establish if the person belongs to the group which can regain enzyme function with the help of vitamin B6. This can be done by prescribing the vitamin and seeing if the homocysteine level falls. Those who are helped by vitamin B6 treatment should receive continued supplements in tablet form. Blood levels of homocysteine and methionine should be regularly checked and the dose adjusted for best results.

Dietary treatment

People who are not helped by vitamin B6 treatment may respond to changes in the diet. Reducing the amount of protein in food causes the intake of methionine to fall. However, even when the amount of protein is reduced to the minimum required by the body, homocysteine levels remain abnormal. If dietary treatment is to be effective most, though not all, protein in the diet should be replaced by a specially-composed mixture of amino acids containing cysteine, but excluding methionine. Treatment should be supervised by a dietician with expertise in the dietary treatment of metabolic diseases and requires time, knowledge and care. Dietary restrictions are life-long. In practice, it may be so difficult to adjust to the taste of protein replacement that this form of treatment will only work if it is started during the first months of life.


Betaine can effectively reduce levels of homocysteine in the blood of many people with the disease when the result of vitamin B treatment and/or dietary treatment is not sufficient. Treatment with betaine supplements is widely used to treat older children and adults. It can be complemented with supplements containing folic acid, vitamin B12, vitamin B6 and sometimes vitamin C.

Other preventive treatments

Many people are also treated with low doses of acetylsalicylic acid in order to prevent complications associated with the blood vessels. However, the success of this form of treatment has yet to be established in any completed scientific study.

For pregnant women with the disease, preventive treatment for blood clots is recommended during the last three months of pregnancy and for a period after delivery. As there are no evaluations of such treatment in the case of homocystinuria, treatment should be supervised by an expert with experience in the increased risk of blood clots during pregnancy.

Treatment of complications

Lens luxation can affect vision and require evaluation by an ophthalmologist. Severe lens luxation may require surgical intervention.

Cataracts may be treated by an operation and glaucoma with eye drops and/or an operation. Permanent visual impairment requires contact with a low vision centre or unit.

Scoliosis (abnormal curvature of the spine) affects posture, and occasionally breathing. An orthopaedic surgeon may be called in in the case of abnormalities and an operation may sometimes be required.

Some children require treatment and following up by a physiotherapist.
Epilepsy can be treated with medication.
Inguinal hernias may require an operation.

Children and young people with an intellectual disability require early contact with a habilitation team. A habilitation team includes professionals with special expertise in how disability affects everyday life, health and development. Support and treatment take place within the medical, educational, psychological, social and technical fields. Habilitation also covers visual disabilities. Interventions may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. It also includes information on support offered by the local authority, and advice on adapting accommodation and other environments.

Habilitation is adapted to the child’s abilities and limitations, and planning and implementation involve collaboration between the child, the parents and personnel from the preschool or school. It is important to stimulate speech development by means including augmentative and alternative communication (AAC), so that the child develops communication skills.

The local authority can offer different forms of support to facilitate the family’s everyday life. Respite care can, for example, take the form of a contact family, care assistants, or short-term accommodation outside the home.

Adults with homocystinuria who have a cognitive impairment require continued, individually-designed habilitation and support in their daily lives including, for example, support and care in special accommodation offering assistance with daily living.

Prior to surgery

The physician responsible for treating the disease should always be contacted before any operations. Many surgical procedures have been carried out on people with homocystinuria without complications, but there are increased risks associated with anaesthesia. Blood clots can be prevented by intravenous fluid replacement and by using thrombelastography, which controls treatment with anti-coagulants. It is important that nitrous oxide is not used as it can increase homocysteine levels. For this reason it should not be used for pain relief in childbirth or in minor surgical interventions. Where serious complications during exposure to nitrous oxide have arisen in people with elevated levels of homocysteine, the cause has not been homocystinuria. However, nitrous oxide should be avoided by everyone with elevated levels of homocysteine in the blood.

Following up

Everyone with homocystinuria should be carefully followed up so the best treatment can be provided and any complications prevented, discovered and treated. A regional centre for metabolic diseases should be responsible for the establishment, execution and updating of a follow-up plan. Regular monitoring can often be carried out in local centres. The number of appointments is adapted to the age of person with the disease and the nature of the symptoms. At least one check-up should be carried out annually at a metabolic centre where physicians and dieticians can evaluate results, give information on diet and other forms of treatment and plan continued treatment in collaboration with patients and their relatives.

Levels of homocysteine and amino acids in the blood should be checked regularly and laboratory tests carried out to show how well the body absorbs nutrients. The mineralization of the skeleton (the process by which the body produces bone) should be measured.

Monitoring also involves measuring pressure in the eye and recording signs of circulatory or mental problems.

Practical advice


National and regional resources in Sweden

Paediatric medical clinics with specialist units for metabolic diseases can provide expert knowledge of homocystinuria. University hospital medical, neurology and eye clinics are also involved.

Resource personnel


Specialist Physician Annika Reims,The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00. Email: annika.reims@vgregion.se.

