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1.
Epilepsia Open ; 9(1): 106-121, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37842880

RESUMO

OBJECTIVE: Adenylosuccinate lyase (ADSL) deficiency is a rare inherited metabolic disorder with a wide phenotypic presentation, classically grouped into three types (neonatal, type I, and type II). We aim to better delineate the pathological spectrum, focusing on the electroclinical characteristics and phenotypic differences of patients with ADSL deficiency. PATIENTS AND METHODS: Seven patients, from four different families, underwent serial electroencephalogram (EEG), clinical assessment, and neuroimaging. We also performed a systematic review of the cases published in the literature, summarizing the available clinical, neurophysiological, and genetic data. RESULTS: We report seven previously unreported ADSL deficiency patients with long-term follow-up (10-34 years). From the literature review, we collected 81 previously reported cases. Of the included patient population, 58 % (51/88) were classified as having ADSL deficiency type I, 28% (25/88) as having type II, and 14% (12/88) as having neonatal. The most frequently reported pathogenic variants are p.R426H homozygous (19 patients), p.Y114H in compound heterozygosity (13 patients), and p.D430N homozygous (6 patients). In the majority (89.2%), disease onset was within the first year of life. Epilepsy is present in 81.8% of the patients, with polymorphic and often intractable seizures. EEG features seem to display common patterns and developmental trajectories: (i) poor general background organization with theta-delta activity; (ii) hypsarrhythmia with spasms, usually adrenocorticotropic hormone-responsive; (iii) generalized epileptic discharges with frontal or frontal temporal predominance; and (iv) epileptic discharge activation in sleep with an altered sleep structure. Imaging features present consistent findings of cerebral atrophy with frontal predominance, cerebellar atrophy, and white matter abnormalities among the three types. SIGNIFICANCE: ADSL deficiency presents variable phenotypic expression, whose severity could be partially attributed to residual activity of the mutant protein. Although a precise phenotype-genotype correlation was not yet feasible, we delineated a common pattern of clinical, neuroradiological, and neurophysiological features.


Assuntos
Adenilossuccinato Liase , Transtorno Autístico , Epilepsia , Erros Inatos do Metabolismo da Purina-Pirimidina , Recém-Nascido , Humanos , Adenilossuccinato Liase/genética , Adenilossuccinato Liase/química , Seguimentos , Transtorno Autístico/genética , Atrofia
2.
PLoS Genet ; 19(9): e1010974, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37773959

RESUMO

Adenylosuccinate lyase deficiency is an ultrarare congenital metabolic disorder associated with muscle weakness and neurobehavioral dysfunction. Adenylosuccinate lyase is required for de novo purine biosynthesis, acting twice in the pathway at non-sequential steps. Genetic models can contribute to our understanding of the etiology of disease phenotypes and pave the way for development of therapeutic treatments. Here, we establish the first model to specifically study neurobehavioral aspects of adenylosuccinate lyase deficiency. We show that reduction of adsl-1 function in C. elegans is associated with a novel learning phenotype in a gustatory plasticity assay. The animals maintain capacity for gustatory plasticity, evidenced by a change in their behavior in response to cue pairing. However, their behavioral output is distinct from that of control animals. We link substrate accumulation that occurs upon adsl-1 deficiency to an unexpected perturbation in tyrosine metabolism and show that a lack of tyramine mediates the behavioral changes through action on the metabotropic TYRA-2 tyramine receptor. Our studies reveal a potential for wider metabolic perturbations, beyond biosynthesis of purines, to impact behavior under conditions of adenylosuccinate lyase deficiency.


