[Kidney allotransplantation from alive related donor in patients with Alport syndrome].

PubMed

Goriaĭnov, V A; Kaabak, M M; Babenko, N N; Morozova, M M; Aganesov, A P; Panin, V V; Platova, E N; Dymova, O V

2016-01-01

To evaluate the results of kidney transplantation from alive related donor in patients with Alport syndrome and to compare with those in patients with kidney hypoplasia. We have analyzed 8 and 27 medical records of patients with Alport syndrome and kidney hypoplasia respectively. Following parameters were used - Kaplan-Meier survival analysis, Wilcox overall risk, percentage of transplants loss and mortality (Fisher's exact test calculation). It is concluded that percentage of transplants loss and mortality rate as well as overall survival and risk were similar in both groups. Despite risk of anti-GBM nephritis development in patients with Alport syndrome results are comparable with those after transplatation for chronic renal failure caused by other reasons.

Shining a Light on Alport Syndrome.

PubMed

Hale, Lorna J; Little, Melissa H

2018-05-17

In this issue of Cell Chemical Biology, Omachi et al. (2018) present a split Nanoluciferase system to identify successful protein trimerization in Alport syndrome. This elegant proof of concept suggests opportunities for drug screening for Alport syndrome and may be transferable to the study of other diseases affecting protein-protein interactions. Copyright © 2018 Elsevier Ltd. All rights reserved.

Outcomes of kidney transplantation in Alport syndrome compared with other forms of renal disease.

PubMed

Kelly, Yvelynne P; Patil, Anish; Wallis, Luke; Murray, Susan; Kant, Saumitra; Kaballo, Mohammed A; Casserly, Liam; Doyle, Brendan; Dorman, Anthony; O'Kelly, Patrick; Conlon, Peter J

2017-11-01

Alport syndrome is an inherited renal disease characterized by hematuria, renal failure, hearing loss and a lamellated glomerular basement membrane. Patients with Alport syndrome who undergo renal transplantation have been shown to have patient and graft survival rates similar to or better than those of patients with other renal diseases. In this national case series, based in Beaumont Hospital Dublin, we studied the cohort of patients who underwent renal transplantation over the past 33 years, recorded prospectively in the Irish Renal Transplant Registry, and categorized them according to the presence or absence of Alport syndrome. The main outcomes assessed were patient and renal allograft survival. Fifty-one patients diagnosed with Alport syndrome in Beaumont Hospital received 62 transplants between 1982 and 2014. The comparison group of non-Alport patients comprised 3430 patients for 3865 transplants. Twenty-year Alport patient survival rate was 70.2%, compared to 44.8% for patients with other renal diseases (p = .01). Factors associated with patient survival included younger age at transplantation as well as differences in recipient sex, donor age, cold ischemia time, and episodes of acute rejection. Twenty-year graft survival was 46.8% for patients with Alport syndrome compared to 30.2% for those with non-Alport disease (p = .11). Adjusting for baseline differences between the groups, patients with end-stage kidney disease (ESKD) due to Alport syndrome have similar patient and graft survival to those with other causes of ESKD. This indicates that early diagnosis and management can lead to favorable outcomes for this patient cohort.

Alport Syndrome Diagnosis

MedlinePlus

... the presence or absence of the type IV collagen alpha-3, alpha-4 and alpha-5 chains ( ... linked Alport syndrome) is suspected. The type IV collagen alpha-5 chain (COL4A5) is normally present in ...

[Clinical and pathological features of Alport syndrome in children].

PubMed

Zhu, Chun-Hua; Huang, Song-Ming; Wu, Hong-Mei; Bao, Hua-Ying; Chen, Ying; Han, Yuan; Zhao, Fei; Zhang, Ai-Hua; Zhang, Wei-Zhen

2010-03-01

To study the clinical and pathological features of Alport syndrome in children. The clinical and histopathological data of 10 hospitalized children with Alport syndrome from February 2007 to February 2009 were retrospectively reviewed. There were 7 males and 3 females, with the age ranging from 2 years to 6 years and 7 months (mean 3 years and 2 months). Five of 10 cases had positive family history. X-linked dominant inheritance Alport syndrome was diagnosed in 8 cases, and autosomal recessive inheritance Alport syndrome in 2 cases. Recurrent gross hematuria was found in 5 cases, hematuria and proteinuria in 3 cases, massive proteinuria in 1 case, and nephritic syndrome in 1 case. Under the light microscope, 8 cases presented with mesangial proliferation glomerulonephritis, and 2 cases with focal segmental glomerulosclerosis. Immunofluorescence assay showed that all cases had IgM deposition in glomerulus. Only 1 case showed typical glomerular basement membrane (GBM) pathological changes. All cases showed abnormal alpha-chain distribution in renal collagen IV. The children with Alport syndrome have diverse clinical manifestations. Characteristic histopathological presentations could not be found under a light microscope, mesangial proliferation glomerulonephritis is the dominant pathological change, and IgM deposition in glomerulus is common. The GBM pathological change in children is not common. Immunofluorescence assay of alpha-chain in collagen IV is needed for the diagnosis of Alport syndrome.

Bilateral giant macular holes: A rare manifestation of Alport syndrome.

PubMed

Raimundo, Miguel; Fonseca, Cristina; Silva, Rufino; Figueira, João

2018-05-01

Alport syndrome is a rare condition characterized by the clinical triad of nephritic syndrome, sensorineural deafness, and ophthalmological alterations. Herein, we present a rare case of a patient diagnosed with Alport syndrome and bilateral giant macular holes. A 40-year-old woman with a previously unreported mutation in the COL4A4 gene suggestive of autosomal-recessive Alport syndrome presented at our department. The patient exhibited bilateral full-thickness macular holes measuring >1500 µm at their smallest diameters. The very large dimensions of both macular holes were indicative of a bad prognosis regarding hole closure, and a conservative approach was adopted. The patient was maintained on renal substitution therapy, and genetic counseling was offered to other family members. Ophthalmological findings associated to Alport syndrome commonly include anterior lenticonus and dot-and-fleck retinopathy, although giant macular holes can also be associated with this condition. A multidisciplinary approach is crucial in the management of these patients, as Alport syndrome is an inherited systemic basement membrane disease.

Alport syndrome--insights from basic and clinical research.

PubMed

Kruegel, Jenny; Rubel, Diana; Gross, Oliver

2013-03-01

In 1927, Arthur C. Alport first published his description of a triad of symptoms in a family with hereditary congenital haemorrhagic nephritis, deafness and ocular changes. A few years after his death, this group of symptoms was renamed Alport syndrome. To this day, Alport syndrome still inevitably leads to end-stage renal disease and the need for renal replacement therapy, starting in young adulthood. During the past two decades, research into this rare disease has focused on the effects of mutations in collagen type IV and the role of changes in podocytes and the glomerular basement membrane that lead to early kidney fibrosis. Animal models of Alport syndrome also demonstrate the pathogenetic importance of interactions between podocytes and the extracellular matrix. Such models might also help researchers to answer basic questions about podocyte function and the development of fibrosis, and to develop new therapeutic approaches that might be of use in other kidney diseases. In this Review, we discuss the latest basic and clinical research on Alport syndrome, focusing on the roles of podocyte pathology and the extracellular matrix. We also highlight early diagnosis and treatment options for young patients with this disorder.

A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population.

PubMed

Webb, B D; Brandt, T; Liu, L; Jalas, C; Liao, J; Fedick, A; Linderman, M D; Diaz, G A; Kornreich, R; Trachtman, H; Mehta, L; Edelmann, L

2014-08-01

Alport syndrome is an inherited progressive nephropathy arising from mutations in the type IV collagen genes, COL4A3, COL4A4, and COL4A5. Symptoms also include sensorineural hearing loss and ocular lesions. We determined the molecular basis of Alport syndrome in a non-consanguineous Ashkenazi Jewish family with multiple affected females using linkage analysis and next generation sequencing. We identified a homozygous COL4A3 mutation, c.40_63del, in affected individuals with mutant alleles inherited from each parent on partially conserved haplotypes. Large-scale population screening of 2017 unrelated Ashkenazi Jewish samples revealed a carrier frequency of 1 in 183 indicating that COL4A3 c.40_63del is a founder mutation which may be a common cause of Alport syndrome in this population. Additionally, we determined that heterozygous mutation carriers in this family do not meet criteria for a diagnosis of Thin Basement Membrane Nephropathy and concluded that carriers of c.40_63del are not likely to develop benign familial hematuria. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Renal, auricular, and ocular outcomes of Alport syndrome and their current management.

PubMed

Zhang, Yanqin; Ding, Jie

2017-09-01

Alport syndrome is a hereditary glomerular basement membrane disease caused by mutations in the COL4A3/4/5 genes encoding the type IV collagen alpha 3-5 chains. Most cases of Alport syndrome are inherited as X-linked dominant, and some as autosomal recessive or autosomal dominant. The primary manifestations are hematuria, proteinuria, and progressive renal failure, whereas some patients present with sensorineural hearing loss and ocular abnormalities. Renin-angiotensin-aldosterone system blockade is proven to delay the onset of renal failure by reducing proteinuria. Renal transplantation is a curative treatment for patients who have progressed to end-stage renal disease. However, only supportive measures can be used to improve hearing loss and visual loss. Although both stem cell therapy and gene therapy aim to repair the basement membrane defects, technical difficulties require more research in Alport mice before clinical studies. Here, we review the renal, auricular, and ocular manifestations and outcomes of Alport syndrome and their current management.

A Novel Mutation in a Kazakh Family with X-Linked Alport Syndrome

PubMed Central

Rakhimova, Saule E.; Nigmatullina, Nazym B.; Momynaliev, Kuvat T.; Ramanculov, Yerlan M.

2015-01-01

Alport syndrome is a genetic condition that results in hematuria, progressive renal impairment, hearing loss, and occasionally lenticonus and retinopathy. Approximately 80% of Alport syndrome cases are caused by X-linked mutations in the COL4A5 gene encoding type IV collagen. The objective of this study was to define the SNP profiles for COL4A5 in patients with hereditary nephritis and hematuria. For this, we examined four subjects from one Kazakh family clinically affected with X-linked Alport syndrome due to COL4A5 gene mutations. All 51 exons of the COL4A5 gene were screened by linkage analysis and direct DNA sequencing, resulting in the identification of a novel mutation (G641E) in exon 25. The mutation was found only in two affected family individuals but was not present in healthy family members or 200 unrelated healthy controls. This result demonstrates that this novel mutation is pathogenic and has meaningful implications for the diagnosis of patients with Alport syndrome. PMID:26168235

A Novel Mutation in a Kazakh Family with X-Linked Alport Syndrome.

PubMed

Baikara, Barshagul T; Zholdybayeva, Elena V; Rakhimova, Saule E; Nigmatullina, Nazym B; Momynaliev, Kuvat T; Ramanculov, Yerlan M

2015-01-01

Alport syndrome is a genetic condition that results in hematuria, progressive renal impairment, hearing loss, and occasionally lenticonus and retinopathy. Approximately 80% of Alport syndrome cases are caused by X-linked mutations in the COL4A5 gene encoding type IV collagen. The objective of this study was to define the SNP profiles for COL4A5 in patients with hereditary nephritis and hematuria. For this, we examined four subjects from one Kazakh family clinically affected with X-linked Alport syndrome due to COL4A5 gene mutations. All 51 exons of the COL4A5 gene were screened by linkage analysis and direct DNA sequencing, resulting in the identification of a novel mutation (G641E) in exon 25. The mutation was found only in two affected family individuals but was not present in healthy family members or 200 unrelated healthy controls. This result demonstrates that this novel mutation is pathogenic and has meaningful implications for the diagnosis of patients with Alport syndrome.

Clinical and genetic features in autosomal recessive and X-linked Alport syndrome.

PubMed

Wang, Yanyan; Sivakumar, Vanessa; Mohammad, Mardhiah; Colville, Deb; Storey, Helen; Flinter, Frances; Dagher, Hayat; Savige, Judy

2014-03-01

This study determined the family history and clinical features that suggested autosomal recessive rather than X-linked Alport syndrome. All patients had the diagnosis of Alport syndrome and the mode of inheritance confirmed by genetic testing, and underwent examination at a single centre. Patients comprised 9 males and 6 females with autosomal recessive Alport syndrome, and 18 males and 22 females with X-linked disease. Fourteen (93 %) individuals with autosomal recessive Alport syndrome developed early end-stage renal failure, all 15 had hearing loss, and most had lenticonus (12, 80 %), and a central (13, 87 %) or peripheral (13, 87 %) retinopathy. These features occurred as often as in males with X-linked disease. Females with autosomal recessive inheritance were less likely to have an affected family member in another generation (p = 0.01) than females with X-linked disease. They were more likely to have renal failure (p = 0.003), hearing loss (p = 0.02) and lenticonus (p < 0.001). Fifty percent had a central retinopathy compared with 18 % with X-linked disease (p = 0.14), but peripheral retinopathy prevalence was not different (p = 0.64). Nonsense mutations accounted for 67 % (8/12) of these disease-causing mutations. Autosomal recessive inheritance is increased in females with Alport syndrome and early onset renal failure, hearing loss, lenticonus, and, possibly, central retinopathy.

Role for Macrophage Metalloelastase in Glomerular Basement Membrane Damage Associated with Alport Syndrome

PubMed Central

Rao, Velidi H.; Meehan, Daniel T.; Delimont, Duane; Nakajima, Motowo; Wada, Takashi; Ann Gratton, Michael; Cosgrove, Dominic

2006-01-01

Alport syndrome is a glomerular basement membrane (GBM) disease caused by mutations in type IV collagen genes. A unique irregular thickening and thinning of the GBM characterizes the progressive glomerular pathology. The metabolic imbalances responsible for these GBM irregularities are not known. Here we show that macrophage metalloelastase (MMP-12) expression is >40-fold induced in glomeruli from Alport mice and is markedly induced in glomeruli of both humans and dogs with Alport syndrome. Treatment of Alport mice with MMI270 (CGS27023A), a broad spectrum MMP inhibitor that blocks MMP-12 activity, results in largely restored GBM ultrastructure and function. Treatment with BAY-129566, a broad spectrum MMP inhibitor that does not inhibit MMP-12, had no effect. We show that inhibition of CC chemokine receptor 2 (CCR2) receptor signaling with propagermanium blocks induction of MMP-12 mRNA and prevents GBM damage. CCR2 receptor is expressed in glomerular podocytes of Alport mice, suggesting MCP-1 activation of CCR2 on podocytes may underlie induction of MMP-12. These data indicate that the irregular GBM that characterizes Alport syndrome may be mediated, in part, by focal degradation of the GBM due to MMP dysregulation, in particular, MMP-12. Thus, MMP-12/CCR2 inhibitors may provide a novel and effective therapeutic strategy for Alport glomerular disease. PMID:16816359

Searching for a treatment for Alport syndrome using mouse models.

PubMed

Katayama, Kan; Nomura, Shinsuke; Tryggvason, Karl; Ito, Masaaki

2014-11-06

Alport syndrome (AS) is a hereditary nephritis caused by mutations in COL4A3, COL4A4 or COL4A5 encoding the type IV collagen α3, α4, and α5 chains, which are major components of the glomerular basement membrane. About 20 years have passed since COL4A3, COL4A4, and COL4A5 were identified and the first Alport mouse model was developed using a knockout approach. The phenotype of Alport mice is similar to that of Alport patients, including characteristic thickening and splitting of the glomerular basement membrane. Alport mice have been widely used to study the pathogenesis of AS and to develop effective therapies. In this review, the newer therapies for AS, such as pharmacological interventions, genetic approaches and stem cell therapies, are discussed. Although some stem cell therapies have been demonstrated to slow the renal disease progression in Alport mice, these therapies demand continual refinement as research advances. In terms of the pharmacological drugs, angiotensin-converting enzyme inhibitors have been shown to be effective in Alport mice. Novel therapies that can provide a better outcome or lead to a cure are still awaited.

Alport syndrome and thin glomerular basement membrane nephropathy: a practical approach to diagnosis.

PubMed

Haas, Mark

2009-02-01

Alport syndrome and thin glomerular basement membrane nephropathy (TBMN) are genetically heterogeneous conditions characterized by structural abnormalities in the glomerular basement membrane and an initial presentation that usually involves hematuria. Approximately 40% of patients with TBMN are heterozygous carriers for autosomal recessive Alport syndrome, with mutations at the genetic locus encoding type IV collagen alpha(3) [alpha(3)(IV)] and alpha(4) chains. However, although the clinical course of TBMN is usually benign, Alport syndrome, particularly the X-linked form with mutations in the locus encoding the alpha(5) chain of type IV collagen [alpha(5)(IV)], typically results in end-stage renal disease. Electron microscopy is essential to diagnosis of TBMN and Alport syndrome on renal biopsy, although electron microscopy alone is of limited value in distinguishing between TBMN, the heterozygous carrier state of X-linked Alport syndrome, autosomal recessive Alport syndrome, and even early stages of X-linked Alport syndrome. To review diagnostic pathologic features of each of the above conditions, emphasizing the need for immunohistology for alpha(3)(IV) and alpha(5)(IV) in addition to electron microscopy to resolve this differential diagnosis on a renal biopsy. The diagnostic value of immunofluorescence studies for alpha(5)(IV) on a skin biopsy in family members of patients with Alport syndrome also is reviewed. Original and comprehensive review articles on the diagnosis of Alport syndrome and TBMN from the past 35 years, primarily the past 2 decades, and experience in our own renal pathology laboratory. Although Alport syndrome variants and TBMN do not show characteristic light microscopic findings and can be difficult to differentiate from each other even by electron microscopy, using a combination of electron microscopy and immunohistology for alpha(3)(IV) and alpha(5)(IV) enables pathologists to definitively diagnose these disorders on renal biopsy in most

A mutation causing Alport syndrome with tardive hearing loss is common in the western United States

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barker, D.F.; Denison, J.C.; Atkin, C.L.

