Homocystinuria due to CBS deficiency

Other Names: Homocystinuria due to cystathionine beta-synthase deficiency; Cystathionine beta-synthase deficiency; CBS deficiency; Classic homocystinuria . Homocystinuria due to CBS deficiency is an inherited disorder in which the body is unable to correctly use the amino acid, homocysteine, one of the building blocks of protein.

Cause

Homocystinuria due to CBS deficiency is caused by mutations in the CBS gene, which lead to missing or low levels of the enzyme, cystathionine beta-synthase (CBS). When this enzyme is missing or there is not enough of it, the body cannot process homocysteine. When this happens, homocysteine and another amino acid, methionine, build up in the blood. It is not clear why this build up of homocysteine and methionine is toxic to the body.

Inheritance

Autosomal recessive inheritance, a 25% chance

Homocystinuria due to CBS deficiency is inherited in an autosomal recessive pattern. The means that both copies of the CBS gene in every cell have mutations. To have the disorder, 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 this disorder inherit one mutation from each of their parents. The parents, who each have one mutation, are known as carriers. Carriers of an autosomal recessive disorder typically do not have any signs or symptoms (they are unaffected). When two carriers of an autosomal recessive condition have children, each child has a: 25% chance to have the disorder 50% chance to be an unaffected carrier like each parent 25% chance to be unaffected and not be a carrier.

Symptoms

The symptoms of homocystinuria due to CBS deficiency can vary from person to person. In infancy, symptoms include poor weight gain and growth, as well as problems with development.If untreated, additional symptoms can develop that include:

• Nearsightedness
• Dislocation of the lens of the eye
• Skeletal abnormalities
• Osteoporosis
• Blood clots
• Seizures
• Intellectual disability
• Psychiatric issues

The symptoms of the vitamin B6 responsive form of homocystinuria are generally milder than those of the non-responsive form. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of amino acid metabolism
• Arachnodactyly(Long slender fingers)
• Dental crowding(Crowded teeth)
• Disproportionate tall stature
• Ectopia lentis
• Intellectual disability(Mental deficiency)
• Osteoporosis
• Recurrent fractures(Increased fracture rate)

30%-79% of people have these symptoms

• Amblyopia(Lazy eye)
• Arterial thrombosis(Blood clot in artery)
• Arteriovenous malformation
• Cerebral ischemia(Disruption of blood oxygen supply to brain)
• Genu valgum(Knock knees)
• Hypertension
• Joint stiffness(Stiff joint)
• Kyphosis(Hunched back)
• Myopia(Close sighted)
• Pectus carinatum(Pigeon chest)
• Pectus excavatum(Funnel chest)
• Pulmonary embolism(Blood clot in artery of lung)
• Scoliosis
• Sparse scalp hair(Reduced/lack of hair on scalp)
• Venous thrombosis(Blood clot in vein)

5%-29% of people have these symptoms

• Abnormality of retinal pigmentation
• Anorexia
• Cataract(Clouding of the lens of the eye)
• Elevated hepatic transaminase(High liver enzymes)
• Esophageal varix(Enlarged vein in esophagus)
• Failure to thrive(Faltering weight)
• Gastrointestinal hemorrhage(Gastrointestinal bleeding)
• Glaucoma
• Hemiplegia/hemiparesis(Paralysis or weakness of one side of body)
• Hepatomegaly(Enlarged liver)
• Hernia
• High palate(Elevated palate)
• Intracranial hemorrhage(Bleeding within the skull)
• Optic atrophy
• Psychosis
• Retinal detachment(Detached retina)
• Seizure
• Subcutaneous hemorrhage(Bleeding below the skin)
• Urticaria(Hives)

Diagnosis

Clinical diagnosis of CbS deficiency is confirmed by blood amino acid analysis (including total homocysteine measurement), assays of CbS enzyme activity, or by screening for CBS mutations.

Treatment

People with homocystinuria due to CBS deficiency who do not respond to vitamin B6 are treated with a special, protein-restricted diet to help lower the amount of methionine and homocysteine in their bodies. In addition, they may be given supplements, such as vitamin B12, folate, and betaine. Specially trained nutritionists and dieticians work with patients to adjust the diet and protein requirements as needed. To avoid the complications seen with CBS deficiency, people with this disorder need to remain on a special diet for life. People with the vitamin B6 responsive form of this disorder are treated with vitamin B6. In some people, diet restrictions are necessary as well. 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.

Prognosis

When treatment is started early, children with this disorder can have normal growth and development, and can avoid the complications seen with this disorder. However, it is still possible that they could develop a dislocation of the lens of the eye or a blood clot. Sometimes the blood clots can be very serious and cause organ damage. In addition, some people may develop osteoporosis in adulthood as a result of this disorder.

Epidemiology

Approximately 1 in 200,000 to 1 in 300,000 people in the US has homocystinuria due to CBS deficiency. In other countries, the prevalence is higher. In Quatar, about 1 in 1800 people has this disorder and in Norway, about 1 in 6400 people has it. World-wide, it is thought that about 1 in 150,000 people has homocystinuria due to CBS deficiency.

NIH genetic and rare disease info

• NIH info on Homocystinuria due to CBS deficiency

Homocystinuria due to CBS deficiency is a rare disease.

Homocystinuria due to CBS deficiency Resources
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