Screening for Adenylosuccinate Lyase Deficiency: Clinical, Biochemical and Molecular Findings in Four Patients

Castro, M. Di; Pérez‐Cerdá, Celia; Merinero, Begoña; García, M.; Bernar, J; Nagel, Anne; Rodríguez‐Torres, Janet; Bermudez, Myrna Virreira; Garavito, Pilar; Marie, Sandrine; Vincent, Fabien B.; Berghe, Georges; Ugarte, Magdalena

doi:10.1055/s-2002-34493

Cited by 26 publications

(17 citation statements)

References 9 publications

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“…The mutations that we investigated in the present study are found paired in patients as follows: R396H/L311V (37) and R396C/R194C (9). These two patients have been described as having severe mental retardation while the two reported patients with the K246E mutation exhibit moderate to severe mental retardation (38).…”

Section: Discussionmentioning

confidence: 97%

Biochemical and Biophysical Analysis of Five Disease-Associated Human Adenylosuccinate Lyase Mutants

et al. 2009

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Adenylosuccinate lyase (ASL), a catalyst of key reactions in purine biosynthesis, is normally a homotetramer in which three subunits contribute to each of four active sites. Human ASL deficiency is an inherited metabolic disease associated with autism and mental retardation. We have characterized five disease-associated ASL mutants: R194C and K246E are located at subunit interfaces, L311V is in the central helical region away from the active site, and R396C and R396H are at the entrance to the active site. The Vmax (at 25 °C) for R194C is comparable to that of WT; while those of L311V, R396C, R396H and K246E are considerably reduced and affinity for adenylosuccinate is retained. The mutant enzymes have decreased positive cooperativity as compared to WT. K246E exists mainly as dimer or monomer, accounting for its negligible activity; whereas the other mutant enzymes are similar to WT in the predominance of tetramer. At 37 °C, the specific activity of WT and these mutant enzymes slowly decreases 30-40% with time and reaches a limiting specific activity without changing significantly the amount of tetramer. Mutant R194C is unique in being rapidly inactivated at the harsher temperature of 60°C, indicating that it is the least stable enzyme in vitro. Conformational changes in the mutant enzymes are evident from protein fluorescence intensity at 25 °C and after incubation at 37 °C, which correlates with the loss of enzymatic activity. Thus, these disease-associated single mutations can yield enzyme with reduced activity either by affecting the active site or by perturbing the enzyme’s structure and/or native conformation which are required for catalytic function.

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Section: Discussionmentioning

confidence: 97%

Biochemical and Biophysical Analysis of Five Disease-Associated Human Adenylosuccinate Lyase Mutants

et al. 2009

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“…Seizures usually start either early in the neonatal period or after the first year of life (Van den Berghe et al 1998;Castro et al 2002) and are intractable.…”

Section: Discussionmentioning

confidence: 99%

d‐Ribose therapy in four Polish patients with adenylosuccinate lyase deficiency: Absence of positive effect

Jurecka

Tylki‐Szymańska

Zikánová

et al. 2008

J of Inher Metab Disea

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SummaryDeficiency of adenylosuccinate lyase (ADSL) (OMIM 103050) is an autosomal recessive disorder of the purine de novo synthesis pathway and purine nucleotide cycle, diagnosed so far in approximately 50 patients. The clinical presentation is characterized by severe neurological involvement including hypotonia, seizures, developmental delay and autistic features. Epilepsy in ADSL deficiency is frequent and occurs in approximately two‐thirds of patients, beginning either early in the neonatal period or after the first year of life. At present there is no treatment of proven clinical efficacy. Despite of the increasing number of ADSL‐deficient patients reported, there are only a few communications of therapeutic considerations or efforts. Among them only two showed some beneficial effects in ADSL‐deficient patients. d‐Ribose, a simple and relatively cheap therapy, has been associated with improvement of behaviour and progressive reduction of the seizure frequency in one 13‐year‐old patient with ADSL deficiency. In this study we have re‐examined d‐ribose treatment in four ADSL‐deficient patients. Assessments consisted of biochemical markers and neurological outcome. The 12‐month trial of d‐ribose failed to show any clinical benefit in ADSL patients with both milder and severe phenotype. d‐Ribose administration was accompanied by neither reduction in seizure frequency nor growth enhancement. Additionally, patients with milder type II presented the first seizure after 4 and 8 months of the d‐ribose treatment. Therefore, we could not confirm a positive effect of d‐ribose as previously reported.

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“…Patients with type II (moderate or mild form), who develop symptoms within the first years of life, usually suffer from slight to moderate psychomotor retardation and transient contact disturbances [7,9,10,13,21]. 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].…”

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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Screening for Adenylosuccinate Lyase Deficiency: Clinical, Biochemical and Molecular Findings in Four Patients

Cited by 26 publications

References 9 publications

Biochemical and Biophysical Analysis of Five Disease-Associated Human Adenylosuccinate Lyase Mutants

Biochemical and Biophysical Analysis of Five Disease-Associated Human Adenylosuccinate Lyase Mutants

d‐Ribose therapy in four Polish patients with adenylosuccinate lyase deficiency: Absence of positive effect

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

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