Pediatric neurotransmitter diseases

Abstract

The pediatric neurotransmitter disorders represent a challenging group of rare neurometabolic disorders classified on the basis of alterations in neurotransmitter metabolic pathways. The disorders are currently classified into disturbances of monoamine and gamma-aminobutyric acid (GABA) metabolism, although disorders of other neurotransmitters, such as glutamate and melatonin, may well be recognized in future investigations. This review summarizes the clinical and laboratory features of selected pediatric neurotransmitter disorders that have been partially delineated. Of the monoamine group, these are Segawa disease or guanosine triphosphate-cyclohydrolase I deficiency, aromatic L-amino acid decarboxylase deficiency, and tyrosine hydroxylase deficiency. Of the GABA disorders, these are pyridoxine-dependent epilepsy, GABA transaminase deficiency, and succinic semialdehyde dehydrogenase deficiency. As proper collection, handling, and interpretation of cerebrospinal fluid is required for assessment of most of these disorders, we end by summarizing important considerations for obtaining cerebrospinal fluid samples.

This is a preview of subscription content, access via your institution.

References and Recommended Reading

  1. 1.

    DeVivo DC, Johnston MV (eds): Pediatric neurotransmitter disorders. Ann Neurol 2003, 53(supp):1–109. Monograph devoted to clinical and basic science aspects of the PNDs, representing proceedings of a symposium held during May 2002 and cosponsored by the Pediatric Neurotransmitter Diseases Association and the National Institutes of Health.

  2. 2.

    Segawa M, Nomura Y, Nishiyama N: Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease). Ann Neurol 2003, 54(suppl 6):S32-S45.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Steinberger D, Korinthenberg R, Topka H, et al.: Dopa-responsive dystonia: mutation analysis of GCH-1 and analysis of therapeutic doses of L-dopa. Neurology 2000, 55:1735–1737.

    PubMed  CAS  Google Scholar 

  4. 4.

    Nikhar NK, Mani H: Dopamine responsive dystonia. eMedicine. November, 2001.

  5. 5.

    Bandmann O, Wood NW: Dopa-responsive dystonia—]the story so far. Neuropediatrics 2002, 33:1–5.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Furukawa Y, Nygaard Tg, Gutlich M, et al.: Striatal biopterin and tyrosine hydroxylase protein reduction in dopa-responsive dystonia. Neurology 1999, 53:1032–1041.

    PubMed  CAS  Google Scholar 

  7. 7.

    Segawa M, Nomura Y, Kase M: Diurnally fluctuating hereditary progessive dystonia. In Handbook of Clinical Neurology: Extrapyramidal Disorders, vol 5. Edited by Vinken PJ, Bruyn GW, Klawans HL. Amsterdam: Elsevier; 1986:529–539.

    Google Scholar 

  8. 8.

    Maller A, Hyland K, Gutlich M, et al.: Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a second family. J Child Neurol 1997, 12:349–354.

    PubMed  CAS  Google Scholar 

  9. 9.

    Hyland K, Clayton PT: Aromatic amino acid decarboxylase deficiency in twins. J Inherit Metab Dis 1990, 13:301–304.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Swoboda K, Saul JP, McKenna CE, et al.: Aromatic L-amino acid decarboxylase deficiency. Overview of clinical features and outcomes. Ann Neurol 2003, 54(suppl 6):S49-S55.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Hoffmann G, Assman B, Brautigam C, et al.: Tyrosine hydroxylase deficiency causes progressive encephalopathy and doparesponsive dystonia. Ann Neurol 2003, 54(suppl 6):S56-S65.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Grattan-Smith PJ, Wevers RA, Steenbergen-Spanjers GC, et al.: Tyrosine hydroxylase deficiency: clinical manifestations of catecholamine insufficiency in infancy. Mov Disord 2002, 17:354–359.

    PubMed  Article  Google Scholar 

  13. 13.

    Gospe SM, Hecht ST: Longitudinal MR findings in pyridoxinedependent seizures. Neurology 1998, 51:74–78.

    PubMed  Google Scholar 

  14. 14.

    Gospe SM: Current Perspectives on pyridoxine-dependent seizures. J Pediatr 1998, 132:919–923.

    PubMed  Article  Google Scholar 

  15. 15.

    Gutieres F, Aicardi J: Atypical presentations of pyridoxinedependent seizures: a treatable cause of intractable epilepsy in infants. Ann Neurol 1985, 17:117–120.

    Article  Google Scholar 

  16. 16.

    Burd L, Stenehjem A, Franceschini LA, Kerbeshian J: A 15 year follow-up of a boy with pyridoxine dependent seizures with autism, breath holding and severe mental retardation. J Child Neurol 2000, 15:763–765.

    PubMed  CAS  Article  Google Scholar 

  17. 17.

    Baxter P, Griffiths P, Kelly T, Gardner-Medwin D: Pyridoxinedependent seizures: demographic clinical, MRI and psychometric features, and effect of dose on intelligence quotient. Dev Med Child Neurol 1996, 38:998–1001.

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Mikati MA, Trevathen E, Krishnamoorthy KS, Lombroso CT: Pyidoxine-dependent epilepsy: EEG investigations and long-term follow-up. Electroencephalogr Clin Neurophysiol 1991, 78:215–222.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Tanaka R, Okumura M, Arima J, et al.: Pyridoxine-dependent seizures: report of a case with atypical clinical features and abnormal MRI scans. J Child Neurol 1992, 7:24–28.

    PubMed  CAS  Google Scholar 

  20. 20.

