What is homocystinuria?

Risk Factors

A child is only at risk for this disorder if both parents are carriers of the faulty gene that causes it. Carriers appear to have an increased risk of thromboembolic events and coronary artery disease.

Etiology and Genetics

Mutations in five separate genes have been shown to cause homocystinuria. In the majority of cases, a mutation is found in the CBS gene, which is located on the long arm of chromosome 21 at position 21q22.3. This gene encodes the enzyme cystathionine beta-synthase, which catalyzes one step in the pathway that processes the amino acid methionine (MET). When the enzyme is missing or nonfunctional, there is a block in the pathway, resulting in the accumulation of homocysteine, one of the intermediate compounds. High levels of homocysteine can be toxic. They are detected by urinalysis, since some of the excess homocysteine is excreted in the urine.

The enzymes specified by the four other genes are all involved in converting homocysteine back to MET, so mutations in these genes can also lead to a cellular accumulation of homocysteine. The responsible genes are MTHFR (found on chromosome 1 at position 1p36.3), MTR (also found on chromosome 1 at position 1q43), MTRR (found on the short arm of chromosome 5 at position 5p15.31), and MMADHC (found on chromosome 2 at position 2q23.2).

Regardless of which gene is responsible, homocystinuria is inherited in an autosomal recessive pattern, which means that both copies of the gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected. If one parent has homocystinuria and the other is a carrier, there is a 50 percent probability that each child will be affected. While carrier individuals do not have homocystinuria, they are more likely than members of the general population to have deficiencies in folic acid and vitamin B12
.

Symptoms

The number and severity of symptoms vary among individuals. Symptoms include nearsightedness and other visual problems, flush across the cheeks, fair complexion, high-arched palate, scoliosis, seizures, a tall and thin build, long limbs, high-arched feet (pes cavus), knock-knees (genu valgum), abnormal formation of the rib cage (pectus excavatum), protrusion of the chest over the sternum (pectus carinatum), intellectual disabilities, and psychiatric disease. Osteoporosis may be noted on an x-ray.

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 myopia.

Some degree of intellectual disability is usually seen, but some affected people have normal intelligence quotients (IQs). When such disabilities are present, they are generally progressive if left untreated. Psychiatric disease can also result.

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. The most serious complications of homocystinuria may be the development of blood clotting, which could result in a stroke, heart attack, or severe hypertension.

Screening and Diagnosis

Many states require that newborns be tested for homocystinuria before they leave the hospital. The test usually looks for high levels of MET. If the test is positive, blood or urine tests can be done to confirm the diagnosis. These tests can detect high levels of MET, homocysteine, and other sulfur-containing amino acids. Tests to detect an enzyme deficiency, such as a test of the enzyme cystathionine synthetase, can also be done.

If a child is not tested at birth, a doctor may later discover the disorder based on symptoms. At this point, tests may be conducted, including blood tests to confirm the diagnosis, x-rays to look for bone problems, and an eye exam to look for eye problems.

Treatment and Therapy

There is no specific cure for homocystinuria. However, treatment should begin as early as possible. Treatment may include medication and a special diet.

Many people respond to high doses of vitamin B6
, also known as pyridoxine. Slightly less than 50 percent respond to this treatment; those that do respond need supplemental vitamin B6 for the rest of their lives. A normal dose of folic acid supplement is also helpful. Individuals who do not respond require a low-methionine diet with supplements of cysteine (an amino acid) and, occasionally, treatment with trimethylglycine

There is some evidence that vitamin C in relatively high dosage can improve blood vessel functioning in persons with homocystinuria. While data remains incomplete, this treatment might prove effective in reducing the risks of blood clotting and heart attacks.

A special diet may help people who do not respond fully or at all to vitamin B6 treatment. Starting the diet early in life can help prevent intellectual disabilities and other complications. In general, the diet should restrict foods with MET; should consist mainly of fruits and vegetables; and should allow very little, if any, meats, eggs, dairy products, breads, and pasta. This diet is supplemented with cysteine and folic acid.

Prevention and Outcomes

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

If the diagnosis is made while a patient is young, a low-methionine diet started promptly and strictly adhered to can spare some intellectual disabilities and other complications of the disease. For this reason, some states screen for homocystinuria in all newborns. Individuals should check to see if their states screen for this condition.

Bibliography

Alan, Rick, and Kari Kassir. "Homocystinuria." Health Library. EBSCO, 30 May 2014. Web. 4 Aug. 2014.

Andria, Generoso, Brian Fowler, and Gianfranco Sebastio. "Disorders of Sulfur Amino Acid Metabolism." Inborn Metabolic Diseases: Diagnosis and Treatment. Ed. Jean Marie Saudubray, Georges van den Berghe, and John H. Walter. 5th ed. Heidelberg: Springer, 2012. 311–22. Print.

Houser, Christine M. Pediatric Genetics and Inborn Errors of Metabolism: A Practically Painless Review. New York: Springer, 2014. Print.

Kleigman, Robert M., et al., eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia: Saunders, 2011. Print.

Porter, Robert S., et al., eds. The Merck Manual of Diagnosis and Therapy. 19th ed. Whitehouse Station: Merck, 2011. Print.

Schiff, Manuel, and Henk J. Blom. "Treatment of Inherited Homocystinurias." Neuropediatrics 43.6 (2012): 295–304. Print.

Singh, Rani. “Homocystinuria.” Pediatric Nutrition in Chronic Diseases and Developmental Disorders: Prevention, Assessment, and Treatment. Ed. Shirley W. Ekvall and Valli K. Ekvall. 2nd ed. New York: Oxford UP, 2005. 263–66. Print