Assuntos
Adenilossuccinato Liase , Adenilossuccinato Liase/deficiência , Transtorno Autístico , Proteínas de Caenorhabditis elegans , Erros Inatos do Metabolismo da Purina-Pirimidina , Receptores de Amina Biogênica , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Adenilossuccinato Liase/genética , Adenilossuccinato Liase/metabolismo , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Proteínas de Caenorhabditis elegans/genética
3.
J Clin Immunol ; 43(8): 2062-2075, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37726596

RESUMO

BACKGROUND: Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive combined immunodeficiency. The phenotype is profound T cell deficiency with variable B and NK cell functions and results in recurrent and persistent infections that typically begin in the first year of life. Neurologic findings occur in approximately two-thirds of patients. The mechanism of neurologic abnormalities is unclear. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for PNP deficiency. METHODS: We report here six patients from five unrelated families with PNP deficiency treated in two centers in Turkey. We evaluated the neurological status of patients and compared to post-transplantation period if available. Then, we performed PubMed, Google Scholar, and Researchgate searches using the terms "PNP" and "hematopoietic stem cell transplantation" to find all reported cases of PNP transplantation and compared to our cohort. RESULTS: Six patients were treated in two centers in Turkey. One patient died from post-transplant complications. The other four patients underwent successful HSCT with good immune reconstitution after transplantation (follow-up 21-48 months) and good neurological outcomes. The other patient with a new mutation is still waiting for a matching HLA donor. DISCUSSION: In PNP deficiency, clinical manifestations are variable, and this disease should be considered in the presence of many different clinical findings. Despite the comorbidities that occurred before transplantation, HSCT currently appears to be the only treatment option for this disease. HSCT not only cures immunologic disorders, but probably also improves or at least stabilizes the neurologic status of patients.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Doenças da Imunodeficiência Primária , Erros Inatos do Metabolismo da Purina-Pirimidina , Humanos , Purina-Núcleosídeo Fosforilase/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/terapia , Doenças da Imunodeficiência Primária/etiologia , Erros Inatos do Metabolismo da Purina-Pirimidina/terapia
4.
Mol Genet Metab ; 140(3): 107686, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37607437

RESUMO

Inborn errors of purine metabolism are rare syndromes with an array of complex phenotypes in humans. One such disorder, adenylosuccinate lyase deficiency (ASLD), is caused by a decrease in the activity of the bi-functional purine biosynthetic enzyme adenylosuccinate lyase (ADSL). Mutations in human ADSL cause epilepsy, muscle ataxia, and autistic-like symptoms. Although the genetic basis of ASLD is known, the molecular mechanisms driving phenotypic outcome are not. Here, we characterize neuromuscular and reproductive phenotypes associated with a deficiency of adsl-1 in Caenorhabditis elegans. We demonstrate that adsl-1 function contributes to regulation of spontaneous locomotion, that adsl-1 functions acutely for proper mobility, and that aspects of adsl-1-related dysfunction are reversible. Using pharmacological supplementation, we correlate phenotypes with distinct metabolic perturbations. The neuromuscular defect correlates with accumulation of a purine biosynthetic intermediate whereas reproductive deficiencies can be ameliorated by purine supplementation, indicating differing molecular mechanisms behind the phenotypes. Because purine metabolism is highly conserved in metazoans, we suggest that similar separable metabolic perturbations result in the varied symptoms in the human disorder and that a dual-approach therapeutic strategy may be beneficial.


Assuntos
Adenilossuccinato Liase , Transtorno Autístico , Erros Inatos do Metabolismo da Purina-Pirimidina , Animais , Humanos , Transtorno Autístico/genética , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Adenilossuccinato Liase/genética , Adenilossuccinato Liase/metabolismo , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Fenótipo , Purinas
6.
J Clin Rheumatol ; 29(2): 59-67, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36126268