1996-06-01

Mutations in the COL4A5 gene, located at Xq22, cause Alport syndrome (AS), a nephritis characterized by progressive deterioration of the glomerular basement membrane and usually associated with progressive hearing loss. We have identified a novel mutation, L1649R, present in 9 of 121 independently ascertained families. Affected males shared the same haplotype of eight polymorphic markers tightly linked to COL4A5, indicating common ancestry. Genealogical studies place the birth of this ancestor >200 years ago. The L1649R mutation is a relatively common cause of Alport syndrome in the western United States, in part because of the rapid growth and migratory expansion ofmore » mid-nineteenth-century pioneer populations carrying the gene. L1649R affects a highly conserved residue in the NC1 domain, which is involved in key inter- and intramolecular interactions, but results in a relatively mild disease phenotype. Renal failure in an L1649R male typically occurs in the 4th or 5th decade and precedes the onset of significant hearing loss by {approximately}10 years. 45 refs., 5 figs.« less

COL4A4 gene study of a European population: description of new mutations causing autosomal dominant Alport syndrome.

PubMed

Rosado, Consolación; Bueno, Elena; Felipe, Carmen; González-Sarmiento, Rogelio

2014-01-01

Autosomal forms of Alport syndrome represent 20% of all patients (15% recessive and 5% dominant). They are caused by mutations in the COL4A3 and COL4A4 genes, which encode a-3 and a-4 collagen IV chains of the glomerular basement membrane, cochlea and eye. Thin basement membrane nephropathy may affect up to 1% of the population. The pattern of inheritance in the 40% of cases is the same as autosomal dominant Alport syndrome: heterozygous mutations in these genes. The aim of this study is to detect new pathogenic mutations in the COL4A4 gene in the patients previously diagnosed with autosomal Alport syndrome and thin basement membrane nephropathy in our hospital. We conducted a clinical and genetic study in eleven patients belonging to six unrelated families with aforementioned clinical symptoms and a negative study of COL4A3 gene. The molecular study was made by conformation of sensitive gel electrophoresis (CSGE) and direct sequencing of the fragments that show an altered electrophoretic migration pattern. We found two pathogenic mutations, not yet described: IVS3 + 1G > C is a replacement of Guanine to Cytosine in position +1 of intron 3, in the splicing region, which leads to a pathogenic mutation. c.4267C > T; p.P1423S is a missense mutation, also considered pathogenic. We also found seven new polymorphisms. We describe two new pathogenic mutations, responsible for autosomal dominant Alport syndrome. The other families of the study were undiagnosed owing to problems in the method employed and the possibility of mutations in other genes, giving rise to other diseases with similar symptoms.

Simultaneous Bilateral Anterior and Posterior Lenticonus in Alport Syndrome.

PubMed

Bamotra, Ravi Kant; Meenakshi; Kesarwani, Prem Chandra; Qayum, Shazia

2017-08-01

Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities like anterior lenticonus, corneal opacities, cataract, central perimacular and peripheral coalescing fleck retinopathies, and temporal retinal thinning. Although anterior lenticonus is common in Alport syndrome, simultaneous anterior and posterior lenticonus is a rare presentation. We report a case of a 22-year-old female with simultaneous anterior and posterior lenticonus presentation in which ocular examination lead to the detection of Alport syndrome. The patient had sensorineural deafness as well as microscopic haematuria. Clear lens extraction was performed in both eyes to eliminate lenticular irregular astigmatism for visual rehabilitation.

Searching for a treatment for Alport syndrome using mouse models

PubMed Central

Katayama, Kan; Nomura, Shinsuke; Tryggvason, Karl; Ito, Masaaki

2014-01-01

Alport syndrome (AS) is a hereditary nephritis caused by mutations in COL4A3, COL4A4 or COL4A5 encoding the type IV collagen α3, α4, and α5 chains, which are major components of the glomerular basement membrane. About 20 years have passed since COL4A3, COL4A4, and COL4A5 were identified and the first Alport mouse model was developed using a knockout approach. The phenotype of Alport mice is similar to that of Alport patients, including characteristic thickening and splitting of the glomerular basement membrane. Alport mice have been widely used to study the pathogenesis of AS and to develop effective therapies. In this review, the newer therapies for AS, such as pharmacological interventions, genetic approaches and stem cell therapies, are discussed. Although some stem cell therapies have been demonstrated to slow the renal disease progression in Alport mice, these therapies demand continual refinement as research advances. In terms of the pharmacological drugs, angiotensin-converting enzyme inhibitors have been shown to be effective in Alport mice. Novel therapies that can provide a better outcome or lead to a cure are still awaited. PMID:25374816

Pathogenicity of a Human Laminin β2 Mutation Revealed in Models of Alport Syndrome.

PubMed

Funk, Steven D; Bayer, Raymond H; Malone, Andrew F; McKee, Karen K; Yurchenco, Peter D; Miner, Jeffrey H

2018-03-01

Pierson syndrome is a congenital nephrotic syndrome with eye and neurologic defects caused by mutations in laminin β 2 ( LAMB2 ), a major component of the glomerular basement membrane (GBM). Pathogenic missense mutations in human LAMB2 cluster in or near the laminin amino-terminal (LN) domain, a domain required for extracellular polymerization of laminin trimers and basement membrane scaffolding. Here, we investigated an LN domain missense mutation, LAMB2-S80R, which was discovered in a patient with Pierson syndrome and unusually late onset of proteinuria. Biochemical data indicated that this mutation impairs laminin polymerization, which we hypothesized to be the cause of the patient's nephrotic syndrome. Testing this hypothesis in genetically altered mice showed that the corresponding amino acid change (LAMB2-S83R) alone is not pathogenic. However, expression of LAMB2-S83R significantly increased the rate of progression to kidney failure in a Col4a3 -/- mouse model of autosomal recessive Alport syndrome and increased proteinuria in Col4a5 +/- females that exhibit a mild form of X-linked Alport syndrome due to mosaic deposition of collagen α 3 α 4 α 5(IV) in the GBM. Collectively, these data show the pathogenicity of LAMB2-S80R and provide the first evidence of genetic modification of Alport phenotypes by variation in another GBM component. This finding could help explain the wide range of Alport syndrome onset and severity observed in patients with Alport syndrome, even for family members who share the same COL4 mutation. Our results also show the complexities of using model organisms to investigate genetic variants suspected of being pathogenic in humans. Copyright © 2018 by the American Society of Nephrology.

Feasibility of Repairing Glomerular Basement Membrane Defects in Alport Syndrome

PubMed Central

Lin, Xiaobo; Suh, Jung Hee; Go, Gloriosa

2014-01-01

Alport syndrome is a hereditary glomerular disease that leads to kidney failure. It is caused by mutations affecting one of three chains of the collagen α3α4α5(IV) heterotrimer, which forms the major collagen IV network of the glomerular basement membrane (GBM). In the absence of the α3α4α5(IV) network, the α1α1α2(IV) network substitutes, but it is insufficient to maintain normal kidney function. Inhibition of angiotensin-converting enzyme slows progression to kidney failure in patients with Alport syndrome but is not a cure. Restoration of the normal collagen α3α4α5(IV) network in the GBM, by either cell- or gene-based therapy, is an attractive and logical approach toward a cure, but whether or not the abnormal GBM can be repaired once it has formed and is functioning is unknown. Using a mouse model of Alport syndrome and an inducible transgene system, we found that secretion of α3α4α5(IV) heterotrimers by podocytes into a preformed, abnormal, filtering Alport GBM is effective at restoring the missing collagen IV network, slowing kidney disease progression, and extending life span. This proof-of-principle study demonstrates the plasticity of the mature GBM and validates the pursuit of therapeutic approaches aimed at normalizing the GBM to prolong kidney function. PMID:24262794

Feasibility of repairing glomerular basement membrane defects in Alport syndrome.

PubMed

Lin, Xiaobo; Suh, Jung Hee; Go, Gloriosa; Miner, Jeffrey H

2014-04-01

Alport syndrome is a hereditary glomerular disease that leads to kidney failure. It is caused by mutations affecting one of three chains of the collagen α3α4α5(IV) heterotrimer, which forms the major collagen IV network of the glomerular basement membrane (GBM). In the absence of the α3α4α5(IV) network, the α1α1α2(IV) network substitutes, but it is insufficient to maintain normal kidney function. Inhibition of angiotensin-converting enzyme slows progression to kidney failure in patients with Alport syndrome but is not a cure. Restoration of the normal collagen α3α4α5(IV) network in the GBM, by either cell- or gene-based therapy, is an attractive and logical approach toward a cure, but whether or not the abnormal GBM can be repaired once it has formed and is functioning is unknown. Using a mouse model of Alport syndrome and an inducible transgene system, we found that secretion of α3α4α5(IV) heterotrimers by podocytes into a preformed, abnormal, filtering Alport GBM is effective at restoring the missing collagen IV network, slowing kidney disease progression, and extending life span. This proof-of-principle study demonstrates the plasticity of the mature GBM and validates the pursuit of therapeutic approaches aimed at normalizing the GBM to prolong kidney function.

Alport syndrome: facts and opinions.

PubMed

Kashtan, Clifford

2017-01-01

In this commentary, I review recent advances in Alport syndrome genetics, diagnostics, and therapeutics. I also offer some opinions regarding strategies to optimize the early identification of affected individuals to promote early therapeutic intervention.

COL4A6 is dispensable for autosomal recessive Alport syndrome.

PubMed

Murata, Tomohiro; Katayama, Kan; Oohashi, Toshitaka; Jahnukainen, Timo; Yonezawa, Tomoko; Sado, Yoshikazu; Ishikawa, Eiji; Nomura, Shinsuke; Tryggvason, Karl; Ito, Masaaki

2016-07-05

Alport syndrome is caused by mutations in the genes encoding α3, α4, or α5 (IV) chains. Unlike X-linked Alport mice, α5 and α6 (IV) chains are detected in the glomerular basement membrane of autosomal recessive Alport mice, however, the significance of this finding remains to be investigated. We therefore generated mice lacking both α3 and α6 (IV) chains and compared their renal function and survival with Col4a3 knockout mice of 129 × 1/Sv background. No significant difference was observed in the renal function or survival of the two groups, or when the mice were backcrossed once to C57BL/6 background. However, the survival of backcrossed double knockout mice was significantly longer than that of the mice of 129 × 1/Sv background, which suggests that other modifier genes were involved in this phenomenon. In further studies we identified two Alport patients who had a homozygous mutation in intron 46 of COL4A4. The α5 and α6 (IV) chains were focally detected in the glomerular basement membrane of these patients. These findings indicate that although α5 and α6 (IV) chains are induced in the glomerular basement membrane in autosomal recessive Alport syndrome, their induction does not seem to play a major compensatory role.

COL4A6 is dispensable for autosomal recessive Alport syndrome

PubMed Central

Murata, Tomohiro; Katayama, Kan; Oohashi, Toshitaka; Jahnukainen, Timo; Yonezawa, Tomoko; Sado, Yoshikazu; Ishikawa, Eiji; Nomura, Shinsuke; Tryggvason, Karl; Ito, Masaaki

2016-01-01

Alport syndrome is caused by mutations in the genes encoding α3, α4, or α5 (IV) chains. Unlike X-linked Alport mice, α5 and α6 (IV) chains are detected in the glomerular basement membrane of autosomal recessive Alport mice, however, the significance of this finding remains to be investigated. We therefore generated mice lacking both α3 and α6 (IV) chains and compared their renal function and survival with Col4a3 knockout mice of 129 × 1/Sv background. No significant difference was observed in the renal function or survival of the two groups, or when the mice were backcrossed once to C57BL/6 background. However, the survival of backcrossed double knockout mice was significantly longer than that of the mice of 129 × 1/Sv background, which suggests that other modifier genes were involved in this phenomenon. In further studies we identified two Alport patients who had a homozygous mutation in intron 46 of COL4A4. The α5 and α6 (IV) chains were focally detected in the glomerular basement membrane of these patients. These findings indicate that although α5 and α6 (IV) chains are induced in the glomerular basement membrane in autosomal recessive Alport syndrome, their induction does not seem to play a major compensatory role. PMID:27377778

Alport syndrome: facts and opinions

PubMed Central

Kashtan, Clifford

2017-01-01

In this commentary, I review recent advances in Alport syndrome genetics, diagnostics, and therapeutics. I also offer some opinions regarding strategies to optimize the early identification of affected individuals to promote early therapeutic intervention. PMID:28163907

En face optical coherence tomography findings in a case of Alport syndrome.

PubMed

Cho, In Hwan; Kim, Hoon Dong; Jung, Sang Joon; Park, Tae Kwann

2017-09-01

Alport syndrome is a rare hereditary disease that is associated with retinal abnormalities such as dot-and-fleck retinopathy and temporal macular thinning. The main pathophysiological process of Alport syndrome is loss of the collagen network in the basement membrane. However, the alterations in each retinal layer have not been fully evaluated. In the case presented here, we evaluated the retina of a patient with Alport syndrome using en face optical coherence tomography (OCT). The findings suggested that the primary alterations occur in the internal limiting membrane and the retinal pigment epithelium basement membrane which is a part of the Bruch's membrane. The adjacent retinal layers are damaged subsequently. In conclusion, en face OCT could be useful in evaluating retinal abnormalities and understanding their underlying pathophysiology in Alport syndrome.

Difficulties in differentiating thin basement membrane disease from Alport syndrome.

PubMed

Żurawski, Jakub; Burchardt, Paweł; Seget, Monika; Moczko, Jerzy; Woźniak, Aldona; Grochowalski, Marcin; Salwa-Żurawska, Wiesława

We examined a group of 83 patients (57 children and 26 adults) with thin basement membrane disease and 17 patients with Alport syndrome. We compared the clinical data and, above all, the morphological patterns of both disease entities, with particular focus on not very advanced changes which might lead to a misdiagnosis due to the non-detection of the early stages of Alport syndrome.

Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy.

PubMed

Savige, Judy; Gregory, Martin; Gross, Oliver; Kashtan, Clifford; Ding, Jie; Flinter, Frances

2013-02-01

Few prospective, randomized controlled clinical trials address the diagnosis and management of patients with Alport syndrome or thin basement membrane nephropathy. Adult and pediatric nephrologists and geneticists from four continents whose clinical practice focuses on these conditions have developed the following guidelines. The 18 recommendations are based on Level D (Expert opinion without explicit critical appraisal, or based on physiology, bench research, or first principles-National Health Service category) or Level III (Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees-U.S. Preventive Services Task Force) evidence. The recommendations include the use of genetic testing as the gold standard for the diagnosis of Alport syndrome and the demonstration of its mode of inheritance; the need to identify and follow all affected members of a family with X-linked Alport syndrome, including most mothers of affected males; the treatment of males with X-linked Alport syndrome and individuals with autosomal recessive disease with renin-angiotensin system blockade, possibly even before the onset of proteinuria; discouraging the affected mothers of males with X-linked Alport syndrome from renal donation because of their own risk of kidney failure; and consideration of genetic testing to exclude X-linked Alport syndrome in some individuals with thin basement membrane nephropathy. The authors recognize that as evidence emerges, including data from patient registries, these guidelines will evolve further.

Pregnancy outcomes in patients with Alport syndrome.

PubMed

Yefet, Enav; Tovbin, David; Nachum, Zohar

2016-04-01

To analyze the maternal and obstetric outcomes of patients with Alport syndrome. We describe the pregnancy course of 8 pregnancies of three family members with the autosomal dominant (the rarest) form of Alport syndrome. We also analyzed 10 previously reported pregnancies with other Alport mutations in order to explore risk factors for unfavorable obstetric outcomes and maternal renal deterioration. In 13 pregnancies (72 %), renal function did not deteriorate permanently. All of these women had pre-pregnancy mild chronic kidney disease (CKD stage G1). In all of them, only a transient increase in proteinuria was recorded and in one case there was a transient decrease in the estimated glomerular filtration rate. In four other pregnancies (22 %), renal function deteriorated following pregnancy. All of them were complicated with pre-eclampsia. One woman had pre-pregnancy CKD-G2A3 and chronic hypertension. Two women had CKD-G1A3 of whom one had pre-pregnancy proteinuria near the nephrotic range. In the fourth case, renal function deterioration was reported without information on the exact pre-pregnancy renal function. In the last case, CKD-G2 was reported after pregnancy without information on CKD stage prior to pregnancy. Severe proteinuria did not imply a permanent renal function deterioration if it developed during pregnancy. Ten pregnancies ended with preterm birth (56 %). Two stillbirths were reported (11 %); however, only one was attributed to maternal health deterioration. Data regarding pregnancy outcomes in Alport syndrome is limited. The outcome seems favorable when pre-pregnancy kidney function is normal or near normal and when chronic hypertension/pre-eclampsia is absent.

