Background The finding of elevated Methionine in a dried blood spot upon newborn screening suggests one of two metabolic defects: 1) Homocystinuria due to Cystathionine β-Synthase (CBS) deficiency or 2) hepatic methionine adenosyltransferase deficiency. The most likely defect is a deficiency of CBS, which causes a connective tissue disease with several manifestations. Many patients with homocystinuria have been described since the deficiency was first reported in 1962. Methionine accumulates at the beginning of a metabolic pathway that sequentially converts this amino acid to Homocysteine, Cystathionine and Cysteine. The step in the pathway that converts Homocysteine to Cystathionine is catalyzed by CBS. Although it is highly elevated, Homocysteine is not detected with newborn screening because of its reactive nature with many components in blood, including itself with the formation of the dimer Cystine. The elevation of Methionine, therefore, is used to detect this disorder in newborn screening. The incidence of CBS deficiency is about 1 in 60,000, although several investigators believe this disease is more common.
Clinical While the metabolic defect is present at birth, initial symptoms of homocystinuria usually have onset later in infancy and childhood. Developmental delay may be the first sign and is a harbinger of mental retardation, but is not obligate. An early and distinctive finding is dislocation of the lens of the eye (ectopia lentis). Patients are at high risk for developing thromboembolism that may occur at any age. These may lead to stroke, seizures, permanent neurologic sequela and death. Increased clotting ability makes surgery a risk. Osteoporosis is a long-term complication of homocystinuria.
Testing
Newborn screening of a dried blood spot using tandem mass spectrometry reveals elevated levels of methionine, which should prompt testing plasma for amino acids, including homocysteine. Elevated methionine and homocysteine in plasma indicate CBS deficiency, while an isolated increase in methionine suggests hepatic methionine adenosyltransferase deficiency. In affected patients, the presence of homocystine in the urine is a consistent finding, especially after early infancy. CBS enzyme activity can be measured in many tissues, including fibroblasts, lymphocytes, liver, amniocytes, and chorionic villi (biopsy or cultured cells). Deficient enzyme activity may be followed with DNA mutation analysis for the several known mutations in the CBS gene.
Treatment
Treatment of CBS deficiency usually begins with a trial of oral vitamin B6 (pyridoxine) supplementation, with daily measurement of plasma amino acids. CBS requires pyridoxine as a coenzyme for enzymatic activity. Overall, about 25% of patients respond to large doses of pyridoxine, although the percentage may be lower for patients identified through newborn screening. This pyridoxine response usually coincides with the presence of some residual enzyme activity. Dietary restriction of Methionine in conjunction with Cystine supplementation reverses the biochemical abnormalities to some extent and appears to reduce the clinical symptoms. Special formulas are available commercially, but the diet is difficult to maintain long term. In an attempt to decrease Homocysteine levels, folic acid, and betaine can be supplemented to induce recycling of this amino acid to Methionine for alternate metabolism. Vitamin B12 (cobalamin) may also be helpful. Because the diagnosis and therapy of Homocystinuria is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.
Inheritance
This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder. As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.
References
Applegarth, D.A., Hardwick, D.F., et al. Excretion of S-adenosylmethionine and S-adenosylhomocysteine in Homocystinuria. New England J. Med. 285:1265, 1971. Mudd, S.H., Levy, H.L., and Kraus, J.P. Disorders of Trans-sulferation. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 88, pg. 2007-2046. Wong, P.W.K., Justice, P., et al. Folic acid non-responsive homocystinuria due to methylenetetrahydrofolate reductase deficiency. Pediatrics 58:749-756, 1977.
Web Sites SaveBabies.org
Site established and maintained by parents of newborns affected with a rare genetic defect, with information for parents and professionals and links to other informative sites. National Newborn Screening and Genetics Resource Center
Provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.
Disclaimers
The analyses conducted by PerkinElmer Genetics produce results that can be used by qualified physicians in the diagnosis of disorders described herein. Evidence of these conditions will be detected in the vast majority of affected individuals; however, due to genetic variability, age of the patient at the time of specimen collection, quality of the specimen, health status of the patient, and other variables, such conditions may not be detected in all affected patients. PerkinElmer Genetics makes no warranty whatsoever, express or implied, including any warranty as to accuracy, completeness or timeliness, concerning the information contained herein, and you should not assume that such information is complete or the most up-to-date information available. PerkinElmer Genetics shall not be liable for any loss, claim or damages caused in whole or in part by our provision of, or your use of, any of the information contained herein. As a general statement, this information was drawn from published literature and is not drawn from our patient population or screening experience. The information contained herein is not intended to be a substitute for professional medical advice and should not be used for the diagnosis or treatment of any medical condition. A licensed physician should be consulted for diagnosis and treatment of any and all medical conditions.
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