RESUMO

OBJECTIVES: The aims of this study were to evaluate the association between hypouricemia and cardiometabolic diseases, such as hypertension, dyslipidemia, and reduced kidney function, and to explore the sex-specific optimal range for serum uric acid (sUA) associated with the lowest risk for these diseases. METHODS: In this cross-sectional study, we identified individuals with sUA data between April 2018 and March 2019 and recorded the frequency of cardiometabolic comorbidities according to sUA. Univariable and multivariable logistic regression analyses were performed for the overall population and after classifying by sex to assess the association between sUA and cardiometabolic comorbidities. RESULTS: Among 796,508 individuals, a J-shaped association was observed between the sUA level and cardiometabolic diseases in the overall population. The adjusted odds ratios (95% confidence interval) for hypertension, dyslipidemia, and reduced renal function in individuals with sUA ≤1.0 mg/dL compared with those with sUA ranging between 2.1 and 3.0 mg/dL were 1.38 (1.13-1.69), 1.52 (1.30-1.78), and 2.17 (1.47-3.20), respectively. A J-shaped association between sUA and hypertension was observed only in women. The optimal range of sUA associated with the lowest risk for hypertension was assumed to be <6 mg/dL in men and 1-4 mg/dL in women. A J-shaped association between the sUA and dyslipidemia and reduced renal function was observed in both men and women. The optimal range of sUA for dyslipidemia and reduced renal function was approximately 2-5 mg/dL in men and 1-4 mg/dL in women. CONCLUSIONS: Excess and extremely low uric acid levels may be related to an increased cardiometabolic risk.


Assuntos
Dislipidemias , Hipertensão , Erros Inatos do Metabolismo da Purina-Pirimidina , Masculino , Humanos , Feminino , Ácido Úrico , Estudos Transversais , Hipertensão/epidemiologia , Seguro Saúde , Fatores de Risco
7.
Am J Med Genet A ; 191(1): 234-237, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36271826

RESUMO

Adenylosuccinase deficiency is a rare inborn error of metabolism. We present a newborn who died at 52 days of age with clinical features suggestive of severe epileptic encephalopathy and leukodystrophy of unknown cause. Post-mortem examination showed an unusual vacuolar appearance of the brain. A molecular autopsy performed via singleton clinical exome analysis revealed a known pathogenic and a variant of uncertain significance in ADSL that encodes adenylosuccinase. Tests on previously stored plasma samples showed elevated succinyladenosine and succinylaminoimidazole carboxamide riboside levels. Adenylosuccinase activity in stored fibroblasts was only ~5% of control confirming the diagnosis of adenylosuccinase deficiency in the child. The parents opted for a chorionic villus biopsy in a subsequent pregnancy and had a child unaffected by adenylosuccinase deficiency. This report adds vacuolating leukodystrophy as a novel feature of adenylosuccinase deficiency and shows the power of biochemical investigations directed by genomic studies to achieve accurate diagnosis. Importantly, this case demonstrates the importance of anticipatory banking of biological samples for reverse biochemical phenotyping in individuals with undiagnosed disorders who may not survive.


Assuntos
Adenilossuccinato Liase , Transtorno Autístico , Erros Inatos do Metabolismo da Purina-Pirimidina , Criança , Recém-Nascido , Lactente , Humanos , Autopsia , Adenilossuccinato Liase/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/genética
8.
Arch Iran Med ; 26(12): 712-716, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38431953

RESUMO

Two Iranian patients with purine nucleoside phosphorylase (PNP) deficiency are described in terms of their clinical and molecular evaluations. PNP deficiency is a rare form of combined immunodeficiency with a profound cellular defect. Patients with PNP deficiency suffer from variable recurrent infections, hypouricemia, and neurological manifestations. Furthermore, patient 1 developed mild cortical atrophy, and patient 2 presented developmental delay, general muscular hypotonia, and food allergy. The two unrelated patients with developed autoimmune hemolytic anemia and T cells lymphopenia and eosinophilia were referred to Immunology, Asthma and Allergy Research Institute (IAARI) in 2019. After taking blood and DNA extraction, genetic analysis of patient 1 was performed by PCR and direct sequencing and whole exome sequencing was applied for patient 2 and the result was confirmed by direct sequencing in the patient and his parents. The genetic result showed two novel variants in exon 3 (c.246_285+9del) and exon 5 (c.569G>T) PNP (NM_000270.4) in the patients, respectively. These variants are considered likely pathogenic based on the American College of Medical Genetics and Genomics (ACMG) guideline. PNP deficiency has a poor prognosis; therefore, early diagnosis would be vital to receive hematopoietic stem cell transplantation (HSCT) as a prominent and successful treatment.


