Recurrent exercise-induced acute renal failure in a young Pakistani man with severe renal hypouricemia and SLC2A9 compound heterozygosity.

BACKGROUND: Familial renal hypouricemia (RHUC) is a hereditary disease characterized by hypouricemia, high renal fractional excretion of uric acid (FE-UA) and can be complicated by acute kidney failure and nephrolithiasis. Loss-of-function mutations in the SLC22A12 gene cause renal hypouricemia type 1 (RHUC1), whereas renal hypouricemia type 2 (RHUC2) is caused by mutations in the SLC2A9 gene. CASE PRESENTATION: We describe a 24-year-old Pakistani man who was admitted twice to our hospital for severe exercise-induced acute renal failure (EIARF), abdominal pain and fever; he had very low serum UA levels (0.2 mg/dl the first time and 0.09 mg/dl the second time) and high FE-UA (200% and 732% respectively), suggestive of RHUC. Mutational analyses of both urate transporters revealed a new compound heterozygosity for two distinct missense mutations in the SLC2A9 gene: p.Arg380Trp, already identified in heterozygosity, and p.Gly216Arg, previously found in homozygosity or compound heterozygosity in some RHUC2 patients. Compared with previously reported patients harbouring these mutations, our proband showed the highest FE-UA levels, suggesting that the combination of p.Arg380Trp and p.Gly216Arg mutations most severely affects the renal handling of UA. CONCLUSIONS: The clinical and molecular findings from this patient and a review of the literature provide new insights into the genotype-phenotype correlation of this disorder, supporting the evidence of an autosomal recessive inheritance pattern for RHUC2. Further investigations into the functional properties of GLUT9, URAT1 and other urate transporters are required to assess their potential research and clinical implications

Clinical and molecular characterization of 40 patients with classic Ehlers--Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations.

Classic Ehlers-Danlos syndrome (cEDS) is a rare autosomal dominant connective tissue disorder that is primarily characterized by skin hyperextensibility, abnormal wound healing/atrophic scars, and joint hypermobility. A recent study demonstrated that more than 90% of patients who satisfy all of these major criteria harbor a type V collagen (COLLV) defect. This cohort included 40 patients with cEDS who were clinically diagnosed according to the Villefranche nosology. The flowchart that was adopted for mutation detection consisted of sequencing the COL5A1 gene and, if no mutation was detected, COL5A2 analysis. In the negative patients the presence of large genomic rearrangements in COL5A1 was investigated using MLPA, and positive results were confirmed via SNP-array analysis. We report the clinical and molecular characterization of 40 patients from 28 families, consisting of 14 pediatric patients and 26 adults. A family history of cEDS was present in 9 patients. The majority of the patients fulfilled all the major diagnostic criteria for cEDS; atrophic scars were absent in 2 females, skin hyperextensibility was not detected in a male and joint hypermobility was negative in 8 patients (20% of the entire cohort). Wide inter- and intra-familial phenotypic heterogeneity was observed. We identified causal mutations with a detection rate of approximately 93%. In 25/28 probands, COL5A1 or COL5A2 mutations were detected. Twenty-one mutations were in the COL5A1 gene, 18 of which were novel (2 recurrent). Of these, 16 mutations led to nonsense-mediated mRNA decay (NMD) and to COLLV haploinsufficiency and 5 mutations were structural. Two novel COL5A2 splice mutations were detected in patients with the most severe phenotypes. The known p. (Arg312Cys) mutation in the COL1A1 gene was identified in one patient with vascular-like cEDS. Our findings highlight that the three major criteria for cEDS are useful and sufficient for cEDS clinical diagnosis in the large majority of the patients. The borderline patients for whom these criteria fail can be diagnosed when minor signs of connective tissue diseases and family history are present and when genetic testing reveals a defect in COLLV. Our data also confirm that COL5A1 and COL5A2 are the major, if not the only, genes involved in cEDS

Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry

Aims: This study aimed to assess age- and sex-related differences in management and 1-year risk for all-cause mortality and hospitalization in chronic heart failure (HF) patients. Methods and results: Of 16 354 patients included in the European Society of Cardiology Heart Failure Long-Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline-directed medical therapy (GDMT) were high (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P\ua0 64 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1-year follow-up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all-cause mortality were lower in women than in men (7.1% vs. 8.7%; P\ua0=\ua00.015), as were rates of all-cause hospitalization (21.9% vs. 27.3%; P\ua075 years. Conclusions: There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all-cause mortality in patients with LVEF 6445%

Further delineation of Loeys-Dietz syndrome type 4 in a family with mild vascular involvement and a TGFB2 splicing mutation.

BACKGROUND: The Loeys-Dietz syndrome (LDS) is a rare autosomal dominant disorder characterized by thoracic aortic aneurysm and dissection and widespread systemic connective tissue involvement. LDS type 1 to 4 are caused by mutations in genes of the TGF-β signaling pathway: TGFBR1 and TGFBR2 encoding the TGF-β receptor (LDS1 and LDS2), SMAD3 encoding the TGF-β receptor cytoplasmic effector (LDS3), and TGFB2 encoding the TGF-β2 ligand (LDS4). LDS4 represents the mildest end of the LDS spectrum, since aneurysms are usually observed in fourth decade and the progression of the disease is slower than in the other forms. CASE PRESENTATION: We report the clinical and molecular findings of an LDS4 Italian family. Genetic testing included TGFBR1, TGFBR2, SMAD3, and TGFB2 analysis by Sanger sequencing. In order to verify the effect of the identified splice mutation, RT-PCR analysis was performed.The proband, a 57-year-old woman, showed high palate, hypoplasic uvula, easy bruising, joint hypermobility, chronic pain, scoliosis, multiple relapsing hernias, dural ectasia, and mitral valve prolapse. Magnetic resonance angiography revealed tortuosity and ectasia of carotid, vertebral, cerebral, and segmental pulmonary arteries. Arterial aneurysm and dissection never occurred. Her 39- and 34-year-old daughters presented with a variable degree of musculoskeletal involvement. Molecular analysis disclosed the novel c.839-1G>A splice site mutation in the TGFB2 gene. This mutation activates a cryptic splice acceptor site in exon 6 leading to frameshift, premature termination codon and haploinsufficiency (p.Gly280Aspfs*41). CONCLUSIONS: Our data confirm that loss-of-function mutations in TGFB2 gene do not always lead to aggressive vascular phenotypes and that articular and skeletal signs are prevalent, therefore suggesting that LDS4 must be considered in patients with sparse signs of LDS and related disorders also in the absence of vascular events