    Lombroso CT: Neonatal polygraph in full term and premature infants: review of normal and abnormal findings. J Clin Neurophysiol 1985, 2:105–155.

    PubMed  CAS  Article  Google Scholar 

  21. 21.

    Nunes ML, Mugnol F, Bica I, Fiori RM: Pryidoxine-dependent seizures associated with hypophosphatemia in a newborn. J Child Neurol 2002, 17:222–224.

    PubMed  Google Scholar 

  22. 22.

    Ulvi H, Mungen B, Yakinci C, Yoldas T: Pyridoxine-dependent seizures: long-term follow-up of two cases with clinical and MRI findings, pyridoxine treatment. J Trop Pediatr 2002, 48:303–306.

    PubMed  Article  Google Scholar 

  23. 23.

    Medina-Kauwe LK, Nyhan WL, Gibson KM, Tobin AJ: Identification of a familial mutation associated with GABA-transaminase deficiency disease. Neurobiol Dis 1998, 5:89–96.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Schor DS, Struys EA, Hogema BM, et al.: Development of a stable-isotope dilution assay for GABA transaminase in isolated leukocytes and evidence that GABA and B-alanine transaminases are identical. Clin Chem 2001, 47:525–531.

    PubMed  CAS  Google Scholar 

  25. 25.

    Osei YD, Churchich JE: Screening and sequence determination of a cDNA encoding the human brain 4-aminobutyrate aminotransferase. Gene 1995, 155:155–187.

    Article  Google Scholar 

  26. 26.

    Jaeken J, Casaer P, de Cock P, et al.: Gamma-aminobutyric acid transaminase deficiency: a newly recognized inborn error of metabolism. Neuropediatrics 1984, 15:165–169.

    PubMed  CAS  Article  Google Scholar 

  27. 27.

    Medina-Kauwe LK, Tobin AJ, De Meirleir L, et al.: 4-Aminobutyrate aminotransferase (GABA-transaminase) deficiency. J Inherit Metab Dis 1999, 22:414–427.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Gibson KM, Sweetman L, Nyhan WL, Jansen I, et al.: Demonstration of 4-aminobutyric acid aminotransferase deficiency in lymphocytes and lymphoblasts. J Inherit Metab Dis 1985, 8:204–208.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Gibson KM, Aramaki S, Sweetman L, et al.: Stable isotope dilution analysis of 4-hydroxybutyric acid:an accurate method for quantification in physiological fluids and the prenatal diagnosis of 4-hydroxybutyric aciduria. Biomed Environ Mass Spectrom 1990, 19:89–93.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Trettel F, Malaspina P, Jodice C, et al.: Human succinic semialdehyde dehydrogenase. Molecular cloning and chromosomal localization. Adv Exp Med Biol 1997, 414:253–260.

    PubMed  CAS  Google Scholar 

  31. 31.

    Gibson KM, Jakobs C: Disorders of beta- and gamma-amino acids in free and peptide linked forms. In The Metabolic and Molecular Bases of Inherited Disease, edn 8. Edited by Scriver CR, Beaudet AL, Valle D, Sly WS. New York: McGrw-Hill; 2000:2079–2105. Comprehensive discussion of GABA metabolism and associated disorders.

    Google Scholar 

  32. 32.

    Pearl PL, Novotny EJ, Acosta MT, et al.: Succinic semialdehyde dehydrogenase deficiency in children and adults. Ann Neurol 2003, 54(suppl 6):S73-S80.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Gibson KM, Hoffman G: Acidemia, gamma-hydroxybutyric. In Birth Defects Encyclopedia. Edited by Buyse ML. Cambridge, MA: Blackwell Scientific; 1990:17–18.

    Google Scholar 

  34. 34.

    Jakobs C, Jaeken J, Gibson KM: Inherited disorders of GABA metabolism. J Inherit Metab Dis 1993, 16:704–715.

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Pearl PL, Tuchman M: Succinic semialdehyde dehydrogenase deficiency: a potentially treatable cause of mental retardation and autistic behaviors. Ann Neurol 2001, 50:S115.

    Article  Google Scholar 

  36. 36.

    Hyland K: The lumbar puncture for the diagnosis of pediatric neurotransmitter disease. Ann Neurology 2003, 54(suppl 6):S13-S17. Discussion of interpretation and practical considerations in use of CSF for diagnosis, authored from the leading laboratory for clinical studies.

    Article  CAS  Google Scholar 

  37. 37.

    Pearl PL, Gibson KM, Acosta MT, et al.: Clinical spectrum of succinic semialdehyde dehydrogenase deficiency. Neurology 2003, 60:1413–1417. New cohort of patients and literature review of clinical, laboratory, and radiographic features.

    PubMed  CAS  Google Scholar 

  38. 38.

    Hyland K, Nygaard TG, Trugman JM, et al.: Oral phenyalanine loading profiles in symptomatic and asymptomatic gene carriers with dopa-responsive dystonia due to dominantly inherited GTP cyclohydroxylase deficiency. J Inherit Metab Dis 1999, 22:213–215.

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Hyland K, Clayton PT: Aromatic L-amino acid decarboxylase deficiency: diagnostic methodology. Clin Chem 1992, 38:2405–2410.

    PubMed  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pearl, P.L., Wallis, D.D. & Gibson, K.M. Pediatric neurotransmitter diseases. Curr Neurol Neurosci Rep 4, 147–152 (2004). https://doi.org/10.1007/s11910-004-0029-1

Download citation

Keywords

  • Dystonia
  • Neopterin
  • Biopterin
  • Oculogyric Crisis
  • SSADH Deficiency