Assuntos
Anemia Hemolítica Autoimune , Doenças da Imunodeficiência Primária , Purina-Núcleosídeo Fosforilase , Humanos , Anemia Hemolítica Autoimune/genética , Eosinofilia/genética , Irã (Geográfico) , Mutação , Purina-Núcleosídeo Fosforilase/genética , Purina-Núcleosídeo Fosforilase/deficiência , Erros Inatos do Metabolismo da Purina-Pirimidina/genética
9.
Methods Mol Biol ; 2546: 421-430, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36127609

RESUMO

Inborn errors of purine metabolism, either deficiencies of synthesis or catabolism pathways, lead to a wide spectrum of clinical presentations: urolithiasis (adenine phosphoribosyltransferase), primary immune deficiency (adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency), severe intellectual disability, and other neurological symptoms (Lesch-Nyhan disease, adenylosuccinase deficiency, and molybdenum cofactor deficiency). A rapid quantitative purine assay was developed using UPLC-MS/MS to determine purine nucleoside and base concentrations in urine. Taking advantages of ultra-performance liquid chromatography, we achieved satisfactory analyte separation and recovery with a polar T3 column in a short run time with no requirement of time-consuming sample preparation or derivatization. This targeted assay is intended for diagnosis and management of purine diseases, newborn screening follow-up of SCID, and evaluation of autism spectrum disorders.


Assuntos
Erros Inatos do Metabolismo da Purina-Pirimidina , Espectrometria de Massas em Tandem , Adenina Fosforribosiltransferase , Cromatografia Líquida , Humanos , Recém-Nascido , Nucleosídeos de Purina , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/urina
10.
Mol Genet Metab ; 137(1-2): 62-67, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35926322

RESUMO

BACKGROUND: Beta-ureidopropionase deficiency, caused by variants in UPB1, has been reported in association with various neurodevelopmental phenotypes including intellectual disability, seizures and autism. AIM: We aimed to reassess the relationship between variants in UPB1 and a clinical phenotype. METHODS: Literature review, calculation of carrier frequencies from population databases, long-term follow-up of a previously published case and reporting of additional cases. RESULTS: Fifty-three published cases were identified, and two additional cases are reported here. Of these, 14 were asymptomatic and four had transient neurological features; clinical features in the remainder were variable and included non-neurological presentations. Several of the variants previously reported as pathogenic are present in population databases at frequencies higher than expected for a rare condition. In particular, the variant most frequently reported as pathogenic, p.Arg326Gln, is very common among East Asians, with a carrier frequency of 1 in 19 and 1 in 907 being homozygous for the variant in gnomAD v2.1.1. CONCLUSION: Pending the availability of further evidence, UPB1 should be considered a 'gene of uncertain clinical significance'. Caution should be used in ascribing clinical significance to biochemical features of beta-ureidopropionase deficiency and/or UPB1 variants in patients with neurodevelopmental phenotypes. UPB1 is not currently suitable for inclusion in gene panels for reproductive genetic carrier screening. SYNOPSIS: The relationship between beta-ureidopropionase deficiency due to UPB1 variants and clinical phenotypes is uncertain.


Assuntos
Transtornos dos Movimentos , Erros Inatos do Metabolismo da Purina-Pirimidina , Humanos , Encefalopatias/diagnóstico , Encefalopatias/genética , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/genética , Fenótipo , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Amidoidrolases/genética
11.
Sci Rep ; 12(1): 9084, 2022 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-35641516

