RESUMO
BACKGROUND: Hereditary renal hypouricemia (RHUC) is a heterogenous disorder characterized by defective uric acid (UA) reabsorption resulting in hypouricemia and increased fractional excretion of UA. RHUC is an important cause of exercise-induced acute kidney injury (EIAKI), nephrolithiasis and posterior reversible encephalopathy syndrome (PRES). We present here an unusual case of a patient with RHUC who presented with recurrent EIAKI and had two heterozygous mutations in the SLC2A9 gene. CASE PRESENTATION: A 43-year old man was admitted to our clinic because of bilateral loin pain, nausea and sleeplessness for 3 days after strenuous exercise. The laboratory results revealed increased levels of blood urea nitrogen (BUN) (15 mmol/l) and serum creatinine (Scr) (450 µmol/l), while the UA level was extremely low at 0.54 mg/dl, and his fractional excretion of urate (FE-UA) was 108%. The patient had an episode of acute kidney injury after playing soccer approximately 20 years ago, and on routine physical examination, his UA was less than 0.50 mg/dl. In view of the marked hypouricemia and high FE-UA, a diagnosis of RHUC was suspected, which led us to perform mutational screening of the SLC22A12 and SLC2A9 genes. DNA sequencing revealed no mutation in SLC22A12 gene, but two heterozygous mutations in the SLC2A9 gene. CONCLUSIONS: This is a rare report of a patient with RHUC2 due to the mutation of SLC2A9. And this unique symptom of EIAKI and decreased or normal serum concentrations of UA warrant more attention as an early cue of RHUC.
Assuntos
Injúria Renal Aguda , Transportadores de Ânions Orgânicos , Síndrome da Leucoencefalopatia Posterior , Masculino , Humanos , Adulto , Síndrome da Leucoencefalopatia Posterior/complicações , Síndrome da Leucoencefalopatia Posterior/diagnóstico , Síndrome da Leucoencefalopatia Posterior/genética , Proteínas Facilitadoras de Transporte de Glucose/genética , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/complicações , Heterozigoto , Mutação , Ácido Úrico , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genéticaRESUMO
Acute intermittent porphyria (AIP) is a rare inherited disorder, which is caused by the partial deficiency of hydroxymethylbilane synthase (HMBS), an enzyme of the heme biosynthetic pathway. Abdominal pain, neuropsychiatric disturbance and neuropathy are the typical manifestations of the disease. Complications such as posterior reversible encephalopathy syndrome (PRES), a rare type of brain lesion present on MRI, are also observed in patients with AIP. The present study reports on the case of a 36yearold Chinese female patient with AIP and PRES. Genomic DNA were obtained from peripheral blood leukocytes and genomic regions of the HMBS gene were amplified as 2 fragments, which together contained all the exons and flanking intronic regions. Sanger sequencing of the amplified DNA fragments from the patient and the patient's family revealed a novel frameshift deletion (c.405406delAA) in exon 8 of the HMBS gene. This mutation leads to a subsequent truncated protein (p.Glu135AspfsX74). The recombinant mutant protein had 62% activity relative to the wildtype protein but similar thermostability. It was confirmed that this novel mutation was the cause of AIP. Accumulation of Daminolevulinic acid (ALA) due to HMBS dysfunction is a potential mechanism of PRES. The manifestation of PRES may be associated with ALAinduced cytotoxicity and the destruction of the bloodbrain barrier. In summary, in the present study, a novel pathogenic HMBS mutation was identified, expanding on the molecular heterogeneity of AIP.