[Analysis of the clinical audiological characteristics in 92 Chinese Alport syndrome cases].

PubMed

Chen, Li; Xue, Junfang; Zhang, Yanqin; Wang, Fang; Chen, Siqi; Duan, Jibo; Liu, Yuhe; Ding, Jie

2014-11-01

To analyze the clinical audiological characteristics in Chinese Alport syndrome, and investigate the relationship between the genotypes of Alport syndrome and hearing phenotype. The clinical hearing data of 92 cases diagnosed as Alport syndrome from 2008 August to 2013 August were reviewed and analyzed. All coding exons of COL4A3 and COL4A5 genes were PCR-amplified and sequenced from genomic DNA, or mRNA of COL4A5 gene was RT-PCR-amplified and sequenced from skin fibroblast in 17 cases. Eighty-seven out of 92 cases were found with X-linked dominant inheritance (XLAS); 5 cases with autosomal recessive (ARAS); 44 cases had normal hearing, but 14 young cases had abnormal OAE; 48 cases (52.2%, 35 male, 13 female) had sensorineural hearing loss. A total of 44 cases with XLAS had hearing loss (49.4%), wherein the incidence of hearing impairment was 55.0% in male XLAS, and 37.0% in female XLAS. Mild and moderate hearing loss were found in XLAS. Audiometric curves including groove type (21 cases), descending type (13 cases), flat type (10 cases), high frequency drop type (3 cases) and ascending type (1 case) were found in AS. Sixteen mutations of COL4A3, COL4A5 gene were found in 17 cases with Alport syndrome, including severe mutation in 8 cases with moderate hearing impairment. Mild and moderate hearing impairment, and groove type of audiometric curve are mainly found in Chinese Alport syndrome, which is different from Alport syndrome in western countries. OAE in the early diagnosis of hearing loss is important. Hearing phenotype is related certainly with genotype.

Accelerated podocyte detachment and progressive podocyte loss from glomeruli with age in Alport Syndrome.

PubMed

Ding, Fangrui; Wickman, Larysa; Wang, Su Q; Zhang, Yanqin; Wang, Fang; Afshinnia, Farsad; Hodgin, Jeffrey; Ding, Jie; Wiggins, Roger C

2017-12-01

Podocyte depletion is a common mechanism driving progression in glomerular diseases. Alport Syndrome glomerulopathy, caused by defective α3α4α5 (IV) collagen heterotrimer production by podocytes, is associated with an increased rate of podocyte detachment detectable in urine and reduced glomerular podocyte number suggesting that defective podocyte adherence to the glomerular basement membrane might play a role in driving progression. Here a genetically phenotyped Alport Syndrome cohort of 95 individuals [urine study] and 41 archived biopsies [biopsy study] were used to test this hypothesis. Podocyte detachment rate (measured by podocin mRNA in urine pellets expressed either per creatinine or 24-hour excretion) was significantly increased 11-fold above control, and prior to a detectably increased proteinuria or microalbuminuria. In parallel, Alport Syndrome glomeruli lose an average 26 podocytes per year versus control glomeruli that lose 2.3 podocytes per year, an 11-fold difference corresponding to the increased urine podocyte detachment rate. Podocyte number per glomerulus in Alport Syndrome biopsies is projected to be normal at birth (558/glomerulus) but accelerated podocyte loss was projected to cause end-stage kidney disease by about 22 years. Biopsy data from two independent cohorts showed a similar estimated glomerular podocyte loss rate comparable to the measured 11-fold increase in podocyte detachment rate. Reduction in podocyte number and density in biopsies correlated with proteinuria, glomerulosclerosis, and reduced renal function. Thus, the podocyte detachment rate appears to be increased from birth in Alport Syndrome, drives the progression process, and could potentially help predict time to end-stage kidney disease and response to treatment. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Progressive Posterior Lenticonus in a Patient with Alport Syndrome

PubMed Central

Al-Mahmood, Ammar M.; Al-Swailem, Samar A.; Al-Khalaf, Abdulrahman; Al-Binali, Ghada Y.

2010-01-01

We report a rare case of Alport syndrome with progressive posterior lenticonus. A 24-year-old male presented to our tertiary eye care center with history of poor vision. At initial presentation, the patient had bilateral anterior lenticonus, posterior subcapsular cataract, and renal failure. The patient was diagnosed with Alport syndrome based on a positive family history of the disease and clinical findings. Further examination revealed progressive posterior lenticonus that was not present initially. The presence of such finding is important because it influences the surgical approach to avoid complications during cataract surgery. PMID:21180444

Femtosecond laser-assisted cataract surgery in Alport syndrome with anterior lenticonus.

PubMed

Ecsedy, Mónika; Súndor, Gúbor L; Takúcs, Úgnes I; Krúnitz, Kinga; Kiss, Zoltún; Kolev, Krasimir; Nagy, Zoltún Z

2015-01-01

To report the surgical treatment of 3 eyes of 2 patients with bilateral anterior lenticonus due to Alport syndrome using femtosecond laser-assisted cataract surgery (FLACS). Two patients with Alport syndrome presented to our department due to anterior lenticonus in both eyes. We performed FLACS with posterior chamber lens implantation in both eyes of one patient and in one eye of the other patient. Anterior segment morphologic changes were visualized with a Scheimpflug camera, and anterior segment optical coherence tomography preoperatively and 3 months after surgery. Ultrastructure of the cut capsule edges was observed with scanning electron microscopy and compared to the edge of femtosecond laser capsulotomy performed on an otherwise healthy patient with cataract (control). The intraocular lens (IOL) postoperative positioning parameters met the international requirements of aspherical and wavefront customized IOLs (tilt <10 degree, decentration <800 µm). Scanning electron microscopy revealed the same characteristics of the cut capsule edges in the Alport and in the control eyes. Femtosecond laser cataract surgery can be a safe and successful method for optical rehabilitation of anterior lenticonus in patients with Alport syndrome.

Femtosecond laser-assisted cataract surgery in anterior lenticonus due to Alport syndrome.

PubMed

Barnes, Alexander C; Roth, Allen S

2017-06-01

We describe a case of bilateral anterior lenticonus in a patient with Alport syndrome treated with femtosecond laser-assisted cataract surgery (FLACS). FLACS was performed without complication, and a desirable postoperative visual acuity was achieved. Femtosecond laser-assisted cataract surgery is an effective approach for managing patients with anterior lenticonus secondary to Alport syndrome.

Ocular Features in Alport Syndrome: Pathogenesis and Clinical Significance

PubMed Central

Sheth, Shivanand; Leys, Anita; Nicholson, Anjali; Mack, Heather G.; Colville, Deb

2015-01-01

Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Mutations in the COL4A5 (X-linked), or COL4A3 and COL4A4 (autosomal recessive) genes result in absence of the collagen IV α3α4α5 network from the basement membranes of the cornea, lens capsule, and retina and are associated with corneal opacities, anterior lenticonus, fleck retinopathy, and temporal retinal thinning. Typically, these features do not affect vision or, in the case of lenticonus, are correctable. In contrast, the rarer ophthalmic complications of posterior polymorphous corneal dystrophy, giant macular hole, and maculopathy all produce visual loss. Many of the ocular features of Alport syndrome are common, easily recognizable, and thus, helpful diagnostically, and in identifying the likelihood of early-onset renal failure. Lenticonus and central fleck retinopathy strongly suggest the diagnosis of Alport syndrome and are associated with renal failure before the age of 30 years, in males with X-linked disease. Sometimes, ophthalmic features suggest the mode of inheritance. A peripheral retinopathy in the mother of a male with hematuria suggests X-linked inheritance, and central retinopathy or lenticonus in a female means that recessive disease is likely. Ocular examination, retinal photography, and optical coherence tomography are widely available, safe, fast, inexpensive, and acceptable to patients. Ocular examination is particularly helpful in the diagnosis of Alport syndrome when genetic testing is not readily available or the results are inconclusive. It also detects complications, such as macular hole, for which new treatments are emerging. PMID:25649157

Spontaneous Anterior Lens Capsule Rupture Of a Patient with Alport Syndrome - A Case Report.

PubMed

Trifonova, Kalina; Jordanoff, George; Stoyanov, Valentin; Slaveykov, Kiril

2017-12-15

Alport syndrome is a progressive genetic disease which is characterised by glomerulonephritis, sensorineural deafness and ocular abnormalities. We aimed to present a clinical case of a patient with Alport syndrome with spontaneous anterior lens capsule rupture. A 16-year-old male with histologically proven Alport syndrome was hospitalised in the Department of Ophthalmology, University Hospital "Prof. Stoyan Kirkovich", Stara Zagora with low vision, pain, redness, high IOP and rupture of the anterior lenticular capsule of the right eye. Phacoaspiration was successfully performed (Millenium, Bausch& Lomb, Rochester, New York, USA) with the bimanual irrigation-aspiration system (Geuder AG, Heidelberg, Germany) with excellent visual results. As the syndrome is quite rare and can lead to diagnostic difficulties for the ophthalmologist complications such as spontaneous or traumatic rupture of the capsule are not uncommon. In such cases, phacoaspiration is an efficient method for clear lens extraction after ruptures of the anterior lenticular capsule of young patients with Alport syndrome.

Contact lens fitting in a patient with Alport syndrome and posterior polymorphous corneal dystrophy: a case report.

PubMed

Rosa, Juliana Maria da Silva; Andrade Sobrinho, Marcelo Vicente de; Lipener, César

2016-02-01

Alport Syndrome is a hereditary disease that is caused by a gene mutation and affects the production of collagen in basement membranes; this condition causes hemorrhagic nephritis associated with deafness and ocular changes. The X-linked form of this disease is the most common and mainly affects males. Typical ocular findings are dot-and-fleck retinopathy, anterior lenticonus, and posterior polymorphous corneal dystrophy. Some cases involving polymorphous corneal dystrophy and corneal ectasia have been previously described. Here we present a case report of a 33-year-old female with Alport syndrome, posterior polymorphous corneal dystrophy, and irregular astigmatism, whose visual acuity improved with a rigid gas permeable contact lens.

Alport syndrome and pregnancy: a case series and literature review.

PubMed

Brunini, Francesca; Zaina, Barbara; Gianfreda, Davide; Ossola, Wally; Giani, Marisa; Fedele, Luigi; Messa, Piergiorgio; Moroni, Gabriella

2018-06-01

To assess pregnancy outcome in women with Alport syndrome and the impact of pregnancy on the disease progression. We describe one of the largest series of pregnancies in Alport syndrome. Seven pregnancies of six women were monitored by a multidisciplinary team of nephrologists and gynecologists. After delivery, patients were followed for at least 3 years. We compare our results with those in the literature. Pregnancy course was uneventful in the patient with isolated microscopic hematuria. In the other cases, all presenting mild proteinuria at conception, some complications occurred. Proteinuria worsened during the last trimester, reaching nephrotic ranges in five out of six pregnancies and was associated with fluid overload leading to hospitalizations and early delivery. The majority of the newborns had a low birth weight. The two patients with arterial hypertension at conception and twin pregnancy developed pre-eclampsia and renal function deterioration persisted after delivery. The one with pre-pregnancy renal dysfunction reached end-stage renal disease. In the other patients, in which renal function and blood pressure were and remained normal, proteinuria improved after delivery and no signs of disease progression were recorded at last observation. Our observations suggest that Alport syndrome should be considered a potential risk factor for pregnancy in proteinuric patients due to the development of pre-eclampsia, renal function deterioration, and/or full-blown nephrotic syndrome that results in anasarca, slowing of fetal growth and pre-term delivery. Thus, all women with Alport syndrome should receive pre-conceptional counseling and be kept in close follow-up during pregnancy.

Ocular features in Alport syndrome: pathogenesis and clinical significance.

PubMed

Savige, Judy; Sheth, Shivanand; Leys, Anita; Nicholson, Anjali; Mack, Heather G; Colville, Deb

2015-04-07

Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Mutations in the COL4A5 (X-linked), or COL4A3 and COL4A4 (autosomal recessive) genes result in absence of the collagen IV α3α4α5 network from the basement membranes of the cornea, lens capsule, and retina and are associated with corneal opacities, anterior lenticonus, fleck retinopathy, and temporal retinal thinning. Typically, these features do not affect vision or, in the case of lenticonus, are correctable. In contrast, the rarer ophthalmic complications of posterior polymorphous corneal dystrophy, giant macular hole, and maculopathy all produce visual loss. Many of the ocular features of Alport syndrome are common, easily recognizable, and thus, helpful diagnostically, and in identifying the likelihood of early-onset renal failure. Lenticonus and central fleck retinopathy strongly suggest the diagnosis of Alport syndrome and are associated with renal failure before the age of 30 years, in males with X-linked disease. Sometimes, ophthalmic features suggest the mode of inheritance. A peripheral retinopathy in the mother of a male with hematuria suggests X-linked inheritance, and central retinopathy or lenticonus in a female means that recessive disease is likely. Ocular examination, retinal photography, and optical coherence tomography are widely available, safe, fast, inexpensive, and acceptable to patients. Ocular examination is particularly helpful in the diagnosis of Alport syndrome when genetic testing is not readily available or the results are inconclusive. It also detects complications, such as macular hole, for which new treatments are emerging. Copyright © 2015 by the American Society of Nephrology.

Advances and unmet needs in genetic, basic and clinical science in Alport syndrome: report from the 2015 International Workshop on Alport Syndrome

PubMed Central

Gross, Oliver; Kashtan, Clifford E.; Rheault, Michelle N.; Flinter, Frances; Savige, Judith; Miner, Jeffrey H.; Torra, Roser; Ars, Elisabet; Deltas, Constantinos; Savva, Isavella; Perin, Laura; Renieri, Alessandra; Ariani, Francesca; Mari, Francesca; Baigent, Colin; Judge, Parminder; Knebelman, Bertrand; Heidet, Laurence; Lagas, Sharon; Blatt, Dave; Ding, Jie; Zhang, Yanqin; Gale, Daniel P.; Prunotto, Marco; Xue, Yong; Schachter, Asher D.; Morton, Lori C.G.; Blem, Jacqui; Huang, Michael; Liu, Shiguang; Vallee, Sebastien; Renault, Daniel; Schifter, Julia; Skelding, Jules; Gear, Susie; Friede, Tim; Turner, A. Neil; Lennon, Rachel

2017-01-01

Abstract Alport syndrome (AS) is a genetic disease characterized by haematuric glomerulopathy variably associated with hearing loss and anterior lenticonus. It is caused by mutations in the COL4A3, COL4A4 or COL4A5 genes encoding the α3α4α5(IV) collagen heterotrimer. AS is rare, but it accounts for >1% of patients receiving renal replacement therapy. Angiotensin-converting enzyme inhibition slows, but does not stop, the progression to renal failure; therefore, there is an urgent requirement to expand and intensify research towards discovering new therapeutic targets and new therapies. The 2015 International Workshop on Alport Syndrome targeted unmet needs in basic science, genetics and diagnosis, clinical research and current clinical care. In three intensive days, more than 100 international experts including physicians, geneticists, researchers from academia and industry, and patient representatives from all over the world participated in panel discussions and breakout groups. This report summarizes the most important priority areas including (i) understanding the crucial role of podocyte protection and regeneration, (ii) targeting mutations by new molecular techniques for new animal models and potential gene therapy, (iii) creating optimal interaction between nephrologists and geneticists for early diagnosis, (iv) establishing standards for mutation screening and databases, (v) improving widespread accessibility to current standards of clinical care, (vi) improving collaboration with the pharmaceutical/biotech industry to investigate new therapies, (vii) research in hearing loss as a huge unmet need in Alport patients and (viii) the need to evaluate the risk and benefit of novel (including ‘repurposing’) therapies on an international basis. PMID:27190345

MACULAR HOLES, VITELLIFORM LESIONS, AND MIDPERIPHERAL RETINOSCHISIS IN ALPORT SYNDROME.

PubMed

Thomas, Akshay S; Baynham, Justin T; Flaxel, Christina J

2016-01-01

To describe the retinal findings in two cases of Alport syndrome. Observational case series. The clinical findings of the two patients were documented with color fundus photography and high resolution spectral domain optical coherence tomography. Patient 1 was found to have fleck retinopathy in both eyes, inner retinal thinning in the right eye and a full-thickness macular hole in the left eye. Patient 2 was found to have a full-thickness macular hole in the right eye as well as retinoschisis in the temporal macula in the right eye. The left eye revealed inner retinal thinning involving the fovea, a vitelliform lesion of the temporal macula and midperipheral retinoschisis involving multiple retinal layers. Retinal abnormalities including fleck retinopathy, retinal thinning, macular holes, retinoschisis, and vitelliform lesions are variably present in Alport syndrome. This is only the second report of a vitelliform lesion in a patient with Alport syndrome and the first report of midperipheral retinoschisis. The array of retinal findings is believed to reflect a dysfunctional Type IV collagen present in the internal limiting membrane and Bruch membrane.

Podocyte Depletion in Thin GBM and Alport Syndrome.