RESUMO

Purine nucleoside phosphorylase (PNP) is an important enzyme in the purine degradation and salvage pathway. PNP deficiency results in marked T lineage lymphopenia and severe immunodeficiency. Additionally, PNP-deficient patients and mice suffer from diverse non-infectious neurological abnormalities of unknown etiology. To further investigate the cause for these neurologic abnormalities, induced pluripotent stem cells (iPSC) from two PNP-deficient patients were differentiated into neurons. The iPSC-derived PNP-deficient neurons had significantly reduced soma and nuclei volumes. The PNP-deficient neurons demonstrated increased spontaneous and staurosporine-induced apoptosis, measured by cleaved caspase-3 expression, together with decreased mitochondrial membrane potential and increased cleaved caspase-9 expression, indicative of enhanced intrinsic apoptosis. Greater expression of tumor protein p53 was also observed in these neurons, and inhibition of p53 using pifithrin-α prevented the apoptosis. Importantly, treatment of the iPSC-derived PNP-deficient neurons with exogenous PNP enzyme alleviated the apoptosis. Inhibition of ribonucleotide reductase (RNR) in iPSC derived from PNP-proficient neurons with hydroxyurea or with nicotinamide and trichostatin A increased the intrinsic neuronal apoptosis, implicating RNR dysfunction as the potential mechanism for the damage caused by PNP deficiency. The findings presented here establish a potential mechanism for the neurological defects observed in PNP-deficient patients and reinforce the critical role that PNP has for neuronal viability.


Assuntos
Apoptose , Células-Tronco Pluripotentes Induzidas , Neurônios , Purina-Núcleosídeo Fosforilase , Proteína Supressora de Tumor p53 , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Neurônios/citologia , Doenças da Imunodeficiência Primária , Purina-Núcleosídeo Fosforilase/deficiência , Purina-Núcleosídeo Fosforilase/metabolismo , Erros Inatos do Metabolismo da Purina-Pirimidina , Proteína Supressora de Tumor p53/genética
12.
Elife ; 112022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35133277

RESUMO

Adenylosuccinate lyase (ADSL) functions in de novo purine synthesis (DNPS) and the purine nucleotide cycle. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly and autism spectrum disorder. ADSLD patients have normal serum purine nucleotide levels but exhibit accumulation of dephosphorylated ADSL substrates, S-Ado, and SAICAr, the latter being implicated in neurotoxic effects through unknown mechanisms. We examined the phenotypic effects of ADSL depletion in human cells and their relation to phenotypic outcomes. Using specific interventions to compensate for reduced purine levels or modulate SAICAr accumulation, we found that diminished AMP levels resulted in increased DNA damage signaling and cell cycle delays, while primary ciliogenesis was impaired specifically by loss of ADSL or administration of SAICAr. ADSL-deficient chicken and zebrafish embryos displayed impaired neurogenesis and microcephaly. Neuroprogenitor attrition in zebrafish embryos was rescued by pharmacological inhibition of DNPS, but not increased nucleotide concentration. Zebrafish also displayed phenotypes commonly linked to ciliopathies. Our results suggest that both reduced purine levels and impaired DNPS contribute to neurodevelopmental pathology in ADSLD and that defective ciliogenesis may influence the ADSLD phenotypic spectrum.


Assuntos
Adenilossuccinato Liase/deficiência , Adenilossuccinato Liase/metabolismo , Transtorno Autístico/metabolismo , Neurogênese , Erros Inatos do Metabolismo da Purina-Pirimidina/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/metabolismo , Animais , Transtorno do Espectro Autista/metabolismo , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Galinhas/metabolismo , Ciliopatias/metabolismo , Dano ao DNA , Humanos , Microcefalia/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Fenótipo , Fosfoproteínas/metabolismo , Purinas/metabolismo , Ribonucleotídeos/metabolismo , Peixe-Zebra/metabolismo
13.
Mol Genet Metab ; 136(3): 177-185, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35151535