Assuntos
Hidroximetilbilano Sintase/genética , Porfiria Aguda Intermitente/genética , Síndrome da Leucoencefalopatia Posterior/genética , Adulto , Povo Asiático/genética , Feminino , Mutação da Fase de Leitura , Heterozigoto , Humanos , Mutação , Linhagem , Porfiria Aguda Intermitente/complicações , Síndrome da Leucoencefalopatia Posterior/complicaçõesAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Mutação , Síndrome da Leucoencefalopatia Posterior/induzido quimicamente , Proteínas Proto-Oncogênicas B-raf/genética , Azetidinas/administração & dosagem , Feminino , Humanos , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Síndrome da Leucoencefalopatia Posterior/genética , Síndrome da Leucoencefalopatia Posterior/patologia , Prognóstico , Vemurafenib/administração & dosagem , Suspensão de TratamentoRESUMO
Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder, caused by heterozygous mutations in TGFBR1 or TGFBR2 and characterized by vascular complications (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections) and skeletal manifestations. We here report the first patient with LDS presenting with reversible cerebral vasoconstriction syndrome (RCVS), a clinico-radiological condition characterized by recurrent thunderclap headaches, with or without neurological symptoms, and reversible vasoconstriction of cerebral arteries. The patient was a 9-year-old boy with a heterozygous TGFBR2 mutation, manifesting camptodactyly, talipes equinovarus, and lamboid craniosynostosis. He complained of severe recurrent headaches 2 months after total aortic replacement for aortic root dilatation and a massive Stanford type B aortic dissection. A thoracic CT scan revealed a left subclavian artery dissection. Brain MRI and MRA detected bilateral internal carotid artery constriction along with a cortical subarachnoid hemorrhage without intracranial aneurysms. Subsequently, he developed visual disturbance and a generalized seizure associated with multiple legions of cortical and subcortical increased signals including the left posterior lobe, consistent with posterior reversible encephalopathy syndrome (PRES), a condition characterized by headaches, visual disorders, seizures, altered mentation, consciousness disturbances, focal neurological signs, and vasogenic edema predominantly in the white matter of the posterior lobe. Vasoconstriction of the internal carotid artery was undetectable 2 months later, and he was diagnosed as having RCVS. Endothelial dysfunction, associated with impaired TGF-ß signaling, might have been attributable to the development of RCVS and PRES.
Assuntos
Dissecção Aórtica/genética , Síndrome de Loeys-Dietz/genética , Síndrome da Leucoencefalopatia Posterior/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Hemorragia Subaracnóidea/genética , Vasoconstrição , Dissecção Aórtica/sangue , Dissecção Aórtica/patologia , Artérias Cerebrais/metabolismo , Artérias Cerebrais/patologia , Criança , Expressão Gênica , Heterozigoto , Humanos , Síndrome de Loeys-Dietz/sangue , Síndrome de Loeys-Dietz/patologia , Masculino , Mutação , Síndrome da Leucoencefalopatia Posterior/sangue , Síndrome da Leucoencefalopatia Posterior/patologia , Proteínas Serina-Treonina Quinases/sangue , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/sangue , Transdução de Sinais , Hemorragia Subaracnóidea/sangue , Hemorragia Subaracnóidea/patologiaRESUMO
Renal hypouricemia (RHU) is an autosomal recessive hereditary disease characterized by impaired renal urate reabsorption and subsequent profound hypouricemia. There are two types of RHU, type 1 and type 2, caused by the loss-of-function mutation of SLC22A12 and SLC2A9 genes, respectively. RHU predisposes affected people to exercise-induced acute renal failure (EIARF), posterior reversible encephalopathy syndrome (PRES) and nephrolithiasis. A Chinese patient had experienced three episodes of EIARF and one episode of PRES. The investigations showed profound hypouricemia and significantly increased renal excretion of UA. Cranial magnetic resonance imaging showed communicating hydrocephalus. Renal biopsy displayed interlobular artery intimal thickening with reduction of lumen and acute tubulointerstitial injury. The mutational analysis revealed a homozygous splice-site mutation in the SLC2A9 gene encoding glucose transporter 9. The patient was diagnosed as RHU type 2 caused by a loss-of-function mutation of the SLC2A9 gene. Consequently, he was strictly prohibited from strenuous exercise. During the 5-year follow-up, EIARF and PRES never recurred. Strenuous exercise may induce systemic (including renal and cerebrovascular) vasoconstriction eventually resulting in EIARF and PRES in patients with RHU. To our knowledge, this is the first report of a homozygous splice-site mutation in the SLC2A9 gene, renal arteriolar chronic lesion, concurrence of RHU and communicating hydrocephalus.
