RESUMO
Metabolic myopathies are muscle disorders caused by a biochemical defect of the skeletal muscle energy system resulting in exercise intolerance. The primary aim of this research was to evaluate the oxygen cost (∆V'O2/∆Work-Rate) during incremental exercise in patients with metabolic myopathies as compared with patients with non-metabolic myalgia and healthy subjects. The study groups consisted of eight patients with muscle glycogenoses (one Tarui and seven McArdle diseases), seven patients with a complete and twenty-two patients with a partial myoadenylate deaminase (MAD) deficiency in muscle biopsy, five patients with a respiratory chain deficiency, seventy-three patients with exercise intolerance and normal muscle biopsy (non-metabolic myalgia), and twenty-eight healthy controls. The subjects underwent a cardiopulmonary exercise test (CPX Medgraphics) performed on a bicycle ergometer. Pulmonary V'O2 was measured breath-by-breath throughout the incremental test. The ∆V'O2/∆Work-Rate slope for exercise was determined by linear regression analysis. Lower oxygen consumption (peak percent of predicted, mean ± SD; p < 0.04, one-way ANOVA) was seen in patients with glycogenoses (62.8 ± 10.2%) and respiratory chain defects (70.8 ± 23.3%) compared to patients with non-metabolic myalgia (100.0 ± 15.9%) and control subjects (106.4 ± 23.5%). ∆V'O2/∆Work-Rate slope (mLO2.min-1.W-1) was increased in patients with MAD absent (12.6 ± 1.5), MAD decreased (11.3 ± 1.1), glycogenoses (14.0 ± 2.5), respiratory chain defects (13.1 ± 1.2), and patients with non-metabolic myalgia (11.3 ± 1.3) compared with control subjects (10.2 ± 0.7; p < 0.001, one-way ANOVA). In conclusion, patients with metabolic myopathies display an increased oxygen cost during exercise and therefore can perform less work for a given VO2 consumption during daily life-submaximal exercises.
Assuntos
Tolerância ao Exercício , Exercício Físico/fisiologia , Doenças Musculares/fisiopatologia , AMP Desaminase/deficiência , Adolescente , Adulto , Antropometria , Teste de Esforço , Feminino , Doença de Depósito de Glicogênio Tipo V/fisiopatologia , Doença de Depósito de Glicogênio Tipo VII/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/fisiopatologia , Mialgia/fisiopatologia , Consumo de Oxigênio , Erros Inatos do Metabolismo da Purina-Pirimidina/fisiopatologia , Adulto JovemAssuntos
Aldeído Oxidase/deficiência , Artrite Juvenil/tratamento farmacológico , Azatioprina , Transtornos da Insuficiência da Medula Óssea , Deficiência de IgA/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina , Ácido Úrico , Xantina Desidrogenase/deficiência , Aldeído Oxidase/genética , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacocinética , Artrite Juvenil/imunologia , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Azatioprina/farmacocinética , Transtornos da Insuficiência da Medula Óssea/sangue , Transtornos da Insuficiência da Medula Óssea/induzido quimicamente , Transtornos da Insuficiência da Medula Óssea/terapia , Transfusão de Eritrócitos/métodos , Humanos , Tolerância Imunológica/genética , Testes Imunológicos/métodos , Masculino , Testes Farmacogenômicos/métodos , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/fisiopatologia , Sulfurtransferases/genética , Ácido Úrico/sangue , Ácido Úrico/urina , Xantina , Xantina Desidrogenase/genética , Adulto JovemRESUMO