RESUMO

ß-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyses the conversion of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid to ß-alanine and ß-aminoisobutyric acid, ammonia and CO2. To date, only a limited number of genetically confirmed patients with a complete ß-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 10 newly identified ß-ureidopropionase deficient individuals. Patients presented mainly with neurological abnormalities and markedly elevated levels of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid in urine. Analysis of UPB1, encoding ß-ureidopropionase, showed 5 novel missense variants and two novel splice-site variants. Functional expression of the UPB1 variants in mammalian cells showed that recombinant ß-ureidopropionase carrying the p.Ala120Ser, p.Thr129Met, p.Ser300Leu and p.Asn345Ile variant yielded no or significantly decreased ß-ureidopropionase activity. Analysis of the crystal structure of human ß-ureidopropionase indicated that the point mutations affect substrate binding or prevent the proper subunit association to larger oligomers and thus a fully functional ß-ureidopropionase. A minigene approach showed that the intronic variants c.[364 + 6 T > G] and c.[916 + 1_916 + 2dup] led to skipping of exon 3 and 8, respectively, in the process of UPB1 pre-mRNA splicing. The c.[899C > T] (p.Ser300Leu) variant was identified in two unrelated Swedish ß-ureidopropionase patients, indicating that ß-ureidopropionase deficiency may be more common than anticipated.


Assuntos
Erros Inatos do Metabolismo da Purina-Pirimidina , Precursores de RNA , Anormalidades Múltiplas , Amidoidrolases/deficiência , Amidoidrolases/genética , Animais , Encefalopatias , Humanos , Mamíferos/genética , Transtornos dos Movimentos , Mutação , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , beta-Alanina/genética , beta-Alanina/urina
14.
Mol Genet Metab ; 136(3): 164-176, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35216884

RESUMO

Inborn errors of purine and pyrimidine (P/P) metabolism are under-reported and rarely mentioned in the general literature or in clinical practice, as well as in reviews dedicated to other inborn errors of metabolism (IEMs). However, their diagnosis is important because genetic counseling can be provided and, in some cases, specific treatment exists that may slow or even reverse clinical signs. The purpose of this review is to provide a practical guideline on the suspicion and investigation of inborn errors of P/P metabolism. Failure of a physician to recognize the presence of these disorders may be devastating for affected infants and children because of its permanent effects in the patient, and for their parents because of implications for future offspring. Diagnosis is crucial because genetic counseling can be provided and, in some cases, specific treatment can be offered that may slow or even reverse clinical symptoms. This review highlights the risk factors in the history, the important examination findings, and the appropriate biochemical investigation of the child. Herein we describe the approach to the diagnosis of P/P disorders and emphasize clinical situations in which physicians should consider these diseases as diagnostic possibilities.


Assuntos
Erros Inatos do Metabolismo da Purina-Pirimidina , Criança , Família , Humanos , Lactente , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/metabolismo , Purinas/metabolismo , Pirimidinas/metabolismo , Fatores de Risco
15.
Mol Genet Metab ; 136(3): 190-198, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34998670

RESUMO

Purines are essential molecules that are components of vital biomolecules, such as nucleic acids, coenzymes, signaling molecules, as well as energy transfer molecules. The de novo biosynthesis pathway starts from phosphoribosylpyrophosphate (PRPP) and eventually leads to the synthesis of inosine monophosphate (IMP) by means of 10 sequential steps catalyzed by six different enzymes, three of which are bi-or tri-functional in nature. IMP is then converted into guanosine monophosphate (GMP) or adenosine monophosphate (AMP), which are further phosphorylated into nucleoside di- or tri-phosphates, such as GDP, GTP, ADP and ATP. This review provides an overview of inborn errors of metabolism pertaining to purine synthesis in humans, including either phosphoribosylpyrophosphate synthetase (PRS) overactivity or deficiency, as well as adenylosuccinate lyase (ADSL), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), and adenylosuccinate synthetase (ADSS) deficiencies. ITPase deficiency is being described as well. The clinical spectrum of these disorders is broad, including neurological impairment, such as psychomotor retardation, epilepsy, hypotonia, or microcephaly; sensory involvement, such as deafness and visual disturbances; multiple malformations, as well as muscle presentations or consequences of hyperuricemia, such as gouty arthritis or kidney stones. Clinical signs are often nonspecific and, thus, overlooked. It is to be hoped that this is likely to be gradually overcome by using sensitive biochemical investigations and next-generation sequencing technologies.


