| Background 3-MethylCrotonyl-CoA Carboxylase (3-MCC) Deficiency has been recognized since 1984. It is a defect in the degradation of the amino acid Leucine. As a carboxylase enzyme, 3-MCC requires biotin for activity. There are four carboxylases in man that utilize biotin and each can be deficient singly or together. If biotin metabolism is defective, activities of all four carboxylases will be low, resulting in Multiple Carboxylase Deficiency. Some of the biochemical findings in 3-MCC Deficiency overlap with those seen in Multiple Carboxylase Deficiency, necessitating careful testing to distinguish the two disorders.
Clinical
The clinical presentations of 3-MCC deficiency range from severe to benign. The age of onset of symptoms is usually during the first several years of life, but later onsets and even asymptomatic adults have been reported. Symptoms often have onset with an infection, illness, or prolonged fasting. Patients with 3-MCC deficiency can lapse into catabolic stress leading to vomiting, lethargy, apnea, hypotonia, or hyperreflexia and seizures. Patients may have profound hypoglycemia, mild metabolic acidosis, hyperammonemia, elevated liver transaminases, and ketonuria. Plasma free carnitine levels may be very low. Other patients may present with failure to thrive beginning in the neonatal period or developmental delay. Some individuals with 3-MCC deficiency have no apparent symptoms. Asymptomatic women with 3-MCC deficiency may pass along the 3-MCC metabolite transplacentally to their infants, who are then found to have elevated 3-MCC by newborn screening with tandem mass spectrometry, but who themselves do not have the disease.
Testing
Newborn Screening using tandem mass spectrometry reveals an elevation of C5-hydroxy acylcarnitine from the dried blood spot of an affected patient. Diagnosis of 3-MCC deficiency then requires further testing. Urine organic acid analysis finds elevation of 3-hydroxyisovaleric acid and usually 3-methylcrotonylglycine. Following carnitine supplementation, 3-hydroxyisovalerylcarnitine is usually elevated in an acylcarnitine profile using tandem mass spectrometry. If C3 acylcarnitine is elevated, the disorder is multiple carboxylase deficiency. To further confirm isolated 3-MCC deficiency, the enzyme activity should be assayed in fibroblasts or leukocytes, along with at least one other carboxylase having normal enzyme activity. 3-MCC activity can also be measured in chorionic villus specimens. Mothers of all infants found to have elevated 3-MCC with newborn screening should be tested with a blood acylcarnitine profile to determine whether they have 3-MCC deficiency rather than their infant. The testing should also extend to other family members.
Treatment
Treatment of 3-MCC deficiency involves reducing dietary Leucine intake using a special leucine-depleted formula or instituting a general protein restricted diet. With onset of illness, IV glucose is needed and the acidosis must be corrected. Both carnitine and glycine supplementation have proven beneficial. Patients should undergo an early trial of biotin supplementation on the possibility that the defect is with biotin metabolism rather than isolated 3-MCC; biotin may be discontinued if there is no response. Because the diagnosis and therapy of 3-MCC 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.
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
Elpeleg, O.N., Havkin, S., Barash, V., et al. Familial hypotonia of childhood caused by isolated 3-MethylCrotonyl-CoA Carboxylase Deficiency. J Pediatrics 121:407, 1992. Gibson, K.M., Bennett, M.J., Naylor, E.W., et al. 3-MethylCrotonyl-CoA Carboxylase Deficiency in Amish/Mennonite adults identified by detection of increased acylcarnitines in blood spots of their children. J Pediatrics 132:519, 1998. Koeberl, D.D., Millington, D.S., Smith, W.E., et al. Evaluation of 3-Methylcrotoonyl-CoA Carboxylase Deficiency Detected by Tandem Mass Spectrometry Newborn Screening. J Inherit Metab Dis 26:25, 2003. 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. Chapter 93, pg. 2125 - 2163. Tsai, M.Y., Johnson, D.D., Sweetman, L., et al. Two siblings with biotin-resistant 3-MethylCrotonyl-CoA Carboxylase Deficiency. J Pediatrics 115:110, 1989. Tuchman, M., Berry, S.A., Thuy, L.P., et al. Partial MethylCrotonyl-CoA Carboxylase Deficiency in an infant with failure to thrive, gastrointestinal dysfunction and hypertonia. Pediatrics 91:664, 1993. 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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