PubMed

Wickman, Larysa; Hodgin, Jeffrey B; Wang, Su Q; Afshinnia, Farsad; Kershaw, David; Wiggins, Roger C

2016-01-01

The proximate genetic cause of both Thin GBM and Alport Syndrome (AS) is abnormal α3, 4 and 5 collagen IV chains resulting in abnormal glomerular basement membrane (GBM) structure/function. We previously reported that podocyte detachment rate measured in urine is increased in AS, suggesting that podocyte depletion could play a role in causing progressive loss of kidney function. To test this hypothesis podometric parameters were measured in 26 kidney biopsies from 21 patients aged 2-17 years with a clinic-pathologic diagnosis including both classic Alport Syndrome with thin and thick GBM segments and lamellated lamina densa [n = 15] and Thin GBM cases [n = 6]. Protocol biopsies from deceased donor kidneys were used as age-matched controls. Podocyte depletion was present in AS biopsies prior to detectable histologic abnormalities. No abnormality was detected by light microscopy at <30% podocyte depletion, minor pathologic changes (mesangial expansion and adhesions to Bowman's capsule) were present at 30-50% podocyte depletion, and FSGS was progressively present above 50% podocyte depletion. eGFR did not change measurably until >70% podocyte depletion. Low level proteinuria was an early event at about 25% podocyte depletion and increased in proportion to podocyte depletion. These quantitative data parallel those from model systems where podocyte depletion is the causative event. This result supports a hypothesis that in AS podocyte adherence to the GBM is defective resulting in accelerated podocyte detachment causing progressive podocyte depletion leading to FSGS-like pathologic changes and eventual End Stage Kidney Disease. Early intervention to reduce podocyte depletion is projected to prolong kidney survival in AS.

The Variability of Estimated Glomerular Filtration Rate Decline in Alport Syndrome.

PubMed

Langsford, David; Tang, Mila; Djurdjev, Ognjenka; Er, Lee; Levin, Adeera

2016-01-01

A progressive trajectory toward renal failure is common in patients with Alport syndrome. Genotype-phenotype correlations have been well described; however, the natural history of the trajectory toward renal failure is not well described. The objective of this study is to describe the natural history of renal function decline in a cohort of Alport syndrome patients. Retrospective observational cohort study. British Columbia, Canada, chronic renal disease registry 1995-2012. 37 biopsy proven Alport syndrome or hematuria with family history of Alport syndrome. Serial estimated glomerular filtration rate (eGFR) Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient's eGFR measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m2 /y decline), stable state (0-2 mL/min/1.73 m2 /y decline), and regressors (>2 mL/min/1.73 m2 /y incline). In this retrospective observational cohort study, participants were identified through a chronic renal disease registry in British Columbia, Canada, from 1995 to 2012. Inclusion criteria were biopsy proven or hematuria with a family history of Alport syndrome. Individual patients and family group members were studied. Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient's serial estimated glomerular filtration rate (eGFR) measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m 2 /y decline), stable state (0-2 mL/min/1.73 m 2 /y decline), and regressors (>2 mL/min/1.73 m 2 /y incline). Histological or genetic evidence of Alport syndrome is not available in all patients. Median follow-up time was 48.2 months of 37 patients (78% male), with a median age of 36 (interquartile range [IQR], 18-47) and a median age of renal replacement therapy commencement (n

[Alport syndrome: Hereditary nephropathy associated with mutations in genes coding for type IV collagen chains].

PubMed

Heidet, Laurence; Gubler, Marie-Claire

2016-12-01

Alport syndrome is an inherited disorder characterized by the association of a progressive haematuric nephropathy with ultrastructural abnormalities of the glomerular basement membranes, a progressive sensorineural hearing loss and sometimes ocular involvement. Its incidence is less than 1 per 5000 individuals and the disease is the cause of about 2% of end stage renal disease in Europe and the United States. Alport syndrome is clinically and genetically heterogeneous. It is related to mutations in the genes encoding one of three chains, α3, α4 α5 of type IV collagen, the main component of basement membranes, expressed in the glomerular basement membrane. COL4A5 mutations are associated with X-linked Alport syndrome, which represents 80 to 85% of cases and is more severe in boys than in girls. Mutations in COL4A3 or COL4A4 are associated with autosomal Alport syndrome. The expression of collagen chains in skin and kidney basement membranes allows for the diagnosis and characterization of the mode of transmission in most patients. It is necessary to diagnose this syndrome because its family involvement, its severity, and the importance of genetic counseling. Angiotensin blockers are increasingly prescribed in proteinuric patients. Prospective studies are needed to assess the effectiveness of these treatments on proteinuria and progression of kidney failure, and to specify indications. Animal studies have shown the potential value of different molecules (protease inhibitors, chemokine receptor blockers, transforming growth factor-β1 inhibitors, hydroxy-methyl-coenzyme A reductase inhibitors, bone morphogenetic protein-7 inhibitors), hematopoietic stem cells, and of a anti-micro-RNA. Copyright © 2016. Published by Elsevier SAS.

Advances and unmet needs in genetic, basic and clinical science in Alport syndrome: report from the 2015 International Workshop on Alport Syndrome.

PubMed

Gross, Oliver; Kashtan, Clifford E; Rheault, Michelle N; Flinter, Frances; Savige, Judith; Miner, Jeffrey H; Torra, Roser; Ars, Elisabet; Deltas, Constantinos; Savva, Isavella; Perin, Laura; Renieri, Alessandra; Ariani, Francesca; Mari, Francesca; Baigent, Colin; Judge, Parminder; Knebelman, Bertrand; Heidet, Laurence; Lagas, Sharon; Blatt, Dave; Ding, Jie; Zhang, Yanqin; Gale, Daniel P; Prunotto, Marco; Xue, Yong; Schachter, Asher D; Morton, Lori C G; Blem, Jacqui; Huang, Michael; Liu, Shiguang; Vallee, Sebastien; Renault, Daniel; Schifter, Julia; Skelding, Jules; Gear, Susie; Friede, Tim; Turner, A Neil; Lennon, Rachel

2017-06-01

Alport syndrome (AS) is a genetic disease characterized by haematuric glomerulopathy variably associated with hearing loss and anterior lenticonus. It is caused by mutations in the COL4A3, COL4A4 or COL4A5 genes encoding the α3α4α5(IV) collagen heterotrimer. AS is rare, but it accounts for >1% of patients receiving renal replacement therapy. Angiotensin-converting enzyme inhibition slows, but does not stop, the progression to renal failure; therefore, there is an urgent requirement to expand and intensify research towards discovering new therapeutic targets and new therapies. The 2015 International Workshop on Alport Syndrome targeted unmet needs in basic science, genetics and diagnosis, clinical research and current clinical care. In three intensive days, more than 100 international experts including physicians, geneticists, researchers from academia and industry, and patient representatives from all over the world participated in panel discussions and breakout groups. This report summarizes the most important priority areas including (i) understanding the crucial role of podocyte protection and regeneration, (ii) targeting mutations by new molecular techniques for new animal models and potential gene therapy, (iii) creating optimal interaction between nephrologists and geneticists for early diagnosis, (iv) establishing standards for mutation screening and databases, (v) improving widespread accessibility to current standards of clinical care, (vi) improving collaboration with the pharmaceutical/biotech industry to investigate new therapies, (vii) research in hearing loss as a huge unmet need in Alport patients and (viii) the need to evaluate the risk and benefit of novel (including 'repurposing') therapies on an international basis. © The Author 2016. Published by Oxford University Press on behalf of ERAEDTA.

Temporal retinal thinning and the diagnosis of Alport syndrome and Thin basement membrane nephropathy.

PubMed

Chen, Yan; Colville, Deb; Ierino, Francesco; Symons, Andrew; Savige, Judy

2018-04-01

Alport syndrome is an inherited disease characterized by renal failure, hearing loss, and ocular abnormalities, including temporal retinal thinning. This study compared retinal thinning in Alport syndrome and other renal diseases. Alport syndrome was diagnosed on renal biopsy and genetic testing. Subjects underwent optical coherence tomography (OCT) (Spectralis OCT, Heidelberg Instruments). Retinal thinning was determined from horizontal macular OCT scans through the foveal center using the formula: Temporal thickness index (TTI) = (nasal - temporal thickness) ÷ nasal thickness × 100%, and compared with the normal range for each age group. Statistical analysis was performed using Student's t test, Mann-Whitney U test, and ROC analysis (SPPS, IBM). The mean temporal retinal thickness index was 12.4 ± 5.2% in men (n = 19) and 7.4 ± 1.4% in women (n = 28) with X-linked Alport syndrome; 13.1 ± 4.5% (n = 4) in recessive disease; 6.4 ± 2.2% (n = 5) in Thin basement membrane nephropathy; and 6.3 ± 3.3% (n = 14) in other renal diseases. Thinning was worse in men than women with X-linked disease (p < 0.01), and worse in men who developed early onset renal failure (R 2  = 0.75). Temporal retinal thinning was 84% sensitive for men with X-linked Alport syndrome and 67% specific (AUC = 0.83) compared with other renal diseases. Retinal temporal thinning is diagnostic for X-linked Alport syndrome in men and distinguishes them this condition from Thin basement membrane nephropathy, but only in men (p = 0.002). Temporal retinal thinning may also identify men and women with the rarer autosomal recessive disease.

Alport syndrome: its effects on the glomerular filtration barrier and implications for future treatment

PubMed Central

Savige, Judy

2014-01-01

The glomerular filtration barrier comprises a fenestrated capillary endothelium, glomerular basement membrane and podocyte slit diaphragm. Over the past decade we have come to realise that permselectivity depends on size and not necessarily charge, that the molecular sieve depends on the podocyte contractile apparatus and is highly dynamic, and that protein uptake by proximal tubular epithelial cells stimulates signalling and the production of transcription factors and inflammatory mediators. Alport syndrome is the second commonest monogenic cause of renal failure after autosomal dominant polycystic kidney disease. Eighty per cent of patients have X-linked disease caused by mutations in the COL4A5 gene. Most of these result in the replacement of the collagen IV α3α4α5 network with the α1α1α2 heterotrimer. Affected membranes also have ectopic laminin and increased matrix metalloproteinase levels, which makes them more susceptible to proteolysis. Mechanical stress, due to the less elastic membrane and hypertension, interferes with integrin-mediated podocyte–GBM adhesion. Proteinuria occurs when urinary levels exceed tubular reabsorption rates, and initiates tubulointerstitial fibrosis. The glomerular mesangial cells produce increased TGFβ and CTGF which also contribute to glomerulosclerosis. Currently there is no specific therapy for Alport syndrome. However treatment with angiotensin converting enzyme (ACE) inhibitors delays renal failure progression by reducing intraglomerular hypertension, proteinuria, and fibrosis. Our greater understanding of the mechanisms underlying the GBM changes and their consequences in Alport syndrome have provided us with further novel therapeutic targets. PMID:25107927

DNA variant databases improve test accuracy and phenotype prediction in Alport syndrome.

PubMed

Savige, Judy; Ars, Elisabet; Cotton, Richard G H; Crockett, David; Dagher, Hayat; Deltas, Constantinos; Ding, Jie; Flinter, Frances; Pont-Kingdon, Genevieve; Smaoui, Nizar; Torra, Roser; Storey, Helen

2014-06-01

X-linked Alport syndrome is a form of progressive renal failure caused by pathogenic variants in the COL4A5 gene. More than 700 variants have been described and a further 400 are estimated to be known to individual laboratories but are unpublished. The major genetic testing laboratories for X-linked Alport syndrome worldwide have established a Web-based database for published and unpublished COL4A5 variants ( https://grenada.lumc.nl/LOVD2/COL4A/home.php?select_db=COL4A5 ). This conforms with the recommendations of the Human Variome Project: it uses the Leiden Open Variation Database (LOVD) format, describes variants according to the human reference sequence with standardized nomenclature, indicates likely pathogenicity and associated clinical features, and credits the submitting laboratory. The database includes non-pathogenic and recurrent variants, and is linked to another COL4A5 mutation database and relevant bioinformatics sites. Access is free. Increasing the number of COL4A5 variants in the public domain helps patients, diagnostic laboratories, clinicians, and researchers. The database improves the accuracy and efficiency of genetic testing because its variants are already categorized for pathogenicity. The description of further COL4A5 variants and clinical associations will improve our ability to predict phenotype and our understanding of collagen IV biochemistry. The database for X-linked Alport syndrome represents a model for databases in other inherited renal diseases.

Renal denervation in a patient with Alport syndrome and rejected renal allograft.

PubMed

Raju, Narayana; Lloyd, Vincent; Yalagudri, Sachin; Das, Bharati; Ravikishore, A G

2015-12-01

Renal denervation is a new intervention to treat resistant hypertension. By applying radiofrequency (RF) to renal arteries, sympathetic nerves in adventitia layer of vascular wall can be denervated. Sympathetic hyperactivity is an important contributory factor in hypertension of hemodialysis patients. Hyperactive sympathetic nervous system aggravates hypertension and it can cause complications like left ventricular hypertrophy, heart failure, arrhythmias and atherogenesis. Our report illustrates the use of renal denervation using conventional RF catheter for uncontrolled hypertension in a patient with Alport syndrome and rejected renal allograft. Progressive and sustained reduction of blood pressure was obtained post-procedure and at 24 months follow-up with antihypertensives decreased from 6 to 2 per day, thereby demonstrating the safety, feasibility, and efficacy of the procedure. There are some reports available on the usefulness of this technique in hemodialysis patients; however, there are no studies of renal denervation in patients with Alport syndrome and failed allograft situation. Copyright © 2015 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.

The Variability of Estimated Glomerular Filtration Rate Decline in Alport Syndrome

PubMed Central

Langsford, David; Tang, Mila; Djurdjev, Ognjenka; Er, Lee; Levin, Adeera

2016-01-01

Background: A progressive trajectory toward renal failure is common in patients with Alport syndrome. Genotype-phenotype correlations have been well described; however, the natural history of the trajectory toward renal failure is not well described. Objective: The objective of this study is to describe the natural history of renal function decline in a cohort of Alport syndrome patients. Design: Retrospective observational cohort study. Setting: British Columbia, Canada, chronic renal disease registry 1995-2012. Patients: 37 biopsy proven Alport syndrome or hematuria with family history of Alport syndrome. Measurements: Serial estimated glomerular filtration rate (eGFR) Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient’s eGFR measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m2 /y decline), stable state (0-2 mL/min/1.73 m2 /y decline), and regressors (>2 mL/min/1.73 m2 /y incline). Methods: In this retrospective observational cohort study, participants were identified through a chronic renal disease registry in British Columbia, Canada, from 1995 to 2012. Inclusion criteria were biopsy proven or hematuria with a family history of Alport syndrome. Individual patients and family group members were studied. Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient’s serial estimated glomerular filtration rate (eGFR) measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m2/y decline), stable state (0-2 mL/min/1.73 m2/y decline), and regressors (>2 mL/min/1.73 m2/y incline). Limitations: Histological or genetic evidence of Alport syndrome is not available in all patients. Results: Median follow-up time was 48.2 months of 37 patients (78% male), with a median age of 36

An Overlapping Case of Alport Syndrome and Thin Basement Membrane Disease.

PubMed

Alganabi, Mashriq; Eter, Ahmad

2016-10-01

We report a case of a 48-year-old male who presented with hematuria of at least 10 years, and has a daughter with hematuria as well. The patient has a history of degenerative hearing loss, decreased vision and cataract formation, but no diabetes, hypertension or proteinuria. A full serology and urology workup was negative for any abnormality. A kidney biopsy for the patient revealed a diagnosis of Alport syndrome but was unable to rule out thin basement membrane disease. The biopsy was inconclusive in making the diagnosis but the patient's clinical presentation led to the diagnosis of Alport syndrome. The patient's 10-year-old daughter also has hematuria with no clear etiology but now can subsequently be anticipatorily managed for Alport syndrome progression. Due to the rarity of the disease, diagnosis is often missed or delayed by primary care providers especially when no associated proteinuria has yet developed. This can lead to confusion and misdiagnosis with thin basement membrane disease, a generally benign hematuria without kidney failure progression. Additionally, biopsy can be inconclusive in these patients, relying on the physician's history and physical examination findings to diagnose. It is important to appropriately diagnose Alport syndrome not only to manage the patient's rate of kidney failure progression but also allow for a higher degree of suspicion, screening and intervention in the patient's family members. Both the inconclusive nature of kidney biopsies and the usefulness of diagnosis for family member screening are often overlooked in medical literature but are explored in this case.

An Overlapping Case of Alport Syndrome and Thin Basement Membrane Disease

PubMed Central

Alganabi, Mashriq; Eter, Ahmad

2016-01-01

We report a case of a 48-year-old male who presented with hematuria of at least 10 years, and has a daughter with hematuria as well. The patient has a history of degenerative hearing loss, decreased vision and cataract formation, but no diabetes, hypertension or proteinuria. A full serology and urology workup was negative for any abnormality. A kidney biopsy for the patient revealed a diagnosis of Alport syndrome but was unable to rule out thin basement membrane disease. The biopsy was inconclusive in making the diagnosis but the patient’s clinical presentation led to the diagnosis of Alport syndrome. The patient’s 10-year-old daughter also has hematuria with no clear etiology but now can subsequently be anticipatorily managed for Alport syndrome progression. Due to the rarity of the disease, diagnosis is often missed or delayed by primary care providers especially when no associated proteinuria has yet developed. This can lead to confusion and misdiagnosis with thin basement membrane disease, a generally benign hematuria without kidney failure progression. Additionally, biopsy can be inconclusive in these patients, relying on the physician’s history and physical examination findings to diagnose. It is important to appropriately diagnose Alport syndrome not only to manage the patient’s rate of kidney failure progression but also allow for a higher degree of suspicion, screening and intervention in the patient’s family members. Both the inconclusive nature of kidney biopsies and the usefulness of diagnosis for family member screening are often overlooked in medical literature but are explored in this case. PMID:27635185

Major COL4A5 gene rearrangements in patients with juvenile type Alport syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Renieri, A.; Galli, L.; Bruttini, M.