Assuntos
Adenilossuccinato Liase , Erros Inatos do Metabolismo da Purina-Pirimidina , Adenilossuccinato Liase/deficiência , Adenilossuccinato Liase/genética , Adenilossuccinato Liase/metabolismo , Transtorno Autístico , Humanos , Inosina Monofosfato , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/metabolismo , Purinas
16.
Clin Rheumatol ; 41(7): 2113-2119, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35072830

RESUMO

We aimed to describe temporal trends in the prevalence and characteristics of hypouricaemia. We analysed medical check-up and administrative claims data to calculate hypouricaemia prevalence from 2009 to 2019. Then, using data from 2018 to 2019, we compared the characteristics of individuals with and without hypouricaemia. We also compared the characteristics of those with lower (serum uric acid [sUA] ≤ 1.0 mg/dL) and higher (1.0 mg/dL < sUA ≤ 2.0 mg/dL) hypouricaemia. In total, 1,600,290 subjects underwent medical check-ups. The age-adjusted prevalence of hypouricaemia remained stable at 0.2% overall (men, 0.1%; women, 0.4%). We identified 1704 subjects with hypouricaemia (598 men and 1106 women) among 796,508 subjects and studied their characteristics. The proportion of most pre-existing diseases, including urinary stones, was lower in those with hypouricaemia than in those without hypouricaemia. Cardio-metabolic diseases and Parkinson's disease were more frequent in men with hypouricaemia than those without hypouricaemia. Women with hypouricaemia tended to have healthier characteristics. Hypertension and dyslipidaemia were more common in the lower hypouricaemia group than in the higher hypouricaemia group. The age-adjusted prevalence of hypouricaemia remained stable over 10 years. The characteristics of hypouricaemia subjects appear to differ between the sexes and between lower and higher hypouricaemia groups. Key Points • The prevalence of hypouricaemia remained almost unchanged over 10 years. • Cardio-metabolic diseases and Parkinson's disease were more frequent in men with hypouricaemia than in those without hypouricaemia. • Subjects with extremely low serum urate (sUA ≤ 1.0 mg/dL) appeared to have higher cardio-metabolic disease risks. • Routine checks of sUA could be useful in screening or predicting these conditions.


Assuntos
Hipertensão , Doença de Parkinson , Erros Inatos do Metabolismo da Purina-Pirimidina , Cálculos Urinários , Criança , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Prevalência , Ácido Úrico
17.
Eur J Med Genet ; 65(3): 104428, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35063692

RESUMO

Purine nucleoside phosphorylase (PNP) is a key enzyme in the purine salvage pathway. PNP deficiency, caused by the autosomal recessive mutations in the PNP gene, can lead to severe combined immunodeficiency (SCID). PNP deficiency patients typically have profound T-cell deficiency with variable B and NK cell functions. They present clinically with recurrent infections, failure to thrive, various neurological disorders, malignancies, and autoimmune diseases. Hematopoietic stem cell transplantation (HSCT) is the only available cure for patients with PNP deficiency. We present three patients, two of whom were successfully treated with HSCT. One patient died prior to HSCT due to EBV-associated lymphoma. Over the course of post-HSCT, there was no further aggravation of the patients' neurological symptoms. Although both of the patients still had mild developmental delay, new developmental milestones were achieved.


Assuntos
Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Erros Inatos do Metabolismo da Purina-Pirimidina , Humanos , Síndromes de Imunodeficiência/genética , Doenças da Imunodeficiência Primária/genética , Purina-Núcleosídeo Fosforilase/deficiência , Purina-Núcleosídeo Fosforilase/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/genética
18.
Artigo em Inglês | MEDLINE | ID: mdl-34643162

RESUMO

In June 2021, the Purine and Pyrimidine Society (PPS) organized the 19th biennial symposium on Purine and Pyrimidine metabolism (PP21). Due to the ongoing pandemic, the conference was organized as a webinar over 3 days with sessions dealing with enzymes, cancer, inborn errors, gout among others. The current issue of Nucleosides, Nucleotides & Nucleic Acids is a special issue covering proceedings from PP21-presentations and other PPS-related manuscripts, and in this editorial, we will give an overview of the scientific program of the meeting.


