Clinical and Laboratory Findings in Twins with Neonatal Epileptic Encephalopathy Mimicking Aromatic L-Amino Acid Decarboxylase Deficiency

 

 Buy Article Permissions and Reprints

Abstract

Aromatic L-amino acid decarboxylase (AADC) is a vitamin B₆ requiring enzyme involved in the biosynthesis of the neurotransmitters dopamine (DA) and serotonin. Lack of AADC leads to a combined deficiency of the catecholamines DA, norepinephrine (NE), epinephrine (E) as well as of serotonin. Here we describe premature twins who presented with severe seizures, myoclonus, rotatory eye movements and sudden clonic contractions. The patients showed an improvement of the clonic contractions under vitamin B₆ supplementation but died in the third week of life. In CSF and urine a biochemical pattern indicative of AADC deficiency was revealed. Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were decreased, in association with increased concentrations of 3-ortho-methyldopa (3-OMD) in CSF and significantly increased vanillactic acid in urine. The AADC enzyme substrates L-dopa and 5-hydroxytryptophan (5-HTP) were elevated in CSF. Elevated concentrations of threonine as well as of an unidentified compound in CSF rounded off the biochemical pattern. AADC activity was found to be increased in plasma and deficient in the liver. Molecular studies effectively ruled out a genetic defect in the AADC gene. The basis for the epileptic encephalopathy in the twins may be located in the metabolism of vitamin B₆ and remains to be defined.

References

• 1 Abeling N GGM, van Gennip A H, Barth P G, van Gruchten A, Westra M, Wijburg F A. Aromatic L-amino acid decarboxylase deficiency: a new case with a mild clinical presentation and unexpected laboratory findings.  J Inherit Metab Dis. 1998;  21 240-242
  CrossrefPubMedGoogle Scholar
• 2 Boosma F, Meerwaldt J D, Man int't Veld A J, Hovestadt A, Schalekamp M ADH. Induction of aromatic-L-amino acid decarboxylase by decarboxylase inhibitors in idiopathic parkinsonism.  Ann Neurol. 1989;  25 624-628
  CrossrefPubMedGoogle Scholar
• 3 Bremer H J, Duran M, Kamerling J P, Przyrembel H, Wadman S K. Disturbance of Amino Acid Metabolism: Clinical Chemistry and Diagnosis. Baltimore, Munich; Urban & Schwarzenberg 1981
  Google Scholar
• 4 Bräutigam C, Wevers R A, Hyland K, Sharma R K, Knust A, Hoffmann G F. The influence of L-dopa on methylation capacity in aromatic L-amino acid decarboxylase deficiency: biochemical findings in two patients.  J Inherit Metab Dis. 2000;  23 321-324
  CrossrefPubMedGoogle Scholar
• 5 Bräutigam C, Wevers R A, Jansen R JT, Smeitink J AM, Rijk-van Andel de J F, Gabreëls F JM. et al . Biochemical hallmarks of tyrosine hydroxylase deficiency.  Clin Chem. 1998;  44 1897-1904
  PubMedGoogle Scholar
• 6 Chang Y T, Mues G, McPherson J D, Bedell J, Marsh J L, Hyland K. Mutations in the human aromatic L-amino acid decarboxylase gene.  J Inherit Metab Dis. 1998;  21 4
  CrossrefPubMedGoogle Scholar
• 7 Cooper J R, Bloom F E, Roth R H. The Biochemical Basis of Neuropharmacology. New York, Oxford; Oxford University Press 1996
  Google Scholar
• 8 Fiumara A, Wevers R A, Barone R, Lagae L, Stoltenborg B, Nigros F. et al . Aromatic L-amino acid decarboxylase deficiency: the first italian case.  J Inherit Metab Dis. 1998;  21 5
  CrossrefPubMedGoogle Scholar
• 9 Hoffmann G F, Feyh P. Organic acid analysis. Blau N, Duran M, Gibson KM, Blaskovics ME Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases. Heidelberg; Springer (in press)
  Google Scholar
• 10 Hyland K, Biaggioni I, Elpeleg O N, Nygaard T G, Gibson K M. Disorders of neurotransmitter metabolism. Blau N, Duran M, Blaskovics ME Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases. London; Chapman & Hall Medica 1996: 79-98
  Google Scholar
• 11 Hyland K, Buist N RM, Powell B R, Hoffmann G F, Rating D, McGrath I. et al . Folinic acid responsive seizures: a new syndrome?.  J Inherit Metab Dis. 1995;  18 177-181
  CrossrefPubMedGoogle Scholar
• 12 Hyland K, Chang Y T, Arnold L A, Bräutigam C, Sharma R K, Hoffmann G. Aromatic L-amino acid decarboxylase deficiency responsive to levodopa: identification of an active site glycine in exon three.  J Inherit Metab Dis. 1998;  21 4
  CrossrefPubMedGoogle Scholar
• 13 Hyland K, Clayton P T. Aromatic amino acid decarboxylase deficiency in twins.  J Inherit Metab Dis. 1990;  13 301-304
  CrossrefPubMedGoogle Scholar
• 14 Hyland K, Clayton P T. Aromatic L-amino acid decarboxylase deficiency: diagnostic methodology.  Clin Chem. 1992;  38 2405-2410
  PubMedGoogle Scholar
• 15 Hyland K, Surtees R AH, Rodeck C, Clayton P T. Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis.  Neurology. 1992;  42 1980-1988
  CrossrefPubMedGoogle Scholar
• 16 Korenke G C, Christen H J, Hyland K, Hunneman D H, Hanefeld F. Aromatic L-amino acid decarboxylase deficiency: an extrapyramidal movement disorder with oculogyric crises.  Eur J Ped Neurol. 1997;  2 67-71
  PubMedGoogle Scholar
• 17 Maller A, Hyland K, Milstien S, Biaggioni I, Butler I J. Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a second family.  J Child Neurology. 1996;  12 349-354
  PubMedGoogle Scholar
• 18 Sumi-Ichinose C, Ichinose H, Takahashi E, Hori T, Nagatsu T. Molecular cloning of genomic DNA and chromosomal assignment of the gene for human aromatic L-amino acid decarboxylase, the enzyme for catecholamine and serotonine biosynthesis.  Biochemistry. 1992;  31 2229-2238
  CrossrefPubMedGoogle Scholar
• 19 Surtees R, Hyland K. L-3, 4-Dihydroxyphenylalanine (levodopa) lowers central nervous system S-adenosylmethionine concentrations in humans.  J Neurol Neurosurg Psychiatry. 1990;  53 569-572
  PubMedGoogle Scholar
• 20 Swoboda K J, Hyland K, Goldstein D S, Kuban K CK, Arnold L A, Holmes C S. et al . Clinical and therapeutic observations in aromatic L-amino acid decarboxylase deficiency.  Neurology. 1999;  53 1205-1211
  PubMedGoogle Scholar
• 21 Torres O A, Miller V S, Buist N MR, Hyland K. Folinic acid neonatal seizures.  J Child Neurology. 1999;  14 529-532
  PubMedGoogle Scholar

Prof. G. F. Hoffmann

Department of Pediatrics I
University Children's Hospital

Im Neuenheimer Feld 153

69120 Heidelberg

Germany

Email: georg_hoffmann@med.uni-heidelberg.de