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Homocystinuria refers to a group of inherited disorders in which the body is unable to process certain building blocks of proteins (amino acids) properly. This leads to increased amounts of homocysteine and other amnio acids in the blood and urine. Homocystinuria can affect the eyes, skeleton, central nervous system and the blood clotting system.

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Homocystinuria due to CBS deficiency; Homocystinuria due to defect in methylation cbl e; Homocystinuria due to defect in methylation cbl g The most common type of genetic homocystinuria, called CBS deficiency, is caused by the lack of an enzyme known as cystathionine beta-synthase (CBS). Most states in the United States test for homocystinuria due to CBS deficiency at birth by newborn screening. Other types are less common, and are caused by different missing or non-working enzymes.


Homocystinuria can be caused by mutations in several different genes. All of these genes are responsible for making enzymes that are involved in the way our body uses and processes amino acids. The most common gene associated with homocystinuria is the CBS gene that causes a lack of the enzyme, cystathionine beta-synthase. Rarer causes of homocystinuria include mutations in the MTHFR, MTR, MTRR and MMADHC genes.

It is not clear why high levels of homocysteine cause the symptoms seen in homocystinuria.

There are other, non-genetic causes of high levels of homocysteine.Non-genetic homocystinuria is not a rare condition. Some of the non-genetic causes are listed here.

•Vitamin B6 or vitamin B12 deficiency

Folate deficiency

•Low thyroid hormones (hypothyroidism)



•High cholesterol

•Physical inactivity

•High blood pressure

•Certain medications (such as carbamazepine, atorvastatin, fenofibrate, methotrexate, phenytoin, and nicotinic acid)


•Advanced age


Autosomal recessive inheritance, a 25% chance

The genetic forms of homocystinuria are inherited in an autosomal recessive pattern, which means both copies of the gene in every cell have mutations.

This means that to have the condition, a person must have a mutation in both copies of the responsible gene in each cell. There is nothing either parent can do, before or during a pregnancy, to cause a child to have this.

People with homocystinuria inherit one mutation from each of their parents. The parents, who each have one mutation, are known as carriers. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:

•25% chance to have the condition •50% chance to be an unaffected carrier like each parent •25% chance to be unaffected and not a carrier.


Symptoms of the most severe form of homocystinuria will start in infancy or early childhood. The first of these symptoms may be poor growth and failure to gain weight. Other people with homocystinuria may not have any symptoms until adulthood. The most common symptom seen in adults with homocystinuria is an abnormal blood clot.

Other symptoms of untreated homocystinuria can include:


•Dislocation of the lens of the eye



•Caved-in chest (pectus excavatum)

•Curvature of the spine (scoliosis)

•Long, thin bones

Osteoporosis (weak, brittle bones)

Central nervous system:

•Learning and intellectual disabilities

•Psychiatric problems

Blood and heart:

•Cardiovascular disease

•Abnormal blood clots


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Most states in the US test for homocystinuria due to CBS deficiency at birth by newborn screening. A baby that has a positive newborn screening test needs to have additional blood testing to look for high levels of homocysteine and methionine in the blood. Genetic testing can also be helpful for diagnosis.

A child or an adult with dislocation of the lens of the eye may also get tested for homocystinuria using blood and urine testing. In addition, a child or adult who has a blood clot, especially at an early age, may also get tested for homocystinuria.

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 homocysteine.

Additionally, organic acid analysis 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 homocysteine itself is complicated because most homocysteine (possibly above 85%) is bound to other thiol amino acids and proteins in the form of disulphides (e.g., cysteine in cystine-homocysteine, homocysteine in homocysteine-homocysteine) via disulfide bonds. Since as an equilibrium process the proportion of free homocystene 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.


People who have the most severe form of homocystinuria are put on a special protein-restricted diet to reduce the blood levels of homocysteine and methionine. In addition, they may be given supplements including vitamin B6, vitamin B12, folate and betaine. The recommendation is that these people stay on the protein-restricted diet for life. People with milder forms may be treated with supplements depending on the level of homocysteine in their blood.

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

  • Betaine (Brand name: Cystadane)Treatment of homocystinuria to decrease elevated homocysteine blood levels.


The life expectancy of patients with homocystinuria is reduced only if untreated. It is known that before the age of 30, almost one quarter of patients die as a result of thrombotic complications (e.g., heart attack).


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