Clinical Findings and a Therapeutic Trial in the First Patient with β-Ureidopropionase Deficiency

Assmann, Birgit; Göhlich, G.; Baethmann, Martina; Wevers, Ron A.; Gennip, A. H. van; Kuilenburg, André B. P.; Dietrich, C. F.; Wagner, L; Rotteveel, J.J.; Schaper, J.; Mayatepek, Ertan; Hoffmann, G. F.; Voït, Thomas

doi:10.1055/s-2006-923933

Cited by 19 publications

(8 citation statements)

References 22 publications

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“…However, the concentration of N-carbamyl--alanine is only marginally elevated in the CSF of individuals affected by BUP-1 deficiency, which seems to argue against a direct role of this metabolite in the neuropathology [252], while -AIB is markedly reduced suggesting that -AIB homeostasis may underlie some of the neurological manifestations, as also hypothesized for DPD and DHP deficiency. The hypothesis that intracerebral deficiency of -alanine might have a role in this neuropathology led to a therapeutic trial with supplementation of -alanine in one patient, with no convincing clinical improvement [256]. Increased oxidative stress might play a role as well, since increased amounts of 5-hydroxymethyluracil and 8-hydroxydeoxyguanosine, metabolites indicating oxidative damage, have been found in some patients with BUP-1 deficiency [252].…”

Section: -Ureidopropionase Deficiencymentioning

confidence: 99%

Neurological Disorders of Purine and Pyrimidine Metabolism

Micheli

Camici²,

Tozzi³

et al. 2011

CTMC

101

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Purines and pyrimidines, regarded for a long time only as building blocks for nucleic acid synthesis and intermediates in the transfer of metabolic energy, gained increasing attention since genetically determined aberrations in their metabolism were associated clinically with various degrees of mental retardation and/or unexpected and often devastating neurological dysfunction. In most instances the molecular mechanisms underlying neurological symptoms remain undefined. This suggests that nucleotides and nucleosides play fundamental but still unknown roles in the development and function of several organs, in particular central nervous system. Alterations of purine and pyrimidine metabolism affecting brain function are spread along both synthesis (PRPS, ADSL, ATIC, HPRT, UMPS, dGK, TK), and breakdown pathways (5NT, ADA, PNP, GCH, DPD, DHPA, TP, UP), sometimes also involving pyridine metabolism. Explanations for the pathogenesis of disorders may include both cellular and mitochondrial damage: e.g. deficiency of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase and deoxyguanosine kinase are associated to the most severe pathologies, the former due to an unexplained adverse effect exerted on the development and/or differentiation of dopaminergic neurons, the latter due to impairment of mitochondrial functions. This review gathers the presently known inborn errors of purine and pyrimidine metabolism that manifest neurological syndromes, reporting and commenting on the available hypothesis on the possible link between specific enzymatic alterations and brain damage. Such connection is often not obvious, and though investigated for many years, the molecular basis of most dysfunctions of central nervous system associated to purine and pyrimidine metabolism disorders are still unexplained.

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Section: -Ureidopropionase Deficiencymentioning

confidence: 99%

Neurological Disorders of Purine and Pyrimidine Metabolism

Micheli

Camici²,

Tozzi³

et al. 2011

CTMC

101

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“…This table also includes 15 patients (from 12 families) with βUP deficiency, and previously published mutations (Assmann et al 1998; Assmann et al 2006; van Kuilenburg et al 2012; Yaplito-Lee et al 2008). All 13 Japanese patients were carriers of the c.977G > A (p.R326Q) mutation, with eight patients being homozygous for this mutation (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…[105-2A > G] + [105-2A > G]splicingInt 1van Kuilenburg 2004 Germany−M0.9NASeizures, MC, MR, hypotoniac. [917-1G > A] + [917-1G > A]splicingInt 8Assmann et al 2006; van Kuilenburg 2004 African−F1.0NASeizuresc. [254C > A] + [254C > A]p.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, altered β-aminoisobutyric acid homeostasis in patients with pyrimidine degradation defects may contribute to neurological abnormalities. Treatment of a ßUP-deficient patient with ß-alanine for over 1.5 years did not result in a clinical improvement (Assmann et al 2006). So far, the clinical effect of ß-aminoisobutyric acid supplementation has not been investigated in ßUP-deficient patients.…”

Section: Discussionmentioning

confidence: 99%

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Clinical, biochemical and molecular analysis of 13 Japanese patients with β‐ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation

Nakajima

Meijer

Dobritzsch

et al. 2014

J of Inher Metab Disea

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β-ureidopropionase (βUP) deficiency is an autosomal recessive disease characterized by N-carbamyl-β-amino aciduria. To date, only 16 genetically confirmed patients with βUP deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 13 Japanese βUP deficient patients. In this group of patients, three novel missense mutations (p.G31S, p.E271K, and p.I286T) and a recently described mutation (p.R326Q) were identified. The p.R326Q mutation was detected in all 13 patients with eight patients being homozygous for this mutation. Screening for the p.R326Q mutation in 110 Japanese individuals showed an allele frequency of 0.9 %. Transient expression of mutant βUP enzymes in HEK293 cells showed that the p.E271K and p.R326Q mutations cause profound decreases in activity (≤ 1.3 %). Conversely, βUP enzymes containing the p.G31S and p.I286T mutations possess residual activities of 50 and 70 %, respectively, suggesting we cannot exclude the presence of additional mutations in the non-coding region of the UPB1 gene. Analysis of a human βUP homology model revealed that the effects of the mutations (p.G31S, p.E271K, and p.R326Q) on enzyme activity are most likely linked to improper oligomer assembly. Highly variable phenotypes ranging from neurological involvement (including convulsions and autism) to asymptomatic, were observed in diagnosed patients. High prevalence of p.R326Q in the normal Japanese population indicates that βUP deficiency is not as rare as generally considered and screening for βUP deficiency should be included in diagnosis of patients with unexplained neurological abnormalities.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-014-9682-y) contains supplementary material, which is available to authorized users.

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“…Treatment with ß-alanine for more than 1.5 years revealed no clinical improvement (Assmann et al 2006a). Treatment with ß-alanine for more than 1.5 years revealed no clinical improvement (Assmann et al 2006a).…”

Section: Compliance With Ethics Guidelinesmentioning

confidence: 99%