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UTILITY OF THE MEASUREMENT OF MONOAMINE NEUROTRANSMITTER METABOLITES AND OTHER SPECIFIC BIOMARKERS IN CSF FROM INFANTS AND CHILDREN WITH EARLY ONSET EPILEPSY [P05.087]
Keith Hyland, Lauren Hyland, John Shoffner, Atlanta, GA
Assessment of monoamine metabolites in samples of cerebrospinal fluid (CSF) makes it possible to identify specific causes of monoamine deficiency in children with movement disorders and other neurologic conditions.1,2 In this poster, Hyland et al describe their efforts to use biochemical analysis of CSF samples to determine the etiology of seizures in infants and children. The investigators demonstrated that examination of CSF monoamine metabolites and other biomarkers may be used to distinguish different causes of seizure disorders from one another in pediatric patients. These observations are significant because some of these etiologies have potential interventions, and because the findings may have implications for families planning to have additional children.
Pyridoxine-dependent epilepsy and folinic acid seizures are potentially reversible causes of neonatal seizures that have both been attributed to mutations of the ALDH7A1 (antiquitin) gene. This mutation results in the deficiency of α-aminoadipic semialdehyde (α-AASA) dehydrogenase, an enzyme that is important in lysine degradation.3 In their poster, the investigators describe 13 children with ALDHA7A1 mutations and initially intractable seizures who subsequently responded to pyridoxine. Separation of CSF neurotransmitter metabolites using high pressure liquid chromatography (HPLC) demonstrated 2 distinct peaks in all 13 patients. Although the presenters noted that the chemical identities of these peaks have not yet been determined, the characteristic HPLC pattern provides an additional tool for the diagnosis of pyridoxine-responsive seizures in children.
The presenters also examined biochemical changes related to pyridoxine phosphate oxidase (PNPO) deficiency. The lack of this enzyme results in abnormally low synthesis of pyridoxal 5’-phosphate (PLP) from dietary pyridoxine.4 PLP is a cofactor for another enzyme (aromatic L-amino acid decarboxylase) that is required for the synthesis of dopamine and serotonin, and PLP deficiency is also associated with elevated levels of the amino acids threonine and glycine. HPLC analysis revealed that PNPO deficiency was associated with a characteristic pattern of biochemical changes that included low levels of serotonin and dopamine metabolites (5-hydroxyindoleacetic acid [5-HIAA] and homovanillic acid [HVA], respectively), and elevated levels of 3-O-methyldopa.
Adenylosuccinate lyase deficiency is a pediatric metabolic disorder with a variable clinical presentation that may include seizures, autism, psychomotor retardation, and hypotonia.5 In this poster, the investigators found that adenylosuccinate lyase deficiency was associated with a characteristic large increase in succinyladenosine on HPLC, compared with normal control values. However, they noted that many drugs also elute within this same HPLC region, and a specific test for succinyladenosine is therefore required to diagnose this condition.
High pressure liquid chromatography may also be used to establish whether the patient had neonatal hypoxia. The presenters noted that hypoxia produces profound reduction or elimination of several distinct HPLC peaks, including the catecholamine metabolites HVA and 5-HIAA. The loss of catecholamine metabolites was much more pronounced in hypoxia than in the children with PNPO deficiency described previously. Biochemical analysis of CSF samples from patients with neonatal hypoxia also revealed a significant loss of tetrahydrobiopterin, a cofactor that is required for the synthesis of dopamine and serotonin.
Finally, the investigators noted that HPLC can provide evidence for aberrant central nervous system (CNS) immune activation by assessing the CSF concentration of neopterin, a protein that is released from astrocytes and macrophages upon stimulation by interferon γ. Elevated levels of neopterin suggest that neurologic symptoms are caused by an underlying immunologic disorder.
The results of the studies presented in this poster demonstrate that the testing of CSF samples can help to establish the cause of seizure disorders in young children including several monoamine neurotransmitter deficits, neonatal hypoxia, CNS infections, and other pathologic processes. However, the authors do not provide information about how frequently the tests actually lead to a specific diagnosis.6
References
1. Hyland K. Presentation, diagnosis, and treatment of the disorders of monoamine neurotransmitter metabolism. Semin Perinatol. 1999;23:194-203.
2. Hyland K. Clinical utility of monoamine neurotransmitter metabolite analysis in cerebrospinal fluid. Clin Chem. 2008;54:633-641.
3. Gallagher RC, Van Hove JL, Scharer G, et al. Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy. Ann Neurol. 2009;65:550-556.
4. Mills PB, Surtees RA, Champion MP, et al. Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5’-phosphate oxidase. Hum Mol Genet. 2005;14:1077-1086.
5. Spiegel EK, Colman RF, Patterson D. Adenylosuccinate lyase deficiency. Mol Genet Metab. 2006;89:19-31.
6. Echenne B, Roubertie A, Leydet J, et al. Monoamine metabolism study in severe, early-onset epilepsy in childhood. Epileptic Disord. 2008;10:130-135.
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