Holocarboxylase Synthetase Deficiency Clinical Presentation
- Author: Karl S Roth, MD; Chief Editor: Luis O Rohena, MD more...
As a water-soluble vitamin, biotin easily crosses the placenta; thus, the infant with holocarboxylase synthetase (HCS) deficiency in utero grows uneventfully.
Birth weight, Apgar scores, and initial physical examination findings are entirely normal.
Because of the autosomal recessive inheritance, a family history of the disorder is unlikely.
The major clinical findings of holocarboxylase synthetase deficiency include severe ketoacidosis, exfoliative dermatitis, and hypoglycemia.
As in individuals with other organic acidemias, whether fed or fasted, the increased accumulation of ketoacids causes tachypnea, irritability, lethargy, vomiting, and, eventually, coma.
Exfoliative dermatitis is usually absent in the earliest stages of clinical presentation.
Observe for unusual odors in the urine.
Presentation must be distinguished from all other causes, such as other organic acidemias, sepsis, and galactosemia.
The gene locus has been mapped to band 21q22.1, with a limited number of allelic variants described. A particular allelic variant, the p.L216R mutation, results in an unstable protein with increased turnover and a clinical picture of relative biotin-resistance. Treatment of these patients with massive amounts of daily biotin (>1 g) has resulted in relatively good outcomes.
Roth K, Cohn R, Yandrasitz J, Preti G, Dodd P, Segal S. Beta-methylcrotonic aciduria associated with lactic acidosis. J Pediatr. 1976 Feb. 88(2):229-35. [Medline].
Saunders M, Sweetman L, Robinson B, Roth K, Cohn R, Gravel RA. Biotin-response organicaciduria. Multiple carboxylase defects and complementation studies with propionicacidemia in cultured fibroblasts. J Clin Invest. 1979 Dec. 64(6):1695-702. [Medline].
Roth KS, Yang W, Foremann JW, Rothman R, Segal S. Holocarboxylase synthetase deficiency: a biotin-responsive organic acidemia. J Pediatr. 1980 May. 96(5):845-9. [Medline].
Burri BJ, Sweetman L, Nyhan WL. Mutant holocarboxylase synthetase: evidence for the enzyme defect in early infantile biotin-responsive multiple carboxylase deficiency. J Clin Invest. 1981 Dec. 68(6):1491-5. [Medline].
Wolf B, Grier RE, Parker WD Jr, Goodman SI, Allen RJ. Deficient biotinidase activity in late-onset multiple carboxylase deficiency. N Engl J Med. 1983 Jan 20. 308(3):161. [Medline].
Tammachote R, Janklat S, Tongkobpetch S, Suphapeetiporn K, Shotelersuk V. Holocarboxylase synthetase deficiency: novel clinical and molecular findings. Clin Genet. 2010 Jul. 78(1):88-93. [Medline].
Zempleni J, Li Y, Xue J, Cordonier EL. The role of holocarboxylase synthetase in genome stability is mediated partly by epigenomic synergies between methylation and biotinylation events. Epigenetics. 2011 Jul. 6(7):892-4. [Medline]. [Full Text].
Bailey LM, Ivanov RA, Jitrapakdee S, Wilson CJ, Wallace JC, Polyak SW. Reduced half-life of holocarboxylase synthetase from patients with severe multiple carboxylase deficiency. Hum Mutat. 2008 Jun. 29(6):E47-57. [Medline].
Mayende L, Swift RD, Bailey LM, et al. A novel molecular mechanism to explain biotin-unresponsive holocarboxylase synthetase deficiency. J Mol Med (Berl). 2012 Jan. 90(1):81-8. [Medline].
Slavin TP, Zaidi SJ, Neal C, Nishikawa B, Seaver LH. Clinical Presentation and Positive Outcome of Two Siblings with Holocarboxylase Synthetase Deficiency Caused by a Homozygous L216R Mutation. JIMD Rep. 2013 Sep 13. [Medline].
De Castro M, Zand DJ, Lichter-Konecki U, Kirmse B. Severe neonatal holocarboxylase synthetase deficiency in west african siblings. JIMD Rep. 2015. 20:1-4. [Medline].
Wilson CJ, Myer M, Darlow BA, Stanley T, Thomson G, Baumgartner ER, et al. Severe holocarboxylase synthetase deficiency with incomplete biotin responsiveness resulting in antenatal insult in samoan neonates. J Pediatr. 2005 Jul. 147(1):115-8. [Medline].
Eldjarn L, Jellum E, Stokke O, Pande H, Waaler PE. Beta-hydroxyisovaleric aciduria and beta-methylcrotonylglycinuria: a new inborn error of metabolism. Lancet. 1970 Sep 5. 2(7671):521-2. [Medline].
Gompertz D, Draffan GH, Watts JL, Hull D. Biotin-responsive beta-methylcrotonylglycinuria. Lancet. 1971 Jul 3. 2(7714):22-4. [Medline].
Gompertz D, Goodey PA, Bartlett K. Evidence for the enzymic defect in beta-methylcrotonylglycinuria. FEBS Lett. 1973 May 15. 32(1):13-4. [Medline].
Malvagia S, Morrone A, Pasquini E, Funghini S, la Marca G, Zammarchi E, et al. First prenatal molecular diagnosis in a family with holocarboxylase synthetase deficiency. Prenat Diagn. 2005 Dec. 25(12):1117-9. [Medline].
Nyhan WL, Willis M, Barshop BA, Gangoiti J. Positive newborn screen in the biochemically normal infant of a mother with treated holocarboxylase synthetase deficiency. J Inherit Metab Dis. 2009 Apr 11. [Medline].
Pacheco-Alvarez D, Solorzano-Vargas RS, Gravel RA, Cervantes-Roldan R, Velazquez A, Leon-Del-Río A. Paradoxical regulation of biotin utilization in brain and liver and implications for inherited multiple carboxylase deficiency. J Biol Chem. 2004 Dec 10. 279(50):52312-8. [Medline].
Santer R, Muhle H, Suormala T, Baumgartner ER, Duran M, Yang X, et al. Partial response to biotin therapy in a patient with holocarboxylase synthetase deficiency: clinical, biochemical, and molecular genetic aspects. Mol Genet Metab. 2003 Jul. 79(3):160-6. [Medline].
Suormala T, Fowler B, Duran M, Burtscher A, Fuchshuber A, Tratzmüller R, et al. Five patients with a biotin-responsive defect in holocarboxylase formation: evaluation of responsiveness to biotin therapy in vivo and comparative biochemical studies in vitro. Pediatr Res. 1997 May. 41(5):666-73. [Medline].
Yang X, Aoki Y, Li X, Sakamoto O, Hiratsuka M, Kure S, et al. Structure of human holocarboxylase synthetase gene and mutation spectrum of holocarboxylase synthetase deficiency. Hum Genet. 2001 Nov. 109(5):526-34. [Medline].