There are four carboxylase enzymes in man that require biotin for activity. These enzymes are propionyl-CoA carboxylase, 3-methylcrotonoyl-CoA carboxylase, pyruvate carboxylase, and acetyl-CoA carboxylase. If biotin metabolism is defective, all four carboxylases will be deficient. Biotin is covalently linked to a key lysine residue in each carboxylase by action of holocarboxylase synthetase. When the carboxylase proteins are degraded, biotinoyl-lysine is subsequently cleaved by biotinidase releasing free biotin that can be reutilized. The two defects in biotin metabolism associated with Multiple Carboxylase Deficiency are caused by deficient activity of holocarboxylase synthetase and biotinidase. The disorders tend to present clinically at different ages, with holocarboxylase synthetase deficiency being known as early-onset (neonatal) multiple carboxylase deficiency and biotinidase deficiency referred to as late-onset multiple carboxylase deficiency. Both respond to biotin supplementation.
Patients affected with deficient holocarboxylase synthetase usually present in the first days or weeks of life with poor feeding, lethargy, hypotonia, and seizures, sometimes progressing to coma. Generalized rash and alopecia may be present. Affected patients exhibit metabolic acidosis and mild to moderate hyperammonemia. In contrast, Biotinidase deficiency, which constitutes the vast majority of patients with Multiple Carboxylase Deficiency, typically presents after several months of life with neurocutaneous symptoms including developmental delay, hypotonia, seizures, ataxia, hearing loss, alopecia, and skin rash. In some patients, the disease can be life-threatening.
Biotinidase deficiency is readily detected by measuring the activity of the enzyme on a heel stick dried blood spot. Newborn screening using tandem mass spectrometry may reveal an elevation of C5-hydroxy acylcarnitine from the dried blood spot of a patient affected with holocarboxylase synthase deficiency. Diagnosis of holocarboxylase synthetase deficiency requires further testing. Urine organic acid analysis reveals elevations of ß-hydroxyisovaleric acid, ß-methylcrotonylglycine, and tyglylglycine. Urine may also contain metabolites seen in Propionyl CoA Carboxylase deficiency and ß-Methylcrontonyl CoA Carboxylase deficiency. Discriminating these disorders is important to ensure proper therapy is initiated.
Treatment of patients with Multiple Carboxylase Deficiency involves administration of high doses of biotin. An excellent and rapid clinical response to biotin is characteristic of both enzyme defects associated with Multiple Carboxylase Deficiency. This highlights the importance of accurate and timely diagnostic evaluation of affected infants.
Because the diagnosis and therapy of Multiple Carboxylase Deficiency 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.
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.
Sweetman, L. and Williams, J.C. Branched Chain Organic Acidurias. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill.
Wolf, B. Disorders of Biotin Metabolism. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill.
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.
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.
(c) 2008 PerkinElmer Genetics, Inc. All Rights Reserved
This information is copyrighted and is only for your personal, non-commercial use, provided that all copyright and other proprietary notices are retained on any copies made of it. The information may not be modified in any way or reproduced or distributed or used for any public or commercial purpose unless expressly permitted. Any use or display of the enclosed information for any purpose is prohibited.