This review is devised to gather the presently known inborn errors of purine metabolism that manifest neurological pediatric syndromes. The aim is to draw a comprehensive picture of these rare diseases, characterized by unexpected and often devastating neurological symptoms. Although investigated for many years, most purine metabolism disorders associated to psychomotor dysfunctions still hide the molecular link between the metabolic derangement and the neurological manifestations. This basically indicates that many of the actual functions of nucleosides and nucleotides in the development and function of several organs, in particular central nervous system, are still unknown. Both superactivity and deficiency of phosphoribosylpyrophosphate synthetase cause hereditary disorders characterized, in most cases, by neurological impairments. The deficiency of adenylosuccinate lyase and 5-amino-4-imidazolecarboxamide ribotide transformylase/IMP cyclohydrolase, both belonging to the de novo purine synthesis pathway, is also associated to severe neurological manifestations. Among catabolic enzymes, hyperactivity of ectosolic 5'-nucleotidase, as well as deficiency of purine nucleoside phosphorylase and adenosine deaminase also lead to syndromes affecting the central nervous system. The most severe pathologies are associated to the deficiency of the salvage pathway enzymes hypoxanthine-guanine phosphoribosyltransferase and deoxyguanosine kinase: the former due to an unexplained adverse effect exerted on the development and/or differentiation of dopaminergic neurons, the latter due to a clear impairment of mitochondrial functions. The assessment of hypo- or hyperuricemic conditions is suggestive of purine enzyme dysfunctions, but most disorders of purine metabolism may escape the clinical investigation because they are not associated to these metabolic derangements. This review may represent a starting point stimulating both scientists and physicians involved in the study of neurological dysfunctions caused by inborn errors of purine metabolism with the aim to find novel therapeutical approaches.
Assuntos
Encefalopatias Metabólicas Congênitas/metabolismo , Encefalopatias Metabólicas Congênitas/fisiopatologia , Erros Inatos do Metabolismo da Purina-Pirimidina/metabolismo , Erros Inatos do Metabolismo da Purina-Pirimidina/fisiopatologia , Purinas/metabolismo , Fatores Etários , Encefalopatias Metabólicas Congênitas/patologia , Sistema Nervoso Central/crescimento & desenvolvimento , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Criança , Pré-Escolar , Enzimas/metabolismo , Humanos , Lactente , Recém-Nascido , Redes e Vias Metabólicas/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Nucleotídeos/metabolismo , Erros Inatos do Metabolismo da Purina-Pirimidina/patologiaRESUMO
Adenylosuccinase (ADSL) deficiency is an autosomal recessive disorder affecting mainly the nervous system. The disease causes psychomotor retardation, frequently with autistic features and epilepsy. ADSL deficiency may be diagnosed by detection of two abnormal metabolites in body fluids--succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr). It is assumed that the former metabolite is neurotoxic. We present clinical, biochemical and neuropathological findings of a child affected by a severe form of ADSL deficiency. She had progressive neurological symptoms that started immediately after birth and died at 2.5 months of age. Macroscopically the brain showed signs of moderate atrophy. Histological examination of all grey matter structures showed widespread damage of neurons accompanied by microspongiosis of neuropile. Cerebral white matter showed lack of myelination in the centrum semiovale and diffuse spongiosis of neuropile. Myelination appropriate for the age was visible in posterior limb of internal capsule, in striatum, thalamus and in brain stem structures but diffuse destruction of myelin sheets was seen with severe marked astroglial reaction with signs of destruction of the cells and their processes. Ultrastructural examination showed enormous destruction of all cellular elements, but astonishingly mitochondria were relatively spared. The neuropathological changes can be considered as the neurotoxic result of metabolic disturbances connected with adenylosuccinase deficiency.