1995-11-20

Mutations in the COL4A5 gene, which encodes the {alpha}5 chain of type IV collagen, are found in a large fraction of patients with X-linked Alport syndrome. The recently discovered COL4A6, tightly linked and highly homologous to COL4A5, represents a second candidate gene for Alport syndrome. We analyzed 177 Italian Alport syndrome families by Southern blotting using cDNA probes from both COL4A5 and COL4A6. Nine unrelated families, accounting for 5% of the cases, were found to have a rearrangement in COL4A5. No rearrangements were found in COL4A6, with the exception of a deletion encompassing the 5{prime} ends of both COL4A5 andmore » COL4A6 genes in a patient with Alport syndrome and leiomyomatosis. COL4A5 rearrangements were all intragenic and included 1 duplication and 7 deletions. Polymerase chain reaction (PCR) analysis was carried out to characterize deletion and duplication boundaries and to predict the resulting protein abnormality. The two smallest deletions involved a single exon (exons 17 and 40, respectively), while the largest ones spanned exons 1 to 36. The clinical phenotype of patients in whom a rearrangement in COL4A5 was detected was severe, with progression to end-stage renal failure in juvenile age and hypoacusis occurring in most cases. These data have some important implications in the diagnosis of patients with Alport syndrome. 34 refs., 3 figs., 1 tab.« less

Alport syndrome and Pierson syndrome: Diseases of the glomerular basement membrane.

PubMed

Funk, Steven D; Lin, Meei-Hua; Miner, Jeffrey H

2018-04-16

The glomerular basement membrane (GBM) is an important component of the kidney's glomerular filtration barrier. Like all basement membranes, the GBM contains type IV collagen, laminin, nidogen, and heparan sulfate proteoglycan. It is flanked by the podocytes and glomerular endothelial cells that both synthesize it and adhere to it. Mutations that affect the GBM's collagen α3α4α5(IV) components cause Alport syndrome (kidney disease with variable ear and eye defects) and its variants, including thin basement membrane nephropathy. Mutations in LAMB2 that impact the synthesis or function of laminin α5β2γ1 (LM-521) cause Pierson syndrome (congenital nephrotic syndrome with eye and neurological defects) and its less severe variants, including isolated congenital nephrotic syndrome. The very different types of kidney diseases that result from mutations in collagen IV vs. laminin are likely due to very different pathogenic mechanisms. A better understanding of these mechanisms should lead to targeted therapeutic approaches that can help people with these rare but important diseases. Copyright © 2017 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

Pathology versus molecular genetics: (re)defining the spectrum of Alport syndrome

PubMed Central

Miner, Jeffrey H.

2014-01-01

Next generation sequencing applied to families with glomerular disease has been instrumental in identifying new genes and pathways involved in podocyte homeostasis. Malone et al. performed sequencing on 70 families with FSGS and discovered that 10% had variants in surprising “old” genes, COL4A3 and COL4A4, which are involved in Alport syndrome and thin basement membrane nephropathy. These data show that a subset of renal manifestations associated with COL4A3 or COL4A4 variants cannot be distinguished from FSGS by clinical data or by histopathology. Thus, a diagnosis of FSGS may sometimes fall within the spectrum of Alport syndrome. PMID:25427084

Matrix Metalloproteinase Dysregulation in the Stria Vascularis of Mice with Alport Syndrome

PubMed Central

Gratton, Michael Anne; Rao, Velidi H.; Meehan, Daniel T.; Askew, Charles; Cosgrove, Dominic

2005-01-01

Alport syndrome results from mutations in genes encoding collagen α3(IV), α4(IV), or α5(IV) and is characterized by progressive glomerular disease associated with a high-frequency sensorineural hearing loss. Earlier studies of a gene knockout mouse model for Alport syndrome noted thickening of strial capillary basement membranes in the cochlea, suggesting that the stria vascularis is the primary site of cochlear pathogenesis. Here we combine a novel cochlear microdissection technique with molecular analyses to illustrate significant quantitative alterations in strial expression of mRNAs encoding matrix metalloproteinases-2, -9, -12, and -14. Gelatin zymography of extracts from the stria vascularis confirmed these findings. Treatment of Alport mice with a small molecule inhibitor of these matrix metalloproteinases exacerbated strial capillary basement membrane thickening, demonstrating that alterations in basement membrane metabolism result in matrix accumulation in the strial capillary basement membranes. This is the first demonstration of true quantitative analysis of specific mRNAs for matrix metalloproteinases in a cochlear microcompartment. Further, these data suggest that the altered basement membrane composition in Alport stria influences the expression of genes involved in basement membrane metabolism. PMID:15855646

Two Pregnancies with a Different Outcome in a Patient with Alport Syndrome.

PubMed

Kitanovska, Biljana Gerasimovska; Gerasimovska, Vesna; Livrinova, Vesna

2016-09-15

Alport syndrome is a genetic disease that progresses to chronic kidney failure, with X-linked, autosomal dominant or autosomal recessive type of inheritance. Women are generally carriers of the mutation and have a milder form of the disease. During pregnancy, they have an increased risk of impaired kidney function and preeclampsia. A 27-year old woman, gravida 1, para 0, in her 23rd gestational week came to the outpatient unit of the University Clinic of Nephrology for the first time because of slowly progressing proteinuria and Alport syndrome. She was admitted to the gynaecological ward in her 29th gw for proteinuria which increased from 3.8 g/day up to 20 g/day and the serum creatinine increased to 120- 150 micromol/l. She was delivered in the 30th gestational week due to obstetrical indications with a cesarian section and delivered a baby with a birth weight of 880 g. After delivery, proteinuria decreased to 2 g/d within 2 months and an angiotensin-converting enzyme inhibitor (ACEI) was started. Her second pregnancy, after 2 years, had an uneventful course and she delivered a healthy baby weighing 3000 g in the 39th week. Six months after the second delivery, her renal function remained normal and her proteinuria was 2 g/d. Pre-pregnancy counselling and frequent controls during pregnancy are necessary for women with Alport syndrome, as well as regular monitoring after delivery. Recent reports are more in favour of good pregnancy and nephrological outcomes in women with Alport syndrome when renal disease is not advanced.

Next generation sequencing as a useful tool in the diagnostics of mosaicism in Alport syndrome.

PubMed

Beicht, Sonja; Strobl-Wildemann, Gertrud; Rath, Sabine; Wachter, Oliver; Alberer, Martin; Kaminsky, Elke; Weber, Lutz T; Hinrichsen, Tanja; Klein, Hanns-Georg; Hoefele, Julia

2013-09-10

Alport syndrome (ATS) is a progressive hereditary nephropathy characterized by hematuria and/or proteinuria with structural defects of the glomerular basement membrane. It can be associated with extrarenal manifestations (high-tone sensorineural hearing loss and ocular abnormalities). Somatic mutations in COL4A5 (X-linked), COL4A3 and COL4A4 genes (both autosomal recessive and autosomal dominant) cause Alport syndrome. Somatic mosaicism in Alport patients is very rare. The reason for this may be due to the difficulty of detection. We report the case of a boy and his mother who presented with Alport syndrome. Mutational analysis showed the novel hemizygote pathogenic mutation c.2396-1G>A (IVS29-1G>A) at the splice acceptor site of the intron 29 exon 30 boundary of the COL4A5 gene in the boy. The mutation in the mother would not have been detected by Sanger sequencing without the knowledge of the mutational analysis result of her son. Further investigation of the mother using next generation sequencing showed somatic mosaicism and implied potential germ cell mosaicism. The mutation in the mother has most likely occurred during early embryogenesis. Analysis of tissue of different embryonic origin in the mother confirmed mosaicism in both mesoderm and ectoderm. Low grade mosaicism is very difficult to detect by Sanger sequencing. Next generation sequencing is increasingly used in the diagnostics and might improve the detection of mosaicism. In the case of definite clinical symptoms of ATS and missing detection of a mutation by Sanger sequencing, mutational analysis should be performed by next generation sequencing. Copyright © 2013 Elsevier B.V. All rights reserved.

Evaluation of anterior lenticonus in alport syndrome using tracey wavefront aberrometry and transmission electron microscopy.

PubMed

Kim, Kwan Soo; Kim, Mo Sae; Kim, Joon Mo; Choi, Chul Young

2010-01-01

To evaluate the efficacy of Tracey wavefront aberrometry (Tracey Technologies, Houston, TX) and transmission electron microscopy for the detection of anterior lenticonus in Alport syndrome. Tracey wavefront aberrometry was used to treat a patient with bilateral anterior lenticonus who had a history of Alport syndrome. For transmission electron microscopic examination, anterior lens capsules were obtained during clear lens phacoemulsification and intraocular lens implantation. Spherical aberrations were the predominant higher-order aberrations in the internal optics of both eyes. The Tracey wavefront aberrometer showed that most of the irregular astigmatism originated from the lenticular portion. Transmission electron microscopy of the specimens showed anterior lens capsules with decreased thickness and multiple dehiscences. Tracey wavefront aberrometry and transmission electron microscopy are effective tools for evaluation of anterior lenticonus in Alport syndrome. Copyright 2010, SLACK Incorporated.

A case of mild phenotype Alport syndrome caused by COL4A3 mutations.

PubMed

Kamijo, Masafumi; Kitamura, Mineaki; Muta, Kumiko; Uramatsu, Tadashi; Obata, Yoko; Nozu, Kandai; Kaito, Hiroshi; Iijima, Kazumoto; Mukae, Hiroshi; Nishino, Tomoya

2017-11-01

In a case of 41-year-old man with mild nephropathy, Alport syndrome (AS) was diagnosed from the renal biopsy. However, the α5 chain of type IV collagen expressed in the glomerular basement membrane, which was the atypical staining pattern of AS. Genetic testing suggested autosomal recessive AS from heterozygous mutations at two positions in the type IV collagen α3 chain. These two gene mutations represented a new pattern of mutation and was suggested the association with an atypical α5 chain expression and mild phenotype.

A new mutation in the COL4A3 gene responsible for autosomal dominant Alport syndrome, which only generates hearing loss in some carriers.

PubMed

Rosado, Consolación; Bueno, Elena; Fraile, Pilar; García-Cosmes, Pedro; González-Sarmiento, Rogelio

2015-01-01

Bilateral sensorineural hearing loss is a characteristic feature of Alport syndrome, which is always linked to renal manifestations so they have a parallel evolution and prognosis, and deafness helps to identify the renal disease. We report a family that suffers an autosomal dominant Alport syndrome caused by a previously undescribed mutation in the COL4A3 gene, in which several members have hearing impairment as the only clinical manifestation, suggesting that in this family deafness can occur independent of renal disease. This mutation is also present in a patient with anterior lenticonus, an observation only found in families with recessive and sex-linked Alport disease. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

A mouse collagen4α4 mutation causing Alport glomerulosclerosis with abnormal collagen α3α4α5(IV) trimers

PubMed Central

Korstanje, Ron; Caputo, Christina; Doty, Rosalinda; Cook, Susan; Bronson, Roderick; Davisson, Muriel; Miner, Jeffrey H.

2013-01-01

A spontaneous mutation termed bilateral wasting kidneys (bwk) was identified in a colony of NONcNZO recombinant inbred mice. These mice exhibit a rapid increase of urinary albumin at an early age associated with glomerulosclerosis, interstitial nephritis, and tubular atrophy. The mutation was mapped to a location on Chromosome 1 containing the Col4a3 and Col4a4 genes, for which mutations in the human orthologs cause the hereditary nephritis Alport syndrome. DNA sequencing identified a G to A mutation in the conserved GT splice donor of Col4a4 intron 30, resulting in skipping of exon 30 but maintaining the mRNA reading frame. Protein analyses showed that mutant collagen α3α4α5(IV) trimers were secreted and incorporated into the glomerular basement membrane (GBM), but levels were low, and GBM lesions typical of Alport syndrome were observed. Moving the mutation into the more renal damage-prone DBA/2J and 129S1/SvImJ backgrounds revealed differences in albuminuria and its rate of increase, suggesting an interaction between the Col4a4 mutation and modifier genes. This novel mouse model of Alport syndrome is the only one shown to accumulate abnormal collagen α3α4α5(IV) in the GBM, as also found in a subset of Alport patients. These mice will be valuable for testing potential therapies, for understanding abnormal collagen IV structure and assembly, for gaining better insights into the mechanisms leading to Alport syndrome and to the variability in the age of onset and associated phenotypes. PMID:24522496

Alport syndrome and pregnancy: Good obstetric and nephrological outcomes in a pregnant woman with homozygous autosomal recessive Alport syndrome.

PubMed

Nishizawa, Yoko; Takei, Takashi; Miyaoka, Tokiko; Kamei, Daigo; Mochizuki, Toshio; Nitta, Kosaku

2016-03-01

We describe the course of pregnancy in a 27-year-old woman with homozygous autosomal recessive Alport syndrome. Genetic analysis revealed a homozygous COL4A4 mutation in exon 36 (c.3307G > A) with p.G1102R inherited from her parents (who were parallel cousins) 1 year before conception. Before pregnancy, the patient's renal function and blood pressure were normal, and her urinary protein excretion was below 2 g/day. The pregnancy course was uneventful in the first and second trimesters. She was detected to have nephrotic-range proteinuria during the third trimester, but was observed closely on an outpatient basis without any medications, as her general condition was good, her renal function and blood pressure remained stable, and the fetal well-being was maintained. At 39(+0) weeks of pregnancy, she vaginally gave birth to an appropriate-birthweight infant and her urinary protein excretion returned to pre-pregnancy level. This is the first report of pregnancy in a patient with autosomal recessive Alport syndrome with good obstetric and nephrological outcomes in the absence of any treatment or hospitalization. © 2015 Japan Society of Obstetrics and Gynecology.

Mild Electrical Stimulation and Heat Shock Ameliorates Progressive Proteinuria and Renal Inflammation in Mouse Model of Alport Syndrome

PubMed Central

Fukuda, Ryosuke; Morino-Koga, Saori; Suico, Mary Ann; Koyama, Kosuke; Sato, Takashi; Shuto, Tsuyoshi; Kai, Hirofumi

2012-01-01

Alport syndrome is a hereditary glomerulopathy with proteinuria and nephritis caused by defects in genes encoding type IV collagen in the glomerular basement membrane. All male and most female patients develop end-stage renal disease. Effective treatment to stop or decelerate the progression of proteinuria and nephritis is still under investigation. Here we showed that combination treatment of mild electrical stress (MES) and heat stress (HS) ameliorated progressive proteinuria and renal injury in mouse model of Alport syndrome. The expressions of kidney injury marker neutrophil gelatinase-associated lipocalin and pro-inflammatory cytokines interleukin-6, tumor necrosis factor-α and interleukin-1β were suppressed by MES+HS treatment. The anti-proteinuric effect of MES+HS treatment is mediated by podocytic activation of phosphatidylinositol 3-OH kinase (PI3K)-Akt and heat shock protein 72 (Hsp72)-dependent pathways in vitro and in vivo. The anti-inflammatory effect of MES+HS was mediated by glomerular activation of c-jun NH2-terminal kinase 1/2 (JNK1/2) and p38-dependent pathways ex vivo. Collectively, our studies show that combination treatment of MES and HS confers anti-proteinuric and anti-inflammatory effects on Alport mice likely through the activation of multiple signaling pathways including PI3K-Akt, Hsp72, JNK1/2, and p38 pathways, providing a novel candidate therapeutic strategy to decelerate the progression of patho-phenotypes in Alport syndrome. PMID:22937108

Combined Alport syndrome and Klinefelter syndrome.

PubMed

Nishida, Masashi; Hashimoto, Fusako; Kaito, Hiroshi; Nozu, Kandai; Iijima, Kazumoto; Asada, Dai; Hamaoka, Kenji

2016-02-01

To date, there have been a very limited number of case reports on combined Alport syndrome (AS) and Klinefelter syndrome (KS). We herein describe the case of a 9-month-old boy diagnosed with concomitant AS and KS. KS was detected on chromosomal analysis of the amniotic fluid, and hematuria/proteinuria was identified in urinary screening at 6 months of age. Renal biopsy indicated AS, with complete deficit of the α5 chain of type IV collagen in the glomerular basement membranes. On genetic analysis for AS, de novo homozygote mutation (c.3605-2a > c) was seen in the gene encoding α5 chain of type IV collagen (COL4A5) on the X chromosomes of maternal origin. This is the first case report of combined AS and KS diagnosed during infancy, and it indicates the need to consider the concurrent existence of these two disorders in infants with urine abnormalities, even in the absence of a family history. © 2015 Japan Pediatric Society.

COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome.