Assuntos
Injúria Renal Aguda/genética , Exercício Físico , Proteínas Facilitadoras de Transporte de Glucose/genética , Homozigoto , Mutação , Síndrome da Leucoencefalopatia Posterior/genética , Erros Inatos do Transporte Tubular Renal/genética , Cálculos Urinários/genética , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/fisiopatologia , Adolescente , Biópsia , Criança , Análise Mutacional de DNA , Predisposição Genética para Doença , Hereditariedade , Humanos , Imageamento por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Síndrome da Leucoencefalopatia Posterior/diagnóstico , Síndrome da Leucoencefalopatia Posterior/fisiopatologia , Valor Preditivo dos Testes , Sítios de Splice de RNA , Recidiva , Erros Inatos do Transporte Tubular Renal/diagnóstico , Erros Inatos do Transporte Tubular Renal/fisiopatologia , Fatores de Risco , Fatores de Tempo , Cálculos Urinários/diagnóstico , Cálculos Urinários/fisiopatologia , Adulto JovemAssuntos
Síndrome da Leucoencefalopatia Posterior/induzido quimicamente , Idoso , Antirreumáticos/efeitos adversos , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Humanos , Imageamento por Ressonância Magnética , Masculino , Metotrexato/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação/genética , Síndrome da Leucoencefalopatia Posterior/diagnóstico , Síndrome da Leucoencefalopatia Posterior/genética , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder that primarily affects the optic nerve. We report a case of reduced visual acuity secondary to optic atrophy in a 13-year-old boy. Transient seizures developed subsequently. Serial magnetic resonance imaging of the brain showed posterior reversible encephalopathy syndrome. Ragged red fibers were not detected on skeletal muscle biopsy. A 11778G>A mitochondrial DNA point mutation was identified in the lymphocytes isolated from peripheral blood. His younger brother was a carrier with the same mutation. The presentation of this case is unusual documenting LHON in association with PRES.
Assuntos
DNA Mitocondrial/genética , Atrofia Óptica Hereditária de Leber/complicações , Síndrome da Leucoencefalopatia Posterior/complicações , Adolescente , Encéfalo/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/patologia , Mutação Puntual , Síndrome da Leucoencefalopatia Posterior/genética , Síndrome da Leucoencefalopatia Posterior/patologiaRESUMO
Renal hypouricemia type 1 is caused by mutations in the SLC22A12 gene, whereas type 2 is caused by defects in the SLC2A9 gene. Although both subtypes predispose to exercise-induced acute kidney injury (EIAKI), posterior reversible encephalopathy syndrome (PRES) occurring with this disorder is an uncommon phenomenon that has only been reported to date in a patient with renal hypouricemia type 2. We describe a 13-year-old boy with renal hypouricemia type 1 (serum uric acid, 0.9 mg/dL) with a homozygous W258X mutation in the SLC22A12 gene, presenting with EIAKI and PRES. On admission, his body weight was 61 kg (11 kg above the dry weight), and blood pressure was 153/88 mmHg. Cranial magnetic resonance imaging revealed high-intensity areas in the cortical and subcortical white matter of the occipital lobe. After admission, the patient responded well to a combination of hemodialysis and intravenous nicardipine. This is the first case of concurrent PRES and EIAKI in a patient with renal hypouricemia type 1. We suggest that PRES is not due to severe hypouricemia caused by SLC2A9 mutation but is a manifestation of severe EIAKI associated with renal hypouricemia.