Assuntos
Adenilossuccinato Liase/deficiência , Encefalopatias Metabólicas Congênitas/patologia , Encéfalo/ultraestrutura , Erros Inatos do Metabolismo da Purina-Pirimidina/patologia , Adenosina/análogos & derivados , Adenosina/líquido cefalorraquidiano , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/líquido cefalorraquidiano , Encefalopatias Metabólicas Congênitas/líquido cefalorraquidiano , Encefalopatias Metabólicas Congênitas/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Polônia , Erros Inatos do Metabolismo da Purina-Pirimidina/líquido cefalorraquidiano , Erros Inatos do Metabolismo da Purina-Pirimidina/fisiopatologia , Ribonucleosídeos/líquido cefalorraquidianoRESUMO
Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is a genetic disease of purine metabolism resulting in uric acid overproduction. Allopurinol, which inhibits the enzyme xanthine oxidase and reduces uric acid synthesis, is widely used for the treatment of gout and uric acid overproduction. The aim of the study was to analyze the long-term efficacy and safety of allopurinol in patients with HPRT deficiency. Nineteen patients (13 with Lesch-Nyhan syndrome and 6 with partial HPRT deficiency) were treated with allopurinol (mean dose, 6.4 mg/kg body weight per day; range, 3.7-9.7 mg/kg body weight per day) and followed up for at least 12 months (mean follow-up, 7.6 years). The efficacy of allopurinol was evaluated by serial measurement of purine metabolic parameters and renal function as well as by clinical manifestations. Safety was assessed by recording adverse events. Treatment with allopurinol normalized serum urate level in all patients and resulted in a mean reduction in serum urate of 47%. Allopurinol treatment was associated with a mean 74% reduction in urinary uric acid-to-creatinine ratio. In contrast, allopurinol treatment increased mean hypoxanthine and xanthine urinary excretion rates 5.4- and 9.5-fold, respectively, compared with baseline levels. The decrease in uric acid excretion in complete and partial HPRT-deficient patients was not accompanied by a stoichiometric substitution of hypoxanthine and xanthine excretion rates. Allopurinol-related biochemical changes were similar in patients with either complete or partial HPRT deficiency. Renal function remained stable or improved with treatment. Three patients had urolithiasis during allopurinol treatment. In 2 patients, xanthine stones were documented and they required allopurinol dose adjustments aimed at reducing excessive oxypurine excretion rates. No allopurinol hypersensitivity reactions occurred. Neurologic manifestations were not influenced by allopurinol therapy. In conclusion, allopurinol is efficacious and generally safe for the treatment of uric acid overproduction in patients with HPRT deficiencies. Xanthine lithiasis, developing as a consequence of allopurinol therapy, should be preventable by adjustment of allopurinol dose.
Assuntos
Alopurinol/uso terapêutico , Hipoxantina Fosforribosiltransferase/genética , Síndrome de Lesch-Nyhan/tratamento farmacológico , Erros Inatos do Metabolismo da Purina-Pirimidina/tratamento farmacológico , Adolescente , Adulto , Alopurinol/administração & dosagem , Alopurinol/efeitos adversos , Antimetabólitos/efeitos adversos , Antimetabólitos/uso terapêutico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Seguimentos , Humanos , Lactente , Rim/fisiopatologia , Síndrome de Lesch-Nyhan/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/metabolismo , Erros Inatos do Metabolismo da Purina-Pirimidina/fisiopatologia , Purinas/metabolismo , Estudos Retrospectivos , Resultado do Tratamento , Ácido Úrico/sangue , Ácido Úrico/urinaAssuntos
Transportadores de Ânions Orgânicos , Erros Inatos do Metabolismo da Purina-Pirimidina , Ácido Úrico/sangue , Proteínas de Transporte/genética , Diagnóstico Diferencial , Humanos , Túbulos Renais/metabolismo , Mutação , Proteínas de Transporte de Cátions Orgânicos , Purina-Núcleosídeo Fosforilase/deficiência , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/etiologia , Erros Inatos do Metabolismo da Purina-Pirimidina/fisiopatologia , Ácido Úrico/metabolismo , Xantina Oxidase/deficiênciaRESUMO
A 60-year-old Japanese man was diagnosed as having hypouricemia at an annual health check-up. The routine laboratory data was not remarkable except that the patient's hypouricemia and plasma levels of xanthine and hypoxanthine were much higher than those of normal subjects. Furthermore, the patient's daily urinary excretion of xanthine and hypoxanthine was markedly increased compared with reference values. The xanthine dehyrogenase activity of the duodenal mucosa was below the limits of detection. Nevertheless, allopurinol was metabolized to oxypurinol in vivo. Based on these findings, a subtype of classical xanthinuria (type I) was diagnosed. The xanthine dehyrogenase protein was detected by Western blotting analysis. Sequencing of the cDNA of the xanthine dehyrogenase obtained from the duodenal mucosa revealed that a point mutation of C to T had occurred in nucleotide 445. This changed codon 149 from CGC (Arg) to TGC (Cys), a finding that has not been previously reported in patients with classical xanthinuria type I.
