Adenylosuccinase Deficiency with Neonatal Onset Severe Epileptic Seizures and Sudden Death

Bergh, F. A. van den; Bosschaart, A.N; Hageman, G.; Duran, Marcos Henrique Coelho; Poll-Thé, Bwee Tien

doi:10.1055/s-2007-973536

Cited by 36 publications

(11 citation statements)

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“…Seizures, if present, appear later, often between the second and fourth year of life [2,10]. Recently, a larger number of patients with a neonatal form have been reported [10,11,14,17,22]. These patients presented with fatal neonatal encephalopathy with a lack of spontaneous movement, respiratory failure, and intractable seizures resulting in early death within the first weeks of life.…”

Section: Introductionmentioning

confidence: 99%

Magnetic resonance imaging of the brain in adenylosuccinate lyase deficiency: a report of seven cases and a review of the literature

2011

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Adenylosuccinate lyase (ADSL) deficiency is a rare autosomal recessive disorder of purine metabolism. Patients may present with a wide range of neurological symptoms. Head imaging abnormalities have been reported only rarely in the scientific literature and include atrophy of the cerebral cortex, corpus callosum, cerebellar vermis, lack of myelination, delayed myelination, anomalies of the white matter, and lissencephaly. The pathogenesis of abnormalities remains unknown. To further the understanding of the spectrum of brain abnormalities associated with ADSL deficiency, we examined the magnetic resonance findings in seven Polish patients with different clinical phenotypes and genotypes. Head MRI showed impaired white matter myelination with various degrees of global supra- and infratentorial white matter loss including widening of the lateral ventricles, enlargement of the subarachnoid spaces, atrophy of the cerebrum, hypoplasia of the cerebellar hemispheres and enlargement of the cisterna magna, and white matter abnormal hyperintense signal on T(2)-weighted sequences. We recommend performing a detailed analysis of urine and plasma purine metabolites in patients who have neurological findings, including developmental delay, microcephaly, autistic features, neonatal encephalopathy, and seizures especially if MRI findings such as delayed or lack of myelination, white matter abnormal signal, and atrophy of the cerebrum and/or cerebellum are also present. Greater awareness of adenylosuccinate lyase deficiency among general pediatricians, neonatologists, pediatric neurologists, and also radiologists is the key to identifying the disorder at an early stage.

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Section: Introductionmentioning

confidence: 99%

Magnetic resonance imaging of the brain in adenylosuccinate lyase deficiency: a report of seven cases and a review of the literature

2011

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“…Symptoms range in severity from mild to severe and are negatively correlated with the degree of residual ADSL activity (6). In the most extreme cases, ASLD is neonatally fatal due to prenatal growth restriction, encephalopathy, and intractable seizures (6,7). This autosomal recessive neurometabolic disorder has been reported in over 50 patients since its original characterization in 1969; for these cases, over 40 separate mutations in adenylosuccinate lyase (ADSL) are associated with the disease state (8–10).…”

Section: Introductionmentioning

confidence: 99%

ACaenorhabditis elegansmodel of adenylosuccinate lyase deficiency reveals neuromuscular and reproductive phenotypes of distinct etiology

