The First Case of 3-Methylcrotonyl-CoA Carboxylase (MCC) Deficiency Responsive to Biotin

 

 Buy Article Permissions and Reprints

Abstract

3-Methylcrotonylglycinuria is an inborn error of leucine catabolism with an autosomal recessive pattern of inheritance that results from a deficiency of 3-methylcrotonyl-CoA carboxylase (MCC). We report on a nine-year-old boy with severe psychomotor retardation who developed infantile spasms at the age of three weeks. Urine analysis at the age of two years revealed massive 3-methylcrotonylglycinuria and 3-hydroxyisovaleric aciduria suggesting MCC deficiency. Carnitine serum levels were decreased. Biotin therapy led to a dramatic decrease in the frequency of seizures, disappearance of hypsarrhythmia, and near normalisation of organic aciduria. Four months later a protein-restricted diet was introduced in addition and the boy remained clinically and metabolically stable. However, severe psychomotor delay persisted, and the seizures partially reoccurred. Biochemical findings showed partial MCC deficiency in cultured fibroblasts. Molecular genetic studies revealed a heterozygote missense mutation, MCCA-R385S, converting arginine to serine in a highly conserved region of the MCCA gene. This is the first patient with MCC deficiency caused by a heterozygote mutation and who demonstrated a substantial and sustained clinical and biochemical response to therapeutic doses of biotin. Sadly, this patient again also demonstrates that the main determinant of the outcome of even easily treatable metabolic diseases is timely diagnosis.

References

• 1 Bannwart C, Wermuth B, Baumgartner R, Suormala T, Wiesmann U N. Isolated biotin-resistant deficiency of 3-methylcrotonyl-CoA carboxylase presenting as a clinically severe form in a newborn with fatal outcome.  J Inherit Metab Dis. 1992;  15 863-868
  CrossrefPubMedGoogle Scholar
• 2 Baumgartner M R, Almashanu S, Suormala T, Obie C, Cole R N, Packman S. et al . The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency.  J Clin Invest. 2001;  107 495-504
  PubMedGoogle Scholar
• 3 Baumgartner M R, Dantas M F, Suormala T, Almashanu S, Giunta C, Friebel D. et al . Isolated 3-methylcrotonyl-CoA carboxylase deficiency.  Am J Hum Genet. 2004;  75 790-800
  CrossrefPubMedGoogle Scholar
• 4 Beemer F A, Bartlett K, Duran M, Gheim H K, Wadmann S K, Bruinvis L. et al . Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency in two sibs.  Eur J Pediatr. 1982;  138 351-354
  CrossrefPubMedGoogle Scholar
• 5 Dantas M F, Suormala T, Randolph A, Coelho D, Fowler B, Valle D, Baumgartner M R. 3-Methylcrotonyl-CoA carboxylase deficiency: mutation analysis in 27 probands, 9 symptomatic and 18 detected by newborn screening.  Hum Mutat. 2005;  26 164
  PubMedGoogle Scholar
• 6 Elpeleg O N, Havkin S, Barash V, Jakobs C, Glick B, Shalev R S. Familial hypotonia of childhood caused by isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency.  J Pediatr. 1992;  121 407-410
  PubMedGoogle Scholar
• 7 Gallardo M E, Desviat L R, Rodriguez J M, Esparza-Gordillo J, Perez-Cerda C, Perez B. et al . The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism.  Am J Hum Genet. 2001;  68 334-346
  CrossrefPubMedGoogle Scholar
• 8 Gibson K M, Bennett M J, Naylor E W, Morton D H. 3-Methylcrotonyl-coenzyme A carboxylase deficiency in Amish/Mennonite adults identified by detection of increased acylcarnitines in blood spots of their children.  J Pediatr. 1998;  132 519-523
  PubMedGoogle Scholar
• 9 Koeberl D D, Millington D S, Smith W E, Weavil S D, Muenzer J, McCandless S E. et al . Evaluation of 3-methylcrotonyl-CoA carboxylase deficiency detected by tandem mass spectrometry newborn screening.  J Inherit Metab Dis. 2003;  26 25-35
  CrossrefPubMedGoogle Scholar
• 10 Lagler F B. 3-Methylcrotonyl-CoA Carboxylasemangel. Molekulare Grundlagen. Dissertationsschrift. Medizinische Fakultät der Universität München 2002: 1-5
  Google Scholar
• 11 Pacheco-Alvarez D, Solorzano-Vargas R S, Del Rio A L. Biotin in metabolism and its relationship to human disease.  Arch Medic Research. 2002;  33 439-447
  PubMedGoogle Scholar
• 12 Schulze A, Lindner M, Kohlmüller D, Olgemöller K, Mayatepek E, Hoffmann G F. Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications.  Pediatrics. 2003;  111 1399-1406
  CrossrefPubMedGoogle Scholar
• 13 Sloane V, Waldrop G L. Kinetic characterization of mutations found in propionic acidemia and methylcrotonylglycinuria: evidence for cooperativity in biotin carboxylase.  J Biol Chem. 2004;  279 15772-15778
  CrossrefPubMedGoogle Scholar
• 14 Suormala T, Wick T, Bonjour J-P, Baumgartner E R. Rapid differential diagnosis of carboxylase deficiencies and evaluation of biotin responsiveness in a single blood sample.  Clin Chim Acta. 1985;  145 151-162
  CrossrefPubMedGoogle Scholar
• 15 Sweetmann L, Williams J C. Branched chain organic acidurias. Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B The Metabolic and Molecular Basis of Inherited Disease (8th ed). New York; McGraw-Hill 2001: 2125-2163
  Google Scholar
• 16 Visser G, Suormala T, Smit G P, Reijngoud D J, Bink-Boelkens M T, Niezen-Koning K E. et al . 3-methylcrotonyl-CoA carboxylase deficiency in an infant with cardiomyopathy, in her brother with developmental delay and in their asymptomatic father.  Eur J Pediatr. 2000;  159 901-904
  CrossrefPubMedGoogle Scholar
• 17 Wiesmann U N, Suormala T, Pfenniger J, Baumgartner E R. Partial 3-methylcrotonyl-CoA carboxylase deficiency in an infant with fatal outcome due to progressive respiratory failure.  Eur J Pediatr. 1998;  157 225-229
  CrossrefPubMedGoogle Scholar
• 18 Wilcken B, Wiley V, Hammond J, Carpenter K. Screening newborns for inborn errors of metabolism by tandem mass spectrometry.  N Engl J Med. 2003;  348 2304-2312
  CrossrefPubMedGoogle Scholar

Prof. Dr. Georg F. Hoffmann

Division of Metabolic and Endocrine Diseases
University Children's Hospital

Im Neuenheimer Feld 153

69120 Heidelberg

Germany

Email: Georg_Hoffmann@med.uni-heidelberg.de