Assuntos
Hipoxantina/urina , Mutação Puntual , Erros Inatos do Metabolismo da Purina-Pirimidina/enzimologia , Xantina Desidrogenase/genética , Xantina/urina , Alopurinol/administração & dosagem , Alopurinol/urina , Humanos , Hipoxantina/sangue , Masculino , Pessoa de Meia-Idade , Oxipurinol/urina , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/fisiopatologia , Erros Inatos do Metabolismo da Purina-Pirimidina/urina , Análise de Sequência de DNA , Xantina/sangue , Xantina Desidrogenase/metabolismoAssuntos
Adenilossuccinato Liase/deficiência , Erros Inatos do Metabolismo da Purina-Pirimidina , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/metabolismo , Adenilossuccinato Liase/genética , Diagnóstico Diferencial , Humanos , Mutação , Prognóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/etiologia , Erros Inatos do Metabolismo da Purina-Pirimidina/fisiopatologiaAssuntos
Adenosina Desaminase/deficiência , Erros Inatos do Metabolismo da Purina-Pirimidina , Adenosina Desaminase/genética , Transplante de Medula Óssea , Humanos , Mutação , Prognóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/etiologia , Erros Inatos do Metabolismo da Purina-Pirimidina/fisiopatologiaRESUMO
The pyrimidines, uracil and thymine, are degraded in four steps. The first three steps of pyrimidine catabolism, controlled by enzyme shared by both pathways, result in the production of the neurotransmitter amino acid beta-alanine from uracil and the nonfunctional (R)-(-)-beta-aminoisobutyrate from thymine. The fourth step is controlled by several aminotransferases, which have different affinities for beta-alanine, beta-aminoisobutyrate and GABA. Defects concerning the first three steps all lead to a reduced production of beta-alanine; defects of the transaminases involving the metabolism of beta-alanine and GABA lead to accumulation of these neurotransmitter substances. In addition, other metabolites will accumulate or be reduced depending on the specific enzyme defect. Analysis of the abnormal concentrations of these metabolites in the body fluids is essential for the detection of patients with pyrimidine degradation defects. Clinically these disorders are often overlooked because symptomatology is highly aspecific. The growth in our knowledge concerning inborn errors of pyrimidine degradation has emphasized the importance of the clinical awareness of these defects as a possible cause of neurological disease and a contraindication for treatment of cancer patients with certain pyrimidine analogues. The various defects are discussed and attention is paid to clinical genetic and diagnostic aspects.
Assuntos
Erros Inatos do Metabolismo da Purina-Pirimidina , Pirimidinas/metabolismo , Amidoidrolases/metabolismo , Animais , Di-Hidrouracila Desidrogenase (NADP) , Humanos , Oxirredutases/metabolismo , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/fisiopatologia , Erros Inatos do Metabolismo da Purina-Pirimidina/terapiaRESUMO
A case of a child presenting with congenital abnormalities at birth is reported. The early development remained severely retarded and acquired skills minimally. The head circumference centile decreased. Magnetic resonance imaging showed progressive neuronal atrophy and secondary delay in myelination. Dihydropyrimidine concentrations in body fluids were quantitated by NMR spectroscopy. Enzymatic assay in the liver biopsy revealed total deficiency of dihydropyrimidinase (DHP) (5,6-dihydropyrimidine amidohydrolase; EC 3.5.2.2). As such, the patient is the first with enzymatically proven DHP deficiency. Thus far dihydropyrimidinuria has been reported in three other patients with a variety of neurological abnormalities. A relation of the enzyme deficiency with the neurodegenerative clinical course in our patient is suggested.