PubMed

Storey, Helen; Savige, Judy; Sivakumar, Vanessa; Abbs, Stephen; Flinter, Frances A

2013-12-01

Alport syndrome is an inherited disease characterized by hematuria, progressive renal failure, hearing loss, and ocular abnormalities. Autosomal recessive Alport syndrome is suspected in consanguineous families and when female patients develop renal failure. Fifteen percent of patients with Alport syndrome have autosomal recessive inheritance caused by two pathogenic mutations in either COL4A3 or COL4A4. Here, we describe the mutations and clinical features in 40 individuals including 9 children and 21 female individuals (53%) with autosomal recessive inheritance indicated by the detection of two mutations. The median age was 31 years (range, 6-54 years). The median age at end stage renal failure was 22.5 years (range, 10-38 years), but renal function was normal in nine adults (29%). Hearing loss and ocular abnormalities were common (23 of 35 patients [66%] and 10 of 18 patients [56%], respectively). Twenty mutation pairs (50%) affected COL4A3 and 20 pairs affected COL4A4. Of the 68 variants identified, 39 were novel, 12 were homozygous changes, and 9 were present in multiple individuals, including c.2906C>G (p.(Ser969*)) in COL4A4, which was found in 23% of the patients. Thirty-six variants (53%) resulted directly or indirectly in a stop codon, and all 17 individuals with early onset renal failure had at least one such mutation, whereas these mutations were less common in patients with normal renal function or late-onset renal failure. In conclusion, patient phenotypes may vary depending on the underlying mutations, and genetic testing should be considered for the routine diagnosis of autosomal recessive Alport syndrome.

COL4A3/COL4A4 Mutations and Features in Individuals with Autosomal Recessive Alport Syndrome

PubMed Central

Savige, Judy; Sivakumar, Vanessa; Abbs, Stephen; Flinter, Frances A.

2013-01-01

Alport syndrome is an inherited disease characterized by hematuria, progressive renal failure, hearing loss, and ocular abnormalities. Autosomal recessive Alport syndrome is suspected in consanguineous families and when female patients develop renal failure. Fifteen percent of patients with Alport syndrome have autosomal recessive inheritance caused by two pathogenic mutations in either COL4A3 or COL4A4. Here, we describe the mutations and clinical features in 40 individuals including 9 children and 21 female individuals (53%) with autosomal recessive inheritance indicated by the detection of two mutations. The median age was 31 years (range, 6–54 years). The median age at end stage renal failure was 22.5 years (range, 10–38 years), but renal function was normal in nine adults (29%). Hearing loss and ocular abnormalities were common (23 of 35 patients [66%] and 10 of 18 patients [56%], respectively). Twenty mutation pairs (50%) affected COL4A3 and 20 pairs affected COL4A4. Of the 68 variants identified, 39 were novel, 12 were homozygous changes, and 9 were present in multiple individuals, including c.2906C>G (p.(Ser969*)) in COL4A4, which was found in 23% of the patients. Thirty-six variants (53%) resulted directly or indirectly in a stop codon, and all 17 individuals with early onset renal failure had at least one such mutation, whereas these mutations were less common in patients with normal renal function or late-onset renal failure. In conclusion, patient phenotypes may vary depending on the underlying mutations, and genetic testing should be considered for the routine diagnosis of autosomal recessive Alport syndrome. PMID:24052634

Osteopontin deficiency ameliorates Alport pathology by preventing tubular metabolic deficits.

PubMed

Ding, Wen; Yousefi, Keyvan; Goncalves, Stefania; Goldstein, Bradley J; Sabater, Alfonso L; Kloosterboer, Amy; Ritter, Portia; Lambert, Guerline; Mendez, Armando J; Shehadeh, Lina A

2018-03-22

Alport syndrome is a rare hereditary renal disorder with no etiologic therapy. We found that osteopontin (OPN) is highly expressed in the renal tubules of the Alport mouse and plays a causative pathological role. OPN genetic deletion ameliorated albuminuria, hypertension, tubulointerstitial proliferation, renal apoptosis, and hearing and visual deficits in the Alport mouse. In Alport renal tubules we found extensive cholesterol accumulation and increased protein expression of dynamin-3 (DNM3) and LDL receptor (LDLR) in addition to dysmorphic mitochondria with defective bioenergetics. Increased pathological cholesterol influx was confirmed by a remarkably increased uptake of injected DiI-LDL cholesterol by Alport renal tubules, and by the improved lifespan of the Alport mice when crossed with the Ldlr-/- mice with defective cholesterol influx. Moreover, OPN-deficient Alport mice demonstrated significant reduction of DNM3 and LDLR expression. In human renal epithelial cells, overexpressing DNM3 resulted in elevated LDLR protein expression and defective mitochondrial respiration. Our results suggest a potentially new pathway in Alport pathology where tubular OPN causes DNM3- and LDLR-mediated enhanced cholesterol influx and impaired mitochondrial respiration.

Clear lens phacoemulsification in Alport syndrome: refractive results and electron microscopic analysis of the anterior lens capsule.

PubMed

Bayar, Sezin Akca; Pinarci, Eylem Yaman; Karabay, Gulten; Akman, Ahmet; Oto, Sibel; Yilmaz, Gursel

2014-01-01

To report the ocular findings of patients with Alport syndrome and the results of clear lens extraction in this patient group. Twenty-three eyes of 15 patients with a diagnosis of Alport syndrome were included in this study. Clear corneal phacoemulsification and intraocular foldable lens implantation was performed in eyes with indeterminate refractive errors and/or poor visual acuity and anterior capsule samples were analyzed with electron microscopy. All patients had a history of hereditary nephritis and/or deafness as systemic involvement. Ophthalmologic examination revealed anterior lenticonus with high myopia and/or irregular astigmatism in all patients. The mean best-corrected visual acuity (BCVA) was 0.67 ± 0.17 logMAR (range 1.0-0.4) preoperatively and 0.17 ± 0.08 logMAR (range 0.3-0.0) postoperatively. Postoperative refractive lenticular astigmatism dramatically decreased and no ocular complications arose during the follow-up period. Transmission electron microscopic analysis of the lens capsules supported the diagnosis of Alport syndrome. Clear lens phacoemulsification and foldable intraocular lens implantation is a safe and effective therapeutic choice for the management of uncorrectable refractive errors and low visual acuity due to anterior lenticonus in patients with Alport syndrome.

Safety and Efficacy of the ACE-Inhibitor Ramipril in Alport Syndrome: The Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase III EARLY PRO-TECT Alport Trial in Pediatric Patients.

PubMed

Gross, Oliver; Friede, Tim; Hilgers, Reinhard; Görlitz, Anke; Gavénis, Karsten; Ahmed, Raees; Dürr, Ulrike

2012-01-01

Introduction. Retrospective observational data show that ACE-inhibitor therapy delays renal failure and improves life expectancy in Alport patients with proteinuria. The EARLY PRO-TECT Alport trial assesses the safety and efficacy of early therapy onset with ramipril in pediatric Alport patients. Methods and analysis. This double-blind, randomized, placebo-controlled, multicenter phase III trial (NCT01485978; EudraCT-number 2010-024300-10) includes 120 pediatric patients aged 24 months to 18 years with early stages of Alport syndrome (isolated hematuria or microalbuminuria). From March 2012, up to 80 patients will be randomized 1:1 to ramipril or placebo. In the event of disease progression during 3-year treatment, patients are unblinded and ramipril is initiated, if applicable. Approximately 40 patients receive open-label ramipril contributing to the safety database. Primary end-points are "time to progression to next disease level" and "incidence of adverse drug events before disease progression." Treatment effect estimates from the randomized comparison and Alport registry data will be combined in supportive analyses to maximize evidence. Conclusion. Without this trial, ACE inhibitors may become standard off-label treatment in Alport syndrome without satisfactory evidence base. The results are expected to be of relevance for therapy of all pediatric patients with kidney disease, and the trial protocol might serve as a model for other rare pediatric glomerulopathies.

Bull's eye and pigment maculopathy are further retinal manifestations of an abnormal Bruch's membrane in Alport syndrome.

PubMed

Savige, Judy; Wang, Yanyan; Crawford, Andrew; Smith, James; Symons, Andrew; Mack, Heather; Nicholls, Kathy; Wilson, Diane; Colville, Deb

2017-01-01

The retinal features of Alport syndrome include a central and peripheral fleck retinopathy, temporal retinal thinning, and a macular hole. Here we describe further retinal abnormalities. We identified a case of bull's eye maculopathy 20 years previously in a 68-year-old female, and reviewed archived retinal images from our cohort of X-linked (28 males, 28 females) or autosomal recessive (n = 13) Alport syndrome. All individuals had Alport syndrome confirmed on genetic testing or renal biopsy, were examined by an ophthalmologist, and underwent retinal imaging (KOWA non-mydriatic camera, Japan). The index case had the p.Q379X variant in COL4A5 and currently had renal impairment, (eGFR = 45 ml/min/1.73 m 2 ), bilateral hearing loss, and central and peripheral retinopathies. Her maculopathy had deteriorated, and she had a bilateral central visual field loss. Optical coherence tomography (Heidelberg Spectralis) demonstrated a disrupted retinal pigment epithelium and retinal atrophy. We identified a further early bull's eye maculopathy (1/69, 1.4%) from a female with autosomal recessive disease and normal renal function. We also noted a subtle pigment maculopathy associated with an abnormal retinal pigment epithelium in 27 (27/69, 39%) subjects with Alport syndrome, in both males (8/28, 29%) and females (13/28, 46%) with X-linked disease, and in autosomal recessive disease (6/13, 38%). The bull's eye and pigment maculopathies in Alport syndrome result mainly from the damaged Bruch's membrane and overlying retinal pigment epithelium. Bull's eye maculopathy affects vision and patients should undergo regular monitoring for retinal complications.

Electron microscopic examination of the anterior lens capsule in a case of Alport's syndrome.

PubMed

Citirik, Mehmet; Batman, Cosar; Men, Gamze; Tuncel, Murvet; Zilelioglu, Orhan

2007-09-01

To report a case of Alport's syndrome and to present electronmicroscopic examination findings of the anterior lens capsule of this patient. A 21-year-old man was referred for low visual acuity and retinal pigment epithelial changes in the left eye. The patient and his relatives underwent detailed ophthalmological examination, including electrophysiological testing. The patient also underwent electronmicroscopic examination of the anterior lens capsule. His visual acuity was 6/18 OD and 6/15 OS. Anterior lenticonus and subcapsular opacities were observed in the left eye. Cataract extraction by phacoemulsification with intraocular lens implantation was performed for his poor visual performance. During the capsulorhexis, the remarkably thin and fragile anterior capsule was noted and removed. Ultrastructural analysis of the anterior lens capsule showed a thinner central zone compared with the periphery. The course of Alport's syndrome can be ameliorated by early diagnosis. Therefore, the ophthalmological examination of a patient with anterior lenticonus must be combined with a detailed medical evaluation. Ultrastructural analysis of the lens capsule can support the diagnosis of Alport's syndrome.

Osteopontin deficiency ameliorates Alport pathology by preventing tubular metabolic deficits

PubMed Central

Ding, Wen; Goncalves, Stefania; Goldstein, Bradley J.; Sabater, Alfonso L.; Kloosterboer, Amy; Ritter, Portia; Lambert, Guerline; Mendez, Armando J.

2018-01-01

Alport syndrome is a rare hereditary renal disorder with no etiologic therapy. We found that osteopontin (OPN) is highly expressed in the renal tubules of the Alport mouse and plays a causative pathological role. OPN genetic deletion ameliorated albuminuria, hypertension, tubulointerstitial proliferation, renal apoptosis, and hearing and visual deficits in the Alport mouse. In Alport renal tubules we found extensive cholesterol accumulation and increased protein expression of dynamin-3 (DNM3) and LDL receptor (LDLR) in addition to dysmorphic mitochondria with defective bioenergetics. Increased pathological cholesterol influx was confirmed by a remarkably increased uptake of injected DiI-LDL cholesterol by Alport renal tubules, and by the improved lifespan of the Alport mice when crossed with the Ldlr–/– mice with defective cholesterol influx. Moreover, OPN-deficient Alport mice demonstrated significant reduction of DNM3 and LDLR expression. In human renal epithelial cells, overexpressing DNM3 resulted in elevated LDLR protein expression and defective mitochondrial respiration. Our results suggest a potentially new pathway in Alport pathology where tubular OPN causes DNM3- and LDLR-mediated enhanced cholesterol influx and impaired mitochondrial respiration. PMID:29563333

End-stage kidney disease due to Alport syndrome: outcomes in 296 consecutive Australia and New Zealand Dialysis and Transplant Registry cases.

PubMed

Mallett, Andrew; Tang, Wen; Clayton, Philip A; Stevenson, Sarah; McDonald, Stephen P; Hawley, Carmel M; Badve, Sunil V; Boudville, Neil; Brown, Fiona G; Campbell, Scott B; Johnson, David W

2014-12-01

Alport syndrome is a rare inheritable renal disease. Clinical outcomes for patients progressing to end-stage kidney disease (ESKD) are not well described. This study aimed to investigate the characteristics and clinical outcomes of patients from Australia and New Zealand commencing renal replacement therapy (RRT) for ESKD due to Alport syndrome between 1965 and 1995 (early cohort) and between 1996 and 2010 (contemporary cohort) compared with propensity score-matched, RRT-treated, non-Alport ESKD controls. A total of 58 422 patients started RRT during this period of which 296 (0.5%) patients had Alport ESKD. In the early cohort, Alport ESKD was associated with superior dialysis patient survival [adjusted hazard ratio (HR): 0.41, 95% confidence interval (CI): 0.20-0.83, P = 0.01], renal allograft survival (HR: 0.74, 95% CI: 0.54-1.01, P = 0.05) and renal transplant patient survival (HR: 0.43, 95% CI: 0.28-0.66, P < 0.001) compared with controls. In the contemporary cohort, no differences were observed between the two groups for dialysis patient survival (HR: 1.42, 95% CI: 0.65-3.11, P = 0.38), renal allograft survival (HR: 1.01, 95% CI: 0.57-1.79, P = 0.98) or renal transplant patient survival (HR: 0.67, 95% CI: 0.26-1.73, P = 0.41). One Alport patient (0.4%) had post-transplant anti-glomerular basement membrane (anti-GBM) disease. Four female and 41 male Alport patients became parents on RRT with generally good neonatal outcomes. Alport syndrome patients experienced comparable dialysis and renal transplant outcomes to matched non-Alport ESKD controls in the contemporary cohort due to relatively greater improvements in outcomes for non-Alport ESKD patients over time. Post-transplant anti-GBM disease was rare. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Alport Syndrome: De Novo Mutation in the COL4A5 Gene Converting Glycine 1205 to Valine.

PubMed

Antón-Martín, Pilar; Aparicio López, Cristina; Ramiro-León, Soraya; Santillán Garzón, Sonia; Santos-Simarro, Fernando; Gil-Fournier, Belén

2012-01-01

Alport syndrome is a primary basement membrane disorder arising from mutations in genes encoding the type IV collagen protein family. It is a genetically heterogeneous disease with different mutations and forms of inheritance that presents with renal affection, hearing loss and eye defects. Several new mutations related to X-linked forms have been previously determined. We report the case of a 12 years old male and his family diagnosed with Alport syndrome after genetic analysis was performed. A new mutation determining a nucleotide change c.3614G > T (p.Gly1205Val) in hemizygosis in the COL4A5 gene was found. This molecular defect has not been previously described. Molecular biology has helped us to comprehend the mechanisms of pathophysiology in Alport syndrome. Genetic analysis provides the only conclusive diagnosis of the disorder at the moment. Our contribution with a new mutation further supports the need of more sophisticated molecular methods to increase the mutation detection rates with lower costs and less time.

ANCA vasculitis in a patient with Alport syndrome: a difficult diagnosis but a treatable disease!

PubMed

Gillion, Valentine; Jadoul, Michel; Aydin, Selda; Godefroid, Nathalie

2017-03-29

Alport syndrome and ANCA-associated vasculitis are both rare diseases. The co-existence of these two conditions has never been reported. There is no obvious pathogenic link between these two glomerular diseases. The management of this case highlights the importance of a systematic approach when investigating the unexpected unfavourable evolution of a known glomerulopathy. A-17 year old caucasian boy with a genetically proven X-linked Alport syndrome presented with progressive dyspnea, fatigue and pallor. His blood tests showed a severe anemia (Hb 6.9 g/dl) with acute worsening of kidney function (serum creatinine, normal 9 months earlier, was now 3.6 mg/dl). Microscopic hematuria and proteinuria also worsened. He soon developed signs of alveolar hemorrhage. Serological tests showed the presence of perinuclear ANCA with anti MPO specificity. Kidney biopsy showed a necrotizing and crescentic glomerulonephritis. Pulses of methylprednisolone were given in combination with plasmapheresis. The patient further received 6 pulses of cyclophosphamide, followed by maintenance oral azathioprine. During the 15-months follow up he remained well with serum creatinine back to normal, and some residual proteinuria and hematuria ascribed to Alport syndrome. We report a young patient with the coexistence of Alport syndrome and ANCA associated vasculitis. Clinicians should be aware of the possibility of a second acquired disease in a patient with a known kidney disease, genetic in this case. This coexistence is very rare, but should be considered even if both diseases are rare, if the evolution is atypical for the single (known) primary disease. The diagnosis of the added vasculitis prompted in our case the initiation of immunosuppressive drugs, with a favourable outcome.

Functional assessment of a novel COL4A5 splice region variant and immunostaining of plucked hair follicles as an alternative method of diagnosis in X-linked Alport syndrome.

