Isolated Neonatal Seizures: Adenylosuccinase Deficiency is Another Cause!

Abstract

I read with great interest the very useful review “Isolated Neonatal Seizures: When to Suspect Inborn Errors of Metabolism” by Ficicioglu and Bearden [ [1] Ficicioglu C. Bearden D. Isolated neonatal seizures: When to suspect inborn errors of metabolism. Pediatr Neurol. 2011; 45: 283-291 Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar ]. I would like to add adenylosuccinase deficiency to their causes for suspicion. This genetic, mainly neurologic disorder of the de novo purine synthesis was first reported in 1984 [ [2] Jaeken J. van den Berghe G. An infantile autistic syndrome characterized by the presence of succinylpurines in body fluids. Lancet. 1984; 2: 1058-1061 PubMed Google Scholar ]. Most of the approximately 60 reported patients demonstrate variable associations of moderate to severe psychomotor retardation, epilepsy after their first years, autistic features, and growth retardation [ [3] van den Berghe G. Vincent M.-F. Marie S. Disorders of purine and pyrimidine metabolism. in: Saudubray J.-M. van den Berghe G. Walter J.H. Inborn metabolic diseases: Diagnosis and treatment. 5th ed. Springer-Verlag, Berlin2012: 499-518 Crossref Scopus (11) Google Scholar ]. However, a subgroup of patients presents with intractable seizures beginning within the first days or weeks of age [ [4] Mouchegh K. Zikánová M. Hoffmann G.F. et al. Lethal fetal and early neonatal presentation of adenylosuccinate lyase deficiency: Observation of 6 patients in 4 families. J Pediatr. 2007; 150: 57-61 Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar ]. Often severe hypotonia is associated such as seen, e.g., in nonketotic hyperglycinemia and γ-aminobutyric acid transaminase deficiency, as mentioned by Ficicioglu and Bearden [ [1] Ficicioglu C. Bearden D. Isolated neonatal seizures: When to suspect inborn errors of metabolism. Pediatr Neurol. 2011; 45: 283-291 Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar ]. These seizures can lead to death or severe mental retardation. In some patients, intrauterine growth retardation, microcephaly, fetal hypokinesia, and a lack of fetal heart rate variability have also been observed. Adenylosuccinase catalyzes two steps in purine synthesis: the conversion of succinyl aminoimidazole carboxamide ribotide to aminoimidazole carboxamide ribotide (in the de novo pathway), and the conversion of adenylosuccinate to adenosine monophosphate. Its deficiency results in the accumulation in body fluids of succinyl purines, i.e., succinyl aminoimidazole carboxamide riboside and succinyl adenosine (the dephosphorylated substrates of the enzyme). A modified Bratton-Marshall (colorimetric) test performed on urine can be used as a screening test, but some medications such as sulfonamides cause a false-positive result. A final diagnosis requires high-pressure liquid chromatography with ultraviolet light detection, or high-pressure liquid chromatography with electrospray ionization tandem mass spectroscopy. Isolated Neonatal Seizures: When to Suspect Inborn Errors of MetabolismPediatric NeurologyVol. 45Issue 5PreviewNeonatal seizures are common, and often comprise the first clinical indicator of central nervous system dysfunction. Although most neonatal seizures are secondary to processes such as hypoxic-ischemic injury, infection, or cortical malformations (which are readily identifiable through routine testing and imaging), seizures secondary to inborn errors of metabolism can be much more difficult to diagnose, and thus a high index of suspicion is required. The early diagnosis of inborn errors of metabolism is crucial, considering that many can receive effective treatment (e.g., dietary supplementation or restriction) with favorable long-term outcomes. Full-Text PDF ResponsePediatric NeurologyVol. 47Issue 3PreviewWe thank Dr. Jaaken for his insightful discussion of adenylosuccinase deficiency as a cause of neonatal seizures. Our review was intended to offer an overview of metabolic disorders presenting with isolated neonatal seizures, i.e., neonatal seizures not associated with other characteristic abnormalities. Dr. Jaaken is correct in observing that neonatal seizures may constitute an atypical presentation of this rare disease, with six cases reported in the literature [1]. However, the severe form of adenylosuccinase deficiency that presents with neonatal seizures is often accompanied by severe hypotonia, intrauterine growth retardation, and magnetic resonance imaging abnormalities that are variable but that generally include dysmyelination [2]. Full-Text PDF