Cystathionine beta synthase deficiency

Alternative names
Homocystinuria

Definition
Homocystinuria is an inherited disorder of the metabolism of the amino acid methionine.

Causes, incidence, and risk factors

Homocystinuria is inherited as an autosomal recessive trait, which means that the child must inherit the defective gene from both parents to be seriously affected. Typical problems seen in people with homocystinuria are nearsightedness, dislocation of the lens of the eye, and a tendency to develop blood clots in the veins and arteries.

Newborn infants appear normal, and early symptoms, if present at all, are vague and may occur as mildly delayed development or failure to thrive. Increasing visual problems may lead to diagnosis of this condition when the child, on examination, is discovered to have dislocated lenses and nearsightedness.

Some degree of mental retardation is usually seen, but some affected people have normal IQs. When mental retardation is present, it is generally progressive if left untreated. The condition can also increase the risk for psychiatric disorders.

Homocystinuria has several features in common with Marfan syndrome, including dislocation of the lens; a tall, thin build with long limbs; spidery fingers (arachnodactyly); and a pectus deformity of the chest. In addition, affected people may have high arches of the feet (pes cavus), knock-knees (genu valgum), and a curved spine (scoliosis).

Unlike Marfan syndrome, in which the joints tend to be “loose,” in homocysturia the joints tend to be “tight.” Individuals with homocysturia may also have generalized osteoporosis.

Affected people commonly develop blood clots. These clots can dislodge and travel (form an embolus) and damage any tissue in which the clot lodges. Clots that travel to the brain can cause stroke, for example.

Symptoms

     
  • A family history of homocystinuria  
  • Nearsightedness  
  • Flush across the cheeks  
  • Tall, thin build  
  • Long limbs  
  • High-arched feet (pes cavus)  
  • Knock-knees (genu valgum)  
  • Pectus excavatum  
  • Pectus carinatum  
  • Mental retardation  
  • Psychiatric disease

Signs and tests

During a physical examination of the child, the health care provider may notice a tall, thin (Marfanoid) stature with pectus deformity of the chest or scoliosis. If there is poor or double vision, an ophthalmologist should perform a dilated eye exam where dislocation of the lens of the eye or nearsightedness may be observed.

There may be a history of frequent blood clots. Mental retardation, slightly low IQ, or psychiatric disease are common.

Tests:

     
  • A skeletal X-ray shows osteoporosis.  
  • A standard ophthalmic exam confirms nearsightedness and a dislocated lens. Affected children may also have cataracts, glaucoma, and retinal detachment.  
  • An amino acid screen of blood and urine shows elevated methionine and homocysteine levels.  
  • A liver biopsy and enzyme assay shows an absence of the enzyme cystathionine beta synthase.  
  • A skin biopsy with a fibroblast culture shows an absence of cystathionine beta synthase.

Genetic testing may show a mutation in the cystathionine beta synthase gene.

Treatment

There is no specific cure for homocystinuria. However, many people respond to high doses of vitamin B-6 (also known as pyridoxine). Slightly less than half of patients respond to this treatment; those that do respond need supplemental vitamin B-6 for the rest of their lives. Those who do not respond require a low methionine diet, and most will need treatment with trimethylglycine (a medication also known as betaine).

Neither a low-methionine diet nor medication will improve existing mental retardation. Medication and diet should be closely supervised by a physician with experience treating homocystinuria.

A normal dose folic acid supplement and occasionally added cysteine (an amino acid) in the diet is helpful.

Expectations (prognosis)

Although no specific cure exists for homocystinuria, approximately half of the affected people can be helped by vitamin B-6 therapy.

If the diagnosis is made while a patient is young, a low methionine diet started promptly and strictly adhered to can spare some mental retardation and other complications of the disease. For this reason, some states screen for homocystinuria in all newborns.

Unfortunately, patients with persistent increases in blood homocysteine levels are at increased risk for blood clots, which can cause significant medical problems and shorten life span.

Complications

Most serious complications result from blood clots, and these episodes can be life threatening. Dislocated lenses of the eyes can severely impair vision and lens replacement surgery should be considered. Mental retardation is a serious consequence of the disease which can be moderated if diagnosed early.

Calling your health care provider
Call your health care provider if you or a family member shows signs and symptoms suggestive of this disorder, particularly if there is a family history of homocystinuria. Also call if you have a family history and are planning a pregnancy.

Prevention
Genetic counseling is recommended for prospective parents with a family history of homocystinuria. Intrauterine diagnosis of homocystinuria is available and is made by culturing amniotic cells or chorionic villi in order to test for the presence or absence of cystathionine synthase (the enzyme that is missing in homocystinuria).

Johns Hopkins patient information

Last revised: December 5, 2012
by Potos A. Aagen, M.D.

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