PubMed

Malone, Andrew F; Funk, Steven D; Alhamad, Tarek; Miner, Jeffrey H

2017-06-01

Many COL4A5 splice region variants have been described in patients with X-linked Alport syndrome, but few have been confirmed by functional analysis to actually cause defective splicing. We sought to demonstrate that a novel COL4A5 splice region variant in a family with Alport syndrome is pathogenic using functional studies. We also describe an alternative method of diagnosis. Targeted next-generation sequencing results of an individual with Alport syndrome were analyzed and the results confirmed by Sanger sequencing in family members. A splicing reporter minigene assay was used to examine the variant's effect on splicing in transfected cells. Plucked hair follicles from patients and controls were examined for collagen IV proteins using immunofluorescence microscopy. A novel splice region mutation in COL4A5, c.1780-6T>G, was identified and segregated with disease in this family. This variant caused frequent skipping of exon 25, resulting in a frameshift and truncation of collagen α5(IV) protein. We also developed and validated a new approach to characterize the expression of collagen α5(IV) protein in the basement membranes of plucked hair follicles. Using this approach we demonstrated reduced collagen α5(IV) protein in affected male and female individuals in this family, supporting frequent failure of normal splicing. Differing normal to abnormal transcript ratios in affected individuals carrying splice region variants may contribute to variable disease severity observed in Alport families. Examination of plucked hair follicles in suspected X-linked Alport syndrome patients may offer a less invasive alternative method of diagnosis and serve as a pathogenicity test for COL4A5 variants of uncertain significance.

Functional assessment of a novel COL4A5 splice region variant and immunostaining of plucked hair follicles as an alternative method of diagnosis in X-linked Alport syndrome

PubMed Central

Malone, Andrew F.; Funk, Steven D.; Alhamad, Tarek; Miner, Jeffrey H.

2016-01-01

Introduction Many COL4A5 splice region variants have been described in patients with X-linked Alport syndrome, but few have been confirmed by functional analysis to actually cause defective splicing. We sought to demonstrate that a novel COL4A5 splice region variant in a family with Alport syndrome is pathogenic using functional studies. We also describe an alternative method of diagnosis. Methods We analyzed targeted next-generation sequencing results of an individual with Alport syndrome and confirmed results by Sanger sequencing in family members. A splicing reporter minigene assay was used to examine the variant’s effect on splicing in transfected cells. Plucked hair follicles from patients and controls were examined for collagen IV proteins using immunofluorescence microscopy. Results A novel splice region mutation in COL4A5, c.1780-6T>G, was identified and segregated with disease in this family. This variant caused frequent skipping of exon 25, resulting in a frameshift and truncation of collagen α5(IV) protein. We also developed and validated a new approach to characterize the expression of collagen α5(IV) protein in the basement membranes of plucked hair follicles. We demonstrated reduced collagen α5(IV) protein in affected male and female individuals in this family, supporting frequent failure of normal splicing. Conclusions Differing normal to abnormal transcript ratios in affected individuals carrying splice region variants may contribute to variable disease severity observed in Alport families. Examination of plucked hair follicles in suspected X-linked Alport syndrome patients may offer a less invasive alternative method of diagnosis and serve as a pathogenicity test for COL4A5 variants of uncertain significance. PMID:28013382

Glomerular pathology in Alport syndrome: a molecular perspective

PubMed Central

Cosgrove, Dominic

2012-01-01

We have known for some time that mutations in the genes encoding 3 of the 6 type IV collagen chains are the underlying defect responsible for both X-linked (where the COL4A5 gene is involved) and autosomal (where either COL4A3 or COL4A4 genes are involved) Alport syndrome. The result of these mutations is the absence of the sub-epithelial network of all three chains in the glomerular basement membrane (GBM) resulting, at maturity, in a type IV collagen GBM network comprised of only α1(IV) and α2(IV) chains. The altered GBM functions adequately in early life. Eventually there is onset of proteinuria associated with the classic and progressive irregular thickening, thinning, and splitting of the GBM, which culminates in end stage renal failure. We have learned much about the molecular events associated with disease onset and progression through the study of animal models for Alport syndrome, and have identified some potential therapeutic approaches that may serve to delay the onset or slow the progression of the disease. This review focuses on where we are in our understanding of the disease, where we need to go to understand the molecular triggers that set the process in motion, and what emergent therapeutic approaches show promise for ameliorating disease progression in the clinic. PMID:21455721

α1β1 Integrin/Rac1-Dependent Mesangial Invasion of Glomerular Capillaries in Alport Syndrome

PubMed Central

Zallocchi, Marisa; Johnson, Brianna M.; Meehan, Daniel T.; Delimont, Duane; Cosgrove, Dominic

2014-01-01

Alport syndrome, hereditary glomerulonephritis with hearing loss, results from mutations in type IV collagen COL4A3, COL4A4, or COL4A5 genes. The mechanism for delayed glomerular disease onset is unknown. Comparative analysis of Alport mice and CD151 knockout mice revealed progressive accumulation of laminin 211 in the glomerular basement membrane. We show mesangial processes invading the capillary loops of both models as well as in human Alport glomeruli, as the likely source of this laminin. l-NAME salt–induced hypertension accelerated mesangial cell process invasion. Cultured mesangial cells showed reduced migratory potential when treated with either integrin-linked kinase inhibitor or Rac1 inhibitor, or by deletion of integrin α1. Treatment of Alport mice with Rac1 inhibitor or deletion of integrin α1 reduced mesangial cell process invasion of the glomerular capillary tuft. Laminin α2–deficient Alport mice show reduced mesangial process invasion, and cultured laminin α2–null cells showed reduced migratory potential, indicating a functional role for mesangial laminins in progression of Alport glomerular pathogenesis. Collectively, these findings predict a role for biomechanical insult in the induction of integrin α1β1–dependent Rac1-mediated mesangial cell process invasion of the glomerular capillary tuft as an initiation mechanism of Alport glomerular pathology. PMID:23911822

Preclinical Alterations in the Serum of COL(IV)A3(-)/(-) Mice as Early Biomarkers of Alport Syndrome.

PubMed

Muckova, Petra; Wendler, Sindy; Rubel, Diana; Büchler, Rita; Alert, Mandy; Gross, Oliver; Rhode, Heidrun

2015-12-04

The efficiency of the inhibition of the angiotensin converting enzyme, the most widely used therapy for the Alport syndrome, depends on the onset of the therapy-the earlier the better. Hence, early progressive biomarkers are urgently required to allow for preclinical diagnosis, an early start of possible therapy as well as the monitoring of this therapy. In the present study, an improved comprehensive and precise proteomic approach has been applied to the serum of juvenile Alport-mice, nontreated and treated, and wild-type controls of various ages to search for biomarkers. With a total of 2542 stringently altered proteins, the serum composition clearly shows a dependency on age, that is, stage, and therapy. Initially, the serum constituents indicate an enhanced extracellular matrix remodeling, cell damage, and the production of particular acute phase proteins. A panel of 15 potential biomarker candidates has been identified. In later stages, renal filtration failure and systemic acute phase reaction determine the composition of the serum; an effect that is well-known for manifested human Alport syndrome. With a small number of mouse urine samples, for example, the proteomic results for gelsolin could be verified using ELISA. Once verified in man, these early biomarkers would allow for a sensitive and specific diagnosis of the Alport syndrome in children as well as facilitate the monitoring of a possible therapy.

A unique evolution of the kidney phenotype in a patient with autosomal recessive Alport syndrome.

PubMed

Vischini, Gisella; Kapp, Meghan E; Wheeler, Ferrin C; Hopp, Laszlo; Fogo, Agnes B

2018-03-09

Alport syndrome is due to mutations in one of the genes encoding (α3,4,5) type IV collagen resulting in defective type IV collagen, a key component of the glomerular basement membrane (GBM). The GBM is initially thin, and with ongoing remodeling, develops a thickened basket-woven appearance. We report a unique case of a 9-year-old boy who was biopsied for hematuria and proteinuria, diagnosed as IgA nephropathy, with normal GBM appearance and thickness. Due to a family history of hematuria and chronic kidney disease, he subsequently underwent genetic evaluation and a mutation of α3 type IV collagen (COL4A3) was detected. Additional studies of the initial biopsy demonstrated abnormal type IV collagen immunostaining. A repeat biopsy 4years later showed characteristic glomerular basement membrane morphology of Alport syndrome, and scarring consistent with sequelae of IgA nephropathy. This is the first description of this unusual transition from an initial normal appearance of the glomerular basement membrane to the classic Alport phenotype. Copyright © 2018. Published by Elsevier Inc.

α1β1 integrin/Rac1-dependent mesangial invasion of glomerular capillaries in Alport syndrome.

PubMed

Zallocchi, Marisa; Johnson, Brianna M; Meehan, Daniel T; Delimont, Duane; Cosgrove, Dominic

2013-10-01

Alport syndrome, hereditary glomerulonephritis with hearing loss, results from mutations in type IV collagen COL4A3, COL4A4, or COL4A5 genes. The mechanism for delayed glomerular disease onset is unknown. Comparative analysis of Alport mice and CD151 knockout mice revealed progressive accumulation of laminin 211 in the glomerular basement membrane. We show mesangial processes invading the capillary loops of both models as well as in human Alport glomeruli, as the likely source of this laminin. L-NAME salt-induced hypertension accelerated mesangial cell process invasion. Cultured mesangial cells showed reduced migratory potential when treated with either integrin-linked kinase inhibitor or Rac1 inhibitor, or by deletion of integrin α1. Treatment of Alport mice with Rac1 inhibitor or deletion of integrin α1 reduced mesangial cell process invasion of the glomerular capillary tuft. Laminin α2-deficient Alport mice show reduced mesangial process invasion, and cultured laminin α2-null cells showed reduced migratory potential, indicating a functional role for mesangial laminins in progression of Alport glomerular pathogenesis. Collectively, these findings predict a role for biomechanical insult in the induction of integrin α1β1-dependent Rac1-mediated mesangial cell process invasion of the glomerular capillary tuft as an initiation mechanism of Alport glomerular pathology. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Mechanical response of wild-type and Alport murine lens capsules during osmotic swelling.

PubMed

Gyoneva, Lazarina; Segal, Yoav; Dorfman, Kevin D; Barocas, Victor H

2013-08-01

The mechanical support of basement membranes, such as the lens capsule, is believed to arise from one of their main constituents - collagen IV. The basement membranes of the lens, kidney, and ear normally contain two different types of collagen IV networks, referred to as the major and minor chain networks. In Alport syndrome, a mutation in one of the minor chain COL4 genes leads to the absence of the minor chain network, causing life-threatening disturbances. We hypothesized that the absence of the minor chain network increases basement membrane distensibility, as measured in wild-type (n = 25) and Alport syndrome (n = 21) mice using the lens capsule as a model. Osmotic swelling experiments revealed direction-dependent changes. As a reflection of lens capsule properties, Alport lenses strained significantly more than wild-type lenses in the anterior-posterior direction, i.e. along their thickness, but not in the equatorial direction (p = 0.03 and p = 0.08, respectively). This is consistent with clinical data: Alport patients develop conical protrusions on the anterior and posterior lenticular poles. There was no evidence of significant change in total amount of collagen between Alport and wild-type lenses (p = 0.6). The observed differences in distensibility could indicate that the major chain network alone cannot fully compensate for the absence of the more highly cross-linked minor chain network, which is believed to be stronger, more stable, and resistant to deformation. The addition of mechanical information on Alport syndrome to the currently available biological data provides a fuller picture into the progression of the disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

[Detection of large deletions in X linked Alport syndrome using competitive multiplex fluorescence polymerase chain reaction].

PubMed

Wang, F; Zhang, Y Q; Ding, J; Yu, L X

2017-10-18

To evaluate the ability of multiplex competitive fluorescence polymerase chain reaction in detection of large deletion and duplication genotypes of X-linked Alport syndrome. Clinical diagnosis of X-linked Alport syndrome was based on either abnormal staining of type IV collagen α5 chain in the epidermal basement membrane alone or with abnormal staining of type IV collagen α5 chain in the glomerular basement membrane and Bowman's capsule/ultrastructural changes in the glomerular basement membrane typical of Alport syndrome. A total of 20 unrelated Chinese patients (13 males and 7 females) clinically diagnosed as X-linked Alport syndrome were included in the study. Their genotypes were unknown. Control subjects included a male patient with other renal disease and two patients who had large deletions in COL4A5 gene detected by multiplex ligation-dependent probe amplification. Genomic DNA was isolated from peripheral blood leukocytes in all the participants. Multiplex competitive fluorescence polymerase chain reaction was used to coamplify 53 exons of COL4A5 gene and four reference genes in a single reaction. When a deletion removed exon 1 of COL4A5 gene was identified, the same method was used to coamplify the first 4 exons of COL4A5 and COL4A6 genes, a promoter shared by COL4A5 and COL4A6 genes, and three reference genes in a single reaction. Any copy number loss suggested by this method was verified by electrophoresis of corresponding polymerase chain reaction amplified products or DNA sequencing to exclude possible DNA variations in the primer regions. Genotypes of two positive controls identified by multiplex competitive fluorescence polymerase chain reaction were consistent with those detected by multiplex ligation-dependent probe amplification. Deletions were identified in 6 of the 20 patients, including two large deletions removing the 5' part of both COL4A5 and COL4A6 genes with the breakpoint located in the second intron of COL4A6, two large deletions

Improved genetic counseling in Alport syndrome by new variants of COL4A5 gene.

PubMed

Fernandez-Rosado, Francisco; Campos, Ana; Alvarez-Cubero, Maria Jesus; Ruiz, Ana; Entrala-Bernal, Carmen

2015-07-01

There are current requirements of using genetic databases for offering a better genetic assistance to patients of some syndromes, especially those with X-linked heredity patterns (like Alport Syndrome) for the high probability of having descendants affected by the disease. We describe the first reported case of COL4A5 gene missense c.1499 G>T mutation in a 16-year-old girl confirmed to be affected by Alport Syndrome after genetic counseling. Next Generation Sequencing procedures let discover this mutation and offer an accurate clinical treatment to this patient. Current scientific understanding of genetic syndromes suggests the high importance of updated databases and the inclusion of Variant of Unknown Significance related to clinical cases. All of this updating could enable patients to have a better opportunity of diagnosis and having genetic and clinical counseling. This event is even more important in women planning to start a family to have correct genetic counseling regarding the risk posed to offspring, and allowing the decision to undergo prenatal testing. © 2015 Asian Pacific Society of Nephrology.

Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome.

PubMed

Tanaka, Mari; Asada, Misako; Higashi, Atsuko Y; Nakamura, Jin; Oguchi, Akiko; Tomita, Mayumi; Yamada, Sachiko; Asada, Nariaki; Takase, Masayuki; Okuda, Tomohiko; Kawachi, Hiroshi; Economides, Aris N; Robertson, Elizabeth; Takahashi, Satoru; Sakurai, Takeshi; Goldschmeding, Roel; Muso, Eri; Fukatsu, Atsushi; Kita, Toru; Yanagita, Motoko

2010-03-01

The glomerular basement membrane (GBM) is a key component of the filtering unit in the kidney. Mutations involving any of the collagen IV genes (COL4A3, COL4A4, and COL4A5) affect GBM assembly and cause Alport syndrome, a progressive hereditary kidney disease with no definitive therapy. Previously, we have demonstrated that the bone morphogenetic protein (BMP) antagonist uterine sensitization-associated gene-1 (USAG-1) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure. Here, we investigated the role of USAG-1 in renal function in Col4a3-/- mice, which model Alport syndrome. Ablation of Usag1 in Col4a3-/- mice led to substantial attenuation of disease progression, normalization of GBM ultrastructure, preservation of renal function, and extension of life span. Immunohistochemical analysis revealed that USAG-1 and BMP-7 colocalized in the macula densa in the distal tubules, lying in direct contact with glomerular mesangial cells. Furthermore, in cultured mesangial cells, BMP-7 attenuated and USAG-1 enhanced the expression of MMP-12, a protease that may contribute to GBM degradation. These data suggest that the pathogenetic role of USAG-1 in Col4a3-/- mice might involve crosstalk between kidney tubules and the glomerulus and that inhibition of USAG-1 may be a promising therapeutic approach for the treatment of Alport syndrome.

Challenge in pathologic diagnosis of Alport syndrome: evidence from correction of previous misdiagnosis

PubMed Central

2012-01-01

Background Pathologic studies play an important role in evaluating patients with Alport syndrome besides genotyping. Difficulties still exist in diagnosing Alport syndrome (AS), and misdiagnosis is a not-so-rare event, even in adult patient evaluated with renal biopsy. Methods We used nested case–control study to investigate 52 patients previously misdiagnosed and 52 patients initially diagnosed in the China Alport Syndrome Treatments and Outcomes Registry e-system. Results We found mesangial proliferative glomerulonephritis (MsPGN, 26.9%) and focal and segmental glomerulosclerosis (FSGS, 19.2%) were the most common misdiagnosis. FSGS was the most frequent misdiagnosis in female X-linked AS (fXLAS) patients (34.8%), and MsPGN in male X-linked AS (mXLAS) patients (41.2%). Previous misdiagnosed mXLAS patients (13/17, 76.5%) and autosomal recessive AS (ARAS) patients (8/12, 66.7%) were corrected after a second renal biopsy. While misdiagnosed fXLAS patients (18/23, 78.3%) were corrected after a family member diagnosed (34.8%) or after rechecking electronic microscopy and/or collagen-IV alpha-chains immunofluresence study (COL-IF) (43.5%) during follow-up. With COL-IF as an additional criterion for AS diagnosis, we found that patients with less than 3 criteria reached have increased risk of misdiagnosis (3.29-fold for all misdiagnosed AS patients and 3.90-fold for fXLAS patients). Conclusion We emphasize timely and careful study of electronic microscopy and COL-IF in pathologic evaluation of AS patients. With renal and/or skin COL-IF as additional criterion, 3 diagnosis criteria reached are the cutoff for diagnosing AS pathologically. PMID:23259488

Murine recombinant angiotensin-converting enzyme 2 attenuates kidney injury in experimental Alport syndrome.