Assuntos
Gota , Erros Inatos do Metabolismo da Purina-Pirimidina , Humanos , Erros Inatos do Metabolismo da Purina-Pirimidina/metabolismo , Purinas/metabolismo , Pirimidinas/metabolismo
19.
J Genet ; 1002021.
Artigo em Inglês | MEDLINE | ID: mdl-34344843

RESUMO

Deficiency of uridine monophosphate synthase (DUMPS) is a lethal genetic disorder associated with early embryonic mortality. Murrah and Mehsana male buffaloes (n = 594) were screened for DUMPS by PCR-RFLP technique. A few Murrah buffalo male calves were found to be carriers of DUMPS in RFLP, which has not been reported earlier. On the Sanger sequencing, a novel A to G substitution mutation was identified in AvaI restriction recognition site of UMPS gene in buffaloes. This mutation hinders digestion of DNA by AvaI which leds to false positive results for DUMPS carrier in RFLP. The results indicated that genome sequencing must be performed before confirming results of RFLP in any new species. All the buffaloes that were tested had only wild-type genotype in exon 5 for DUMPS specific allele.


Assuntos
Búfalos/genética , Doenças dos Bovinos/genética , Doenças Genéticas Inatas/veterinária , Orotato Fosforribosiltransferase/deficiência , Orotidina-5'-Fosfato Descarboxilase/deficiência , Polimorfismo de Fragmento de Restrição , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Alelos , Animais , Bovinos , Mapeamento Cromossômico , Éxons , Reações Falso-Positivas , Genótipo , Masculino , Mutação , Orotato Fosforribosiltransferase/genética , Orotidina-5'-Fosfato Descarboxilase/genética , Reação em Cadeia da Polimerase/métodos , Sequenciamento Completo do Genoma
20.
Orphanet J Rare Dis ; 16(1): 112, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648541

RESUMO

BACKGROUND: Adenylosuccinate lyase deficiency (ADSLD) is an ultrarare neurometabolic recessive disorder caused by loss-of-function mutations in the ADSL gene. The disease is characterized by wide clinical variability. Here we provide an updated clinical profiling of the disorder and discuss genotype-phenotype correlations. RESULTS: Data were collected through "Our Journey with ADSL deficiency Association" by using a dedicated web survey filled-in by parents. Clinical and molecular data were collected from 18 patients (12 males, median age 10.9 years ± 7.3), from 13 unrelated families. The age at onset ranged from birth to the first three years (median age 0.63 years ± 0.84 SD), and age at diagnosis varied from 2 months to 17 years, (median age 6.4 years ± 6.1 SD). The first sign was a psychomotor delay in 8/18 patients, epilepsy in 3/18, psychomotor delay and epilepsy in 3/18, and apneas, hypotonia, nystagmus in single cases. One patient (sibling of a previously diagnosed child) had a presymptomatic diagnosis. The diagnosis was made by exome sequencing in 7/18 patients. All patients were definitively diagnosed with ADSL deficiency based on pathogenic variants and/or biochemical assessment. One patient had a fatal neonatal form of ADSL deficiency, seven showed features fitting type I, and nine were characterized by a milder condition (type II), with two showing a very mild phenotype. Eighteen different variants were distributed along the entire ADSL coding sequence and were predicted to have a variable structural impact by impairing proper homotetramerization or catalytic activity of the enzyme. Six variants had not previously been reported. All but two variants were missense. CONCLUSIONS: The study adds more details on the spectrum of ADSLD patients' phenotypes and molecular data.


Assuntos
Adenilossuccinato Liase , Transtorno Autístico , Erros Inatos do Metabolismo da Purina-Pirimidina , Adenilossuccinato Liase/deficiência , Adenilossuccinato Liase/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/genética
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