Prenatal diagnosis in adenylosuccinate lyase deficiency

Marie, Sandrine; Flipsen, Jolanda W. A. M.; Durán, Marinus; Poll-Thé, Bwee Tien; Beemer, Fritz A.; Bosschaart, A.N; Vincent, M F; Berghe, Georges

doi:10.1002/(sici)1097-0223(200001)20:1<33::aid-pd751>3.0.co;2-3

Cited by 16 publications

(5 citation statements)

References 12 publications

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“…The identification of the causative mutation in the family presented here makes it possible to perform a reliable and rapid prenatal diagnosis, using molecular studies [Marie et al, 2000]. Finally, considering the wide phenotypic variability observed in ADSL deficiency, we recommend using a very simple and inexpensive urinary screening method such as the modified Bratton‐Marshall test in any patient presenting a neurodegenerative disorder or psychomotor delay of unknown origin.…”

Section: Discussionmentioning

confidence: 99%

Intrafamilial variability in the phenotypic expression of adenylosuccinate lyase deficiency: A report on three patients

Edery

Chabrier

Ceballos-Picot

et al. 2003

American J of Med Genetics Pt A

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We report on the striking variable expression of adenylosuccinate lyase (ADSL) deficiency in three patients belonging to a family which originates from Portugal. ADSL deficiency is a rare autosomal recessive disorder of the de novo purine synthesis which results in accumulation of succinylpurines in body fluids. As a result, patients may have variable combinations of psychomotor retardation and/or regression, seizures, autistic features and cerebellar vermis hypoplasia. However, intrafamilial variable expression of the phenotype has not been documented to date in this disease and is not commonly observed in metabolic disorders. Here, while the proband had marked psychomotor regression and progressive cerebellar vermis atrophy, the other two affected patients presented mainly autistic features. Mutation analysis of the ADSL gene revealed the presence of a homozygous R426H mutation in this family. Finally, although ADSL deficiency is a rare disorder, this diagnosis should be considered and assessed using a simple urinary screening method for the presence of succinylpurines in any patient with mental retardation of unexplained origin.

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Section: Discussionmentioning

confidence: 99%

Intrafamilial variability in the phenotypic expression of adenylosuccinate lyase deficiency: A report on three patients

Edery

Chabrier

Ceballos-Picot

et al. 2003

American J of Med Genetics Pt A

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“…Prenatal diagnosis is limited to families having a previous child with ADSL deficiency and is based on mutational analysis for at-risk fetuses. Diagnostic testing may be conducted for prenatal diagnosis on viable fetal cells from chorionic villi, cultured amniotic fluid cells or in the newborn dried blood spots (Marie et al 2000 ).…”

Section: Prenatal Diagnosis Selective Screening and Genetic Counselimentioning

confidence: 99%

Adenylosuccinate lyase deficiency

Jurecka

Zikánová

Kmoch

et al. 2014

J of Inher Metab Disea

113

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Adenylosuccinate lyase ADSL) deficiency is a defect of purine metabolism affecting purinosome assembly and reducing metabolite fluxes through purine de novo synthesis and purine nucleotide recycling pathways. Biochemically this defect manifests by the presence in the biologic fluids of two dephosphorylated substrates of ADSL enzyme: succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado). More than 80 individuals with ADSL deficiency have been identified, but incidence of the disease remains unknown. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The fatal neonatal form has onset from birth and presents 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. Patients with type I (severe form) present with a purely neurologic clinical picture characterized by severe psychomotor retardation, microcephaly, early onset of seizures, and autistic features. A more slowly progressing form has also been described (type II, moderate or mild form), as having later onset, usually within the first years of life, slight to moderate psychomotor retardation and transient contact disturbances. Diagnosis is facilitated by demonstration of SAICAr and S-Ado in extracellular fluids such as plasma, cerebrospinal fluid and/or followed by genomic and/or cDNA sequencing and characterization of mutant proteins. Over 50 ADSL mutations have been identified and their effects on protein biogenesis, structural stability and activity as well as on purinosome assembly were characterized. To date there is no specific and effective therapy for ADSL deficiency.

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“…The assay of fibroblast ADSL was performed as described previously, using both SAICAR and S-AMP as substrates, and measuring the products of the reaction by HPLC (26).…”

Section: Fibroblast Culturementioning

confidence: 99%

Clinical, biochemical and molecular genetic correlations in adenylosuccinate lyase deficiency

Race

Marie

Vincent

et al. 2000

Human Molecular Genetics

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Adenylosuccinate lyase (ADSL) deficiency (MIM 103050) is an autosomal recessive inborn error of purine synthesis characterized by the accumulation in body fluids of succinylaminoimidazolecarboxamide (SAICA) riboside and succinyladenosine (S-Ado), the dephosphorylated derivatives of the two substrates of the enzyme. Because ADSL-deficient patients display widely variable degrees of psychomotor retardation, we have expressed eight mutated ADSL enzymes as thioredoxin fusions and compared their properties with the clinical and biochemical characteristics of 10 patients. Three expressed mutated ADSL enzymes (M26L, R426H and T450S) were thermolabile, four (A2V, R141W, R303C and S395R) were thermostable and one (del206-218), was inactive. Thermolabile mutations decreased activities with SAICA ribotide (SAICAR) and adenylosuccinate (S-AMP) in parallel, or more with SAICAR than with S-AMP. Patients homozygous for one of these mutations, R426H, displayed similarly decreased ADSL activities in their fibroblasts, S-Ado:SAICA riboside ratios of approximately 1 in their cerebrospinal fluid and were profoundly retarded. With the exception of A2V, thermostable mutations decreased activity with S-AMP to a much more marked extent than with SAICAR. Two unrelated patients homozygous for one of the thermostable mutations, R303C, also displayed a much more marked decrease in the activity of fibroblast ADSL with S-AMP than with SAICAR, had S-Ado:SAICA riboside ratios between 3 and 4 in their cerebrospinal fluid and were mildly retarded. These results suggest that, in some cases, the genetic lesion of ADSL determines the ratio of its activities with S-AMP versus SAICAR, which in turn defines the S-Ado:SAICA riboside ratio and the patients' mental status.

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Prenatal diagnosis in adenylosuccinate lyase deficiency

Cited by 16 publications

References 12 publications

Intrafamilial variability in the phenotypic expression of adenylosuccinate lyase deficiency: A report on three patients

Intrafamilial variability in the phenotypic expression of adenylosuccinate lyase deficiency: A report on three patients

Adenylosuccinate lyase deficiency

Clinical, biochemical and molecular genetic correlations in adenylosuccinate lyase deficiency

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