Janowitz

et al. 2017

Preprint

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22Inborn errors of purine metabolism are rare syndromes with an array of complex phenotypes in 23 humans. One such disorder, adenylosuccinate lyase deficiency (ASLD), is caused by a decrease in the 24 activity of the bi-functional purine biosynthetic enzyme, adenylosuccinate lyase (ADSL). Mutations in 25 human ADSL cause epilepsy, muscle ataxia, and autistic-like symptoms. Although the genetic basis of 26 ASLD syndrome is known, the molecular mechanisms driving phenotypic outcome are not. Here, we 27 characterize neuromuscular and reproductive phenotypes associated with a deficiency of adsl-1 in 28Caenorhabditis elegans. Characterization of the neuromuscular phenotype reveals a disruption of 29 cholinergic transmission affecting muscular contraction. Using genetics, pharmacological 30 supplementation, and metabolite measurements, we correlate phenotypes with distinct metabolic 31 perturbations. The neuromuscular defect is associated with a toxic accumulation of a purine biosynthetic 32 intermediate whereas the reproductive defect can be ameliorated by purine supplementation, indicating 33 differing molecular mechanisms behind the phenotypes of ASLD. Because purine metabolism is highly 34 conserved in metazoans, we suggest that similar separable metabolic perturbations result in the varied 35 symptoms in the human disorder and that a dual-approach therapeutic strategy may be beneficial. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/181719 doi: bioRxiv preprint first posted online 3 Author summary 41Adenylosuccinate lyase deficiency is a rare metabolic disorder that is associated with epilepsy, 42 muscle ataxia, and autistic-like symptoms in humans. This disorder arises from mutations in 43 adenylosuccinate lyase, an enzyme involved in purine nucleotide biosynthesis. While we understand the 44 genetic basis of this disorder, the mechanism of pathogenesis is unknown. Moreover, the linkage between 45 phenotype and metabolic perturbation remains unclear. We report here on neuromuscular and 46 reproductive phenotypes caused by a deficiency of adsl-1 in Caenorhabditis elegans. For each defect, we 47 identified a specific metabolic perturbation that causes the phenotype. The neuromuscular phenotype is 48 associated with a toxic accumulation of a purine metabolic intermediate whereas the reproductive 49 phenotype can be alleviated by purine supplementation. Our results point to separate molecular 50 mechanisms as causative for the phenotypes, suggesting that there may be a similar relationship between 51 phenotype and metabolic perturbation in humans. As such, our model suggests the use of a multi-pronged 52 approach in humans to therapeutically target the metabolic perturbation contributing to each symptom. 53 55All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display t...

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“…No treatment of ADSL de®ciency is presently available, and its prognosis for survival is very variable. Some mildly retarded patients have reached adult age, but several children, particularly those presenting with severe epilepsy within the ®rst days to weeks of life, have died at a few months of age (Van den Bergh et al, 1998;Ko È hler et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Prenatal diagnosis in adenylosuccinate lyase deficiency

et al. 2000

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Adenylosuccinate lyase deficiency, an autosomal recessive inborn error of purine synthesis, provokes accumulation in body fluids of succinylaminoimidazolecarboxamide riboside and succinyladenosine, the dephosphorylated derivatives of the two substrates of the enzyme. Most patients display severe psychomotor retardation, often accompanied by epilepsy and/or autistic features, although some are only mildly retarded. About 20 mutations are known. Prenatal diagnosis was performed twice on chorion villi of the mother of a previously diagnosed patient with a C5T mutation (exon 1) on the maternal allele, and a C1185A mutation (exon 11) on the paternal allele. Both suppress a Fnu4HI restriction site. In a first fetus, incubation of PCR products generated from genomic DNA of exon 1 with Fnu4HI yielded a 113 bp fragment from a control and the father's gene, and both a 113 bp and 170 bp fragment from the mother, affected sibling and fetus. Incubation of PCR products of exons 11-12 with Fnu4HI yielded a 550 bp fragment from a control and the mother's gene, and a 550 bp and 600 bp fragment from the father, affected sibling and fetus. Assay of adenylosuccinate lyase on the aborted fetal liver confirmed the enzyme deficiency. A second fetus displayed only the maternal mutation.

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Adenylosuccinase Deficiency with Neonatal Onset Severe Epileptic Seizures and Sudden Death

Cited by 36 publications

References 0 publications

Magnetic resonance imaging of the brain in adenylosuccinate lyase deficiency: a report of seven cases and a review of the literature

Magnetic resonance imaging of the brain in adenylosuccinate lyase deficiency: a report of seven cases and a review of the literature

ACaenorhabditis elegansmodel of adenylosuccinate lyase deficiency reveals neuromuscular and reproductive phenotypes of distinct etiology

Prenatal diagnosis in adenylosuccinate lyase deficiency

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