Matthias Galiano

Idiopathic infantile hypercalcemia (IIH) is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis. Recently, mutations in the vitamin D catabolizing enzyme 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) were described that lead to increased sensitivity to vitamin D due to accumulation of the active metabolite 1,25-(OH)2D3. In a subgroup of patients who presented in early infancy with renal phosphate wasting and symptomatic hypercalcemia, mutations in CYP24A1 were excluded. Four patients from families with parental consanguinity were subjected to homozygosity mapping that identified a second IIH gene locus on chromosome 5q35 with a maximum logarithm of odds (LOD) score of 6.79. The sequence analysis of the most promising candidate gene, SLC34A1 encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four index cases and in 12 patients with sporadic IIH. Functional studies of mutant NaPi-IIa in Xenopus oocytes and opossum kidney (OK) cells demonstrated disturbed trafficking to the plasma membrane and loss of phosphate transport activity. Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice highlighted the effect of phosphate depletion and fibroblast growth factor-23 suppression on the development of the IIH phenotype. The human and mice data together demonstrate that primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25-(OH)2D3 with subsequent symptomatic hypercalcemia. Clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation. Therefore, early differentiation between SLC34A1 (NaPi-IIa) and CYP24A1 (24-hydroxylase) defects appears critical for targeted therapy in patients with IIH.

IMPORTANCE: Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE: To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS: This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES: Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS: Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001). CONCLUSIONS AND RELEVANCE: The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12–2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants. Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12–2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants. see commentary on page 1104 see commentary on page 1104 Chronic kidney disease (CKD) affects more than 10% of people worldwide.1Levin A. Tonelli M. Bonventre J. et al.Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy.Lancet. 2017; 390: 1888-1917Abstract Full Text Full Text PDF PubMed Scopus (493) Google Scholar Renal fibrosis is the common endpoint of most CKD.2Assady S. Benzing T. Kretzler M. Skorecki K.L. Glomerular podocytes in kidney health and disease.Lancet. 2019; 393: 856-858Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Therefore, preventing or delaying the progression of renal fibrosis is one of the most urgent goals in renoprotective medicine.2Assady S. Benzing T. Kretzler M. Skorecki K.L. Glomerular podocytes in kidney health and disease.Lancet. 2019; 393: 856-858Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar The type IV collagen disease Alport syndrome (AS) is the second most common monogenic cause of end-stage renal failure (ESRF), responsible for almost 4% of CKD in adults.3Groopman E.E. Marasa M. Cameron-Christie S. et al.Diagnostic utility of exome sequencing for kidney disease.N Engl J Med. 2019; 380: 142-151Crossref PubMed Scopus (268) Google Scholar, 4Hertz J.M. Thomassen M. Storey H. Flinter F. Clinical utility gene card for: Alport syndrome—update 2014.Eur J Hum Genet. 2015; 23https://doi.org/10.1038/ejhg.2014.254Crossref PubMed Scopus (34) Google Scholar, 5Hudson B.G. Tryggvason K. Sundaramoorthy M. Neilson E.G. Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen.N Engl J Med. 2003; 348: 2543-2556Crossref PubMed Scopus (752) Google Scholar, 6Kruegel J. Rubel D. Gross O. Alport syndrome—insights from basic and clinical research.Nat Rev Nephrol. 2013; 9: 170-178Crossref PubMed Scopus (171) Google Scholar AS is caused by variants in the COL4A3, COL4A4, and COL4A5 genes, which encode for the α3, α4, and α5 chains of type IV collagen.4Hertz J.M. Thomassen M. Storey H. Flinter F. Clinical utility gene card for: Alport syndrome—update 2014.Eur J Hum Genet. 2015; 23https://doi.org/10.1038/ejhg.2014.254Crossref PubMed Scopus (34) Google Scholar,7Kashtan C.E. Ding J. Garosi G. et al.Alport syndrome: a unified classification of genetic disorders of collagen IV α345: a position paper of the Alport Syndrome Classification Working Group.Kidney Int. 2018; 93: 1045-1051Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar The defective type IV collagen leads to basement membrane defects in the inner ear, eye, and glomerular basement membrane, leading to ESRF early in life (median age: 22 years in Europe).6Kruegel J. Rubel D. Gross O. Alport syndrome—insights from basic and clinical research.Nat Rev Nephrol. 2013; 9: 170-178Crossref PubMed Scopus (171) Google O. et in Alport syndrome renal failure and life Int. Full Text Full Text PDF PubMed Scopus Google Scholar In a of to ESRF therapy with the ramipril is the of O. et ramipril therapy renal failure and renal fibrosis in with Alport Int. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar in a benefit therapy is data that with an ESRF in with AS in a O. et in Alport syndrome renal failure and life Int. Full Text Full Text PDF PubMed Scopus Google Scholar in CKD or ESRF by a of years, in CKD ESRF by a of years, open the of an or is more of AS to the type IV collagen in in with J. Rubel D. Gross O. Alport syndrome—insights from basic and clinical research.Nat Rev Nephrol. 2013; 9: 170-178Crossref PubMed Scopus (171) Google D. et a to study the of Alport Int. Full Text Full Text PDF PubMed Scopus Google Scholar, Alport syndrome and syndrome: of the glomerular basement 2018; PubMed Scopus Google Scholar, M. et to Alport syndrome: a 2015; PubMed Scopus Google Scholar The of in with AS a of to with an the to the glomerular basement membrane B.G. Tryggvason K. Sundaramoorthy M. Neilson E.G. Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen.N Engl J Med. 2003; 348: 2543-2556Crossref PubMed Scopus (752) Google O. et in Alport syndrome renal failure and life Int. Full Text Full Text PDF PubMed Scopus Google Alport syndrome and syndrome: of the glomerular basement 2018; PubMed Scopus Google Scholar AS by genetic testing and a with and to renal J. Rubel D. Gross O. Alport syndrome—insights from basic and clinical research.Nat Rev Nephrol. 2013; 9: 170-178Crossref PubMed Scopus (171) Google Scholar of of renal failure to the study The for trial to a of randomized which is in a pediatric trial for a O. 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Nerve injury triggers numerous changes in the injured neurons and surrounding non-neuronal cells. Of particular interest are molecular signals that play a role in the overall orchestration of this multifaceted cellular response. Here we investigated the function of interleukin-6 (IL6), a multifunctional neurotrophin and cytokine rapidly expressed in the injured nervous system, using the facial axotomy model in IL6-deficient mice and wild-type controls. Transgenic deletion of IL6 caused a massive decrease in the recruitment of CD3-positive T-lymphocytes and early microglial activation during the first 4 days after injury in the axotomized facial nucleus. This was accompanied by a more moderate reduction in peripheral regeneration at day 4, lymphocyte recruitment (day 14) and enhanced perikaryal sprouting (day 14). Motoneuron cell death, phagocytosis by microglial cells and recruitment of granulocytes and macrophages into injured peripheral nerve were not affected. In summary, IL6 lead to a variety of effects on the cellular response to neural trauma. However, the particularly strong actions on lymphocytes and microglia suggest that this cytokine plays a central role in the initiation of immune surveillance in the injured central nervous system.