Recurrent exercise-induced acute kidney injury associated with hypouricemia: a case report and literature review.

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.

A novel heterozygous mutation in the HMBS gene in a patient with acute intermittent porphyria and posterior reversible encephalopathy syndrome.

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.

Reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome in a boy with Loeys-Dietz syndrome.

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.

A novel homozygous GLUT9 mutation cause recurrent exercise-induced acute renal failure and posterior reversible encephalopathy syndrome.

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.

Posterior reversible encephalopathy syndrome in a leber hereditary optic neuropathy patient with mitochondrial DNA 11778G>A point mutation.

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.

Posterior reversible encephalopathy syndrome with exercise-induced acute kidney injury in renal hypouricemia type 1.

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.