Holocarboxylase Synthetase Deficiency Clinical Presentation

  • Author: Karl S Roth, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Apr 2, 2012
 

History

  • 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.
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Physical

  • 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.
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Causes

  • 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.
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Contributor Information and Disclosures
Author

Karl S Roth, MD  Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Christian J Renner, MD  Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Margaret M McGovern, MD, PhD  Professor and Chair of Pediatrics, Stony Brook University, New York

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics

Disclosure: Genzyme Grant/research funds PI

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

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  2. 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. Dec 1979;64(6):1695-702. [Medline].

  3. Roth KS, Yang W, Foremann JW, Rothman R, Segal S. Holocarboxylase synthetase deficiency: a biotin-responsive organic acidemia. J Pediatr. May 1980;96(5):845-9. [Medline].

  4. 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. Dec 1981;68(6):1491-5. [Medline].

  5. Wolf B, Grier RE, Parker WD Jr, Goodman SI, Allen RJ. Deficient biotinidase activity in late-onset multiple carboxylase deficiency. N Engl J Med. Jan 20 1983;308(3):161. [Medline].

  6. Tammachote R, Janklat S, Tongkobpetch S, Suphapeetiporn K, Shotelersuk V. Holocarboxylase synthetase deficiency: novel clinical and molecular findings. Clin Genet. Jul 2010;78(1):88-93. [Medline].

  7. 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. Jul 2011;6(7):892-4. [Medline]. [Full Text].

  8. 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. Jun 2008;29(6):E47-57. [Medline].

  9. [Guideline] Cunniff C. Prenatal screening and diagnosis for pediatricians. Pediatrics. Sep 2004;114(3):889-94. [Medline]. [Full Text].

  10. 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. Jul 2005;147(1):115-8. [Medline].

  11. Eldjarn L, Jellum E, Stokke O, Pande H, Waaler PE. Beta-hydroxyisovaleric aciduria and beta-methylcrotonylglycinuria: a new inborn error of metabolism. Lancet. Sep 5 1970;2(7671):521-2. [Medline].

  12. Gompertz D, Draffan GH, Watts JL, Hull D. Biotin-responsive beta-methylcrotonylglycinuria. Lancet. Jul 3 1971;2(7714):22-4. [Medline].

  13. Gompertz D, Goodey PA, Bartlett K. Evidence for the enzymic defect in beta-methylcrotonylglycinuria. FEBS Lett. May 15 1973;32(1):13-4. [Medline].

  14. 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. Dec 2005;25(12):1117-9. [Medline].

  15. 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. Apr 11 2009;[Medline].

  16. 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. Dec 10 2004;279(50):52312-8. [Medline].

  17. 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. Jul 2003;79(3):160-6. [Medline].

  18. 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. May 1997;41(5):666-73. [Medline].

  19. 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. Nov 2001;109(5):526-34. [Medline].

 
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Urea cycle. Compounds that comprise the urea cycle are numbered sequentially, beginning with carbamyl phosphate. At the first step (1), the first waste nitrogen is incorporated into the cycle; also at this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamyl phosphate synthetase (CPS). Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (4); the reaction is mediated by argininosuccinate (ASA) synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.
 
 
 
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