Associate Professor Olov Ekwall, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00. Email: olov.ekwall@vgregion.se.

Dietician Karina Eftring, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00. Email: karina.eftring@vgregion.se.


Associate Professor Anna Nordenström, Children’s Hospital, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00. Email: anna.nordenstrom@ki.se.

Specialist Physician Rolf Zetterström, Children’s Hospital, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00. Email: rolf.zetterstrom@ki.se.

Dietician Carina Heidenborg, Children’s Hospital, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00. Email: carina.heidenborg@karolinska.se.

Courses, exchanges of experience, recreation


Organizations for the disabled/patient associations etc.

FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities, Industrivägen 7 (visitors address), Box 1181, 171 23 Solna, Sweden. Tel: +46 8 508 866 00, fax: +46 8 508 866 66. Email: fub@fub.se, www.fub.se.

SRF, The Swedish Association of the Visually Impaired, Sandsborgsvägen 52, SE-122 88 Enskede, Sweden. Tel: +46 8 39 90 00, fax: +46 8 39 93 22, email: info@srf.nu, www.srf.nu.

Courses, exchanges of experience for personnel


Research and development

Research into homocystinuria is being actively pursued in different locations around the world. Among other developments, attempts are being made to identify how damage to blood vessels occurs in order to develop methods of treatment. Several studies have shown that potentially dangerous substances, free radicals, are formed as a result of the disease and trials of medication designed to reduce their effects is under way. Vitamin C is thought to produce similar results, although this has not yet been established in a systematic study.

Projects are also under way to identify substances which can repair genetic damage to the critical enzyme. Such damage affects the form and normal folding patterns of the enzyme, resulting in loss of functionality. If these substances could be identified and safe medication developed, forms of the disease caused by specific types of genetic mutation could be cured.

Information material

An information leaflet on homocystinuria summarising the information in this database text is available free of charge from the Publishing Department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2011-09-17). Address: SE-106 30 Stockholm, Sweden. Fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se, or tel: +46 75 247 38 80. Postage will be charged for bulk orders.


Brattstrom L, Wilcken DE. homocysteine and cardiovascular disease: cause or effect? Am J Clin Nutr 2000; 72: 315-323. Review.

Finkelstein JD. homocysteine : a history in progress. Nutr Rev 2000; 58: 193-204. Review.

Finkelstein JD. Inborn errors of sulphur-containing amino acid metabolism. J Nutr 2006; 136: 1750S-1754S.

Gerding H. Ocular complications and a new surgical approach to lens dislocation in homocystinuria due to cystathionine-beta-synthetase deficiency. Eur J Pediatr 1998; Suppl 2: 94-101.

Harrison DA, Mullanney PB, Mesfer SA, Awad AH, Dhindsa H. Management of ophtalmic complications of homocystinuria. Ophtalmology 1998; 105: 1886-1890.

Kluijtmans LA, Boers GH, Kraus JP, van den Heuvel LP, Cruysberg JR, Trijbels FJ et al. The molecular basis of cystathionine beta-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype and response to treatment. Am J Hum Genet 1999; 65: 59-67.

Lawson-Yuen A, Levy HL. The use of betaine in the treatment of elevated homocysteine . Mol Genet Metab 2006; 88: 201-207.

Lowe S, Johnson DA, Tobias JD. Anesthetic implications of the child with homocystinuria. J Clin Anesth 1994; 6: 142-144.

Miles EW, Krauss JP. Cystathionine beta-synthase: Structure, function, regulation, and location of homocystinuria-causing mutations. J Biol Chem 2004; 279: 29871-29874.

Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 1985; 37: 1-31.

Mudd SH. Hypermethioninemias of genetic and non-genetic origin: A review. Am J Med Genet C Semin Med Genet 2011; 57: 3-32.

Singh LR, Gupta S, Honig NH, Kraus JP, Kruger WD. Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70. PLoS Genet 2010; 6: e1000807. Epub 2010 Jan 8.

Skovby F, Gaustadnes M, Mudd SH. A revisit to the natural history of homocystinuria due to cystathionine β-synthase deficiency. Mol Genet Metab 2010; 99: 1-3.

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.

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.

Yap S. Classical homocystinuria: Vascular risk and its prevention. J Inherit Metab Dis 2003; 26: 259-265.

Database references

OMIM (Online Mendelian Inheritance in Man)
Search: homocystinuria, cystathionine beta synthase deficiency

GeneReviews (University of Washington)
www.genetests.org (select “GeneReviews”, then “Titles”)
Search: homocystinuria, cystathionine beta synthase deficiency

Orphanet, www.orpha.net
Search: homocystinuria due to cystathionine beta-synthase deficiency

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Professor Agne Larsson, Karolinska University Hospital, Huddinge in Stockholm, Sweden.

The material has been revised by Professor Ola Hjalmarson, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2013-01-23
Version: 1.1
Publication date of the Swedish version: 2011-10-18

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.


About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.