PubMed

Bae, Eun Hui; Fang, Fei; Williams, Vanessa R; Konvalinka, Ana; Zhou, Xiaohua; Patel, Vaibhav B; Song, Xuewen; John, Rohan; Oudit, Gavin Y; Pei, York; Scholey, James W

2017-06-01

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase in the renin-angiotensin system that catalyzes the breakdown of angiotensin II to angiotensin 1-7. We have reported that ACE2 expression in the kidney is reduced in experimental Alport syndrome but the impact of this finding on disease progression has not been studied. Accordingly, we evaluated effects of murine recombinant ACE2 treatment in Col4a3 knockout mice, a model of Alport syndrome characterized by proteinuria and progressive renal injury. Murine recombinant ACE2 (0.5 mg/kg/day) was administered from four to seven weeks of age via osmotic mini-pump. Pathological changes were attenuated by murine recombinant ACE2 treatment which ameliorated kidney fibrosis as shown by decreased expression of COL1α1 mRNA, less accumulation of extracellular matrix proteins, and inhibition of transforming growth factor-β signaling. Further, increases in proinflammatory cytokine expression, macrophage infiltration, inflammatory signaling pathway activation, and heme oxygenase-1 levels in Col4a3 knockout mice were also reduced by murine recombinant ACE2 treatment. Lastly, murine recombinant ACE2 influenced the turnover of renal ACE2, as it suppressed the expression of tumor necrosis factor-α converting enzyme, a negative regulator of ACE2. Thus, treatment with exogenous ACE2 alters angiotensin peptide metabolism in the kidneys of Col4a3 knockout mice and attenuates the progression of Alport syndrome nephropathy. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

A Split-Luciferase-Based Trimer Formation Assay as a High-throughput Screening Platform for Therapeutics in Alport Syndrome.

PubMed

Omachi, Kohei; Kamura, Misato; Teramoto, Keisuke; Kojima, Haruka; Yokota, Tsubasa; Kaseda, Shota; Kuwazuru, Jun; Fukuda, Ryosuke; Koyama, Kosuke; Matsuyama, Shingo; Motomura, Keishi; Shuto, Tsuyoshi; Suico, Mary Ann; Kai, Hirofumi

2018-05-17

Alport syndrome is a hereditary glomerular disease caused by mutation in type IV collagen α3-α5 chains (α3-α5(IV)), which disrupts trimerization, leading to glomerular basement membrane degeneration. Correcting the trimerization of α3/α4/α5 chain is a feasible therapeutic approach, but is hindered by lack of information on the regulation of intracellular α(IV) chain and the absence of high-throughput screening (HTS) platforms to assess α345(IV) trimer formation. Here, we developed sets of split NanoLuc-fusion α345(IV) proteins to monitor α345(IV) trimerization of wild-type and clinically associated mutant α5(IV). The α345(IV) trimer assay, which satisfied the acceptance criteria for HTS, enabled the characterization of intracellular- and secretion-dependent defects of mutant α5(IV). Small interfering RNA-based and chemical screening targeting the ER identified several chemical chaperones that have potential to promote α345(IV) trimer formation. This split luciferase-based trimer formation assay is a functional HTS platform that realizes the feasibility of targeting α345(IV) trimers to treat Alport syndrome. Copyright © 2018 Elsevier Ltd. All rights reserved.

Integration-free induced pluripotent stem cells derived from a patient with autosomal recessive Alport syndrome (ARAS).

PubMed

Kuebler, Bernd; Aran, Begoña; Miquel-Serra, Laia; Muñoz, Yolanda; Ars, Elisabet; Bullich, Gemma; Furlano, Monica; Torra, Roser; Marti, Merce; Veiga, Anna; Raya, Angel

2017-12-01

A skin biopsy was obtained from a 25-year-old female patient with autosomal recessive Alport syndrome (ARAS) with the homozygous COL4A3 mutation c.345delG, p.(P166Lfs*37). Dermal fibroblasts were derived and reprogrammed by nucleofection with episomal plasmids carrying OCT3/4, SOX2, KLF4 LIN28, L-MYC and p53shRNA. The generated induced Pluripotent Stem Cell (iPSC) clone AS FiPS1 Ep6F-2 was free of genomically integrated reprogramming genes, had the specific homozygous mutation, a stable karyotype, expressed pluripotency markers and generated embryoid bodies which were differentiated towards the three germ layers in vitro. This iPSC line offers a useful resource to study Alport syndrome pathomechanisms and drug testing. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Role for transforming growth factor-beta1 in alport renal disease progression.

PubMed

Sayers, R; Kalluri, R; Rodgers, K D; Shield, C F; Meehan, D T; Cosgrove, D

1999-11-01

Alport syndrome results from mutations in either the alpha3(IV), alpha4(IV), or alpha5(IV) collagen genes. The disease is characterized by a progressive glomerulonephritis usually associated with a high-frequency sensorineural hearing loss. A mouse model for an autosomal form of Alport syndrome [collagen alpha3(IV) knockout] was produced and characterized. In this study, the model was exploited to demonstrate a potential role for transforming growth factor-beta1 (TGF-beta1) in Alport renal disease pathogenesis. Kidneys from normal and Alport mice, taken at different stages during the course of renal disease progression, were analyzed by Northern blot, in situ hybridization, and immunohistology for expression of TGF-beta1 and components of the extracellular matrix. Normal and Alport human kidney was examined for TGF-beta1 expression using RNase protection. The mRNAs encoding TGF-beta1 (in both mouse and human), entactin, fibronectin, and the collagen alpha1(IV) and alpha2(IV) chains were significantly induced in total kidney as a function of Alport renal disease progression. The induction of these specific mRNAs was observed in the glomerular podocytes of animals with advanced disease. Type IV collagen, laminin-1, and fibronectin were markedly elevated in the tubulointerstitium at 10 weeks, but not at 6 weeks, suggesting that elevated expression of specific mRNAs on Northern blots reflects events associated with tubulointerstitial fibrosis. The concomitant accumulation of mRNAs encoding TGF-beta1 and extracellular matrix components in the podocytes of diseased kidneys may reflect key events in Alport renal disease progression. These data suggest a role for TGF-beta1 in both glomerular and tubulointerstitial damage associated with Alport syndrome.

Identification of four novel mutations in the COL4A5 gene of patients with Alport syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lemmink, H.H.; Schroeder, C.H.; Brunner, H.G.

1993-08-01

The type IV collagen [alpha]5 chain (COL4A5) genes of patients with Alport syndrome were tested for major gene rearrangements by Southern blot analysis, using COL4A5 cDNA clones as probes. In addition, individual exons were screened for small mutations by single-strand conformation polymorphism (SSCP) analysis. Four new COL4A5 mutations were detected. A duplication of the nine most 3[prime] located nucleotides of exon 49 and the first nucleotide of intron 49 was identified in the COL4A5 gene of one patient. Two patients displayed single base substitutions leading to, respectively, a proline to threonine and an arginine to glutamine substitution in the C-terminalmore » end. Both substitutions involve amino acids conserved through evolution. In COL4A5 intron 41 a mutation changing the splice acceptor site from AG to AA was identified. All mutations cosegregate with the clinical phenotype of Alport syndrome in affected family members. In a control population of 50 individuals tested by PCR-SSCP these mutations were never identified. Together with two mutations reported previously, a total of six mutations were found in 26 patients with Alport syndrome (23%) after systematic screening of about 30% of the COL4A5 coding region. The clinical features of these six patients are described in detail. 21 refs., 2 figs., 3 tabs.« less

A Case of Alport Syndrome with Posttransplant Antiglomerular Basement Membrane Disease despite Negative Antiglomerular Basement Membrane Antibodies by EIA Treated with Plasmapheresis and Intravenous Immunoglobulin.

PubMed

Armstead, Sumiko I; Hellmark, Thomas; Wieslander, Jorgen; Zhou, Xin J; Saxena, Ramesh; Rajora, Nilum

2013-01-01

Posttransplant antiglomerular basement membrane (anti-GBM) disease occurs in approximately 5% of Alport patients and usually ends in irreversible graft failure. Recent research has focused on characterizing the structure of the anti-GBM alloepitope. Here we present a case of a 22-year-old male with end-stage renal disease secondary to Alport syndrome, with a previously failed renal allograft, who received a second deceased-donor kidney transplant. Six days after transplantation, he developed acute kidney injury. The serum anti-GBM IgG was negative by enzyme immunoassay (EIA). On biopsy, he had crescentic glomerulonephritis with linear GBM fixation of IgG. With further analysis by western blotting, we were able to detect antibodies to an unidentified protein from the basement membrane. This patient was treated with plasmapheresis twice per week and monthly intravenous immunoglobulin (IVIG) for a total of five months. At the end of treatment, these unknown antibodies were no longer detected. His renal function improved, and he has not required dialysis. We conclude that anti-GBM disease in patients with Alport Syndrome may be caused by circulating antibodies to other components of the basement membrane that are undetectable by routine anti-GBM EIA and may respond to treatment with plasmapheresis and IVIG.

Treatment of breast cancer in a patient of Alport syndrome-induced chronic renal failure: A triumph story.

PubMed

Modi, Gaurang; Madabhavi, Irappa; Patel, Apurva; Anand, Asha

2018-01-01

Alport syndrome is a hereditary disease of the glomerular basement membrane, characterized by the familial occurrence of progressive, hematuric nephropathy with sensorineural deafness. We are reporting here a young adult female, suffering from Alport syndrome with significant family history and on maintenance twice-weekly hemodialysis (HD), had been diagnosed with triple negative earlystage right-sided breast cancer. The patient was managed successfully with surgery and adjuvant chemotherapy with 3 cycles of 5-flurouracil, doxorubicin, and cyclophosphamide and 3 cycles of docetaxel. In this case, our clinical challenge was dose reduction of chemotherapeutic agents according to creatinine clearance and timing of HD in each cycle of chemotherapy. We confronted this by dose reduction of cyclophosphamide and timing of chemotherapy was at least 12 h after HD for each and every cycle. Patient is in regular follow-up in our department since 20 months without any recurrence of the disease.

Generation of integration-free induced pluripotent stem cell lines derived from two patients with X-linked Alport syndrome (XLAS).

PubMed

Kuebler, Bernd; Aran, Begoña; Miquel-Serra, Laia; Muñoz, Yolanda; Ars, Elisabet; Bullich, Gemma; Furlano, Monica; Torra, Roser; Marti, Merce; Veiga, Anna; Raya, Angel

2017-12-01

Skin biopsies were obtained from two male patients with X-linked Alport syndrome (XLAS) with hemizygous COL4A5 mutations in exon 41 or exon 46. Dermal fibroblasts were extracted and reprogrammed by nucleofection with episomal plasmids carrying OCT3/4, SOX2, KLF4 LIN28, L-MYC and p53 shRNA. The generated induced Pluripotent Stem Cell (iPSC) lines AS-FiPS2-Ep6F-28 and AS-FiPS3-Ep6F-9 were free of genomically integrated reprogramming genes, had the specific mutations, a stable karyotype, expressed pluripotency markers and generated embryoid bodies which were differentiated towards the three germ layers in vitro. These iPSC lines offer a useful resource to study Alport syndrome pathomechanisms and drug testing. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Collagen IV Diseases: A Focus on the Glomerular Basement Membrane in Alport Syndrome

PubMed Central

Cosgrove, Dominic; Liu, Shiguang

2016-01-01

Alport syndrome is the result of mutations in any of three type IV collagen genes, COL4A3, COL4A4, or COL4A5. Because the three collagen chains form heterotrimers, there is an absence of all three proteins in the basement membranes where they are expressed. In the glomerulus, the mature glomerular basement membrane type IV collagen network, normally comprised of two separate networks, α3(IV)/α4(IV)/α5(IV) and α1(IV)/α2(IV), is comprised entirely of collagen α1(IV)/α2. This review addresses the current state of our knowledge regarding the consequence of this change in basement membrane composition, including both the direct, via collagen receptor binding, and indirect, regarding influences on glomerular biomechanics. The state of our current understanding regarding mechanisms of glomerular disease initiation and progression will be examined, as will the current state of the art regarding emergent therapeutic approaches to slow or arrest glomerular disease in Alport patients. PMID:27576055

A novel COL4A3 mutation causes autosomal-recessive Alport syndrome in a large Turkish family.

PubMed

Uzak, Asli Subasioglu; Tokgoz, Bulent; Dundar, Munis; Tekin, Mustafa

2013-03-01

Alport syndrome (AS) is a genetically heterogeneous disorder that is characterized by hematuria, progressive renal failure typically resulting in end-stage renal disease, sensorineural hearing loss, and variable ocular abnormalities. Only 15% of cases with AS are autosomal recessive and are caused by mutations in the COL4A3 or COL4A4 genes, encoding type IV collagen. Clinical data in a large consanguineous family with four affected members were reviewed, and genomic DNA was extracted. For mapping, 15 microsatellite markers flanking COL4A3, COL4A4, and COL4A5 in 16 family members were typed. For mutation screening, all coding exons of COL4A3 were polymerase chain reaction- amplified and Sanger-sequenced from genomic DNA. The disease locus was mapped to chromosome 2q36.3, where COL4A3 and COL4A4 reside. Sanger sequencing revealed a novel mis-sense mutation (c.2T>C; p.M1T) in exon 1 of COL4A3. The identified nucleotide change was not found in 100 healthy ethnicity-matched controls via Sanger sequencing. We present a large consanguineous Turkish family with AS that was found to have a COL4A3 mutation as the cause of the disease. Although the relationship between the various genotypes and phenotypes in AS has not been fully elucidated, detailed clinical and molecular analyses are helpful for providing data to be used in genetic counseling. It is important to identify new mutations to clarify their clinical importance, to assess the prognosis of the disease, and to avoid renal biopsy for final diagnosis.

Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis: a new X linked contiguous gene deletion syndrome?

PubMed Central

Jonsson, J J; Renieri, A; Gallagher, P G; Kashtan, C E; Cherniske, E M; Bruttini, M; Piccini, M; Vitelli, F; Ballabio, A; Pober, B R

1998-01-01

We describe a family with four members, a mother, two sons, and a daughter, who show clinical features consistent with X linked Alport syndrome. The two males presented with additional features including mental retardation, dysmorphic facies with marked midface hypoplasia, and elliptocytosis. The elliptocytosis was not associated with any detectable abnormalities in red cell membrane proteins; red cell membrane stability and rigidity was normal on ektacytometry. Molecular characterisation suggests a submicroscopic X chromosome deletion encompassing the entire COL4A5 gene. We propose that the additional abnormalities found in the affected males of this family are attributable to deletion or disruption of X linked recessive genes adjacent to the COL4A5 gene and that this constellation of findings may represent a new X linked contiguous gene deletion syndrome. Images PMID:9598718

Transfer of the α5(IV) Collagen Chain Gene to Smooth Muscle Restores in Vivo Expression of the α6(IV) Collagen Chain in a Canine Model of Alport Syndrome

PubMed Central

Harvey, Scott J.; Zheng, Keqin; Jefferson, Barbara; Moak, Peter; Sado, Yoshikazu; Naito, Ichiro; Ninomiya, Yoshifumi; Jacobs, Robert; Thorner, Paul S.

2003-01-01

X-linked Alport syndrome is a progressive renal disease caused by mutations in the COL4A5 gene, which encodes the α5(IV) collagen chain. As an initial step toward gene therapy for Alport syndrome, we report on the expression of recombinant α5(IV) collagen in vitro and in vivo. A full-length cDNA-encoding canine α5(IV) collagen was cloned and expressed in vitro by transfection of HEK293 cells that synthesize the α1(IV) and α2(IV), but not the α3(IV) to α6(IV) collagen chains. By Northern blotting, an α5(IV) mRNA transcript of 5.2 kb was expressed and the recombinant protein was detected by immunocytochemistry. The chain was secreted into the medium as a 190-kd monomer; no triple helical species were detected. Transfected cells synthesized an extracellular matrix containing the α1(IV) and α2(IV) chains but the recombinant α5(IV) chain was not incorporated. These findings are consistent with the concept that the α5(IV) chain requires one or more of the α3(IV), α4(IV), or α6(IV) chains for triple helical assembly. In vivo studies were performed in dogs with X-linked Alport syndrome. An adenoviral vector containing the α5(IV) transgene was injected into bladder smooth muscle that lacks both the α5(IV) and α6(IV) chains in these animals. At 5 weeks after injection, there was expression of both the α5(IV) and α6(IV) chains by smooth muscle cells at the injection site in a basement membrane distribution. Thus, this recombinant α5(IV) chain is capable of restoring expression of a second α(IV) chain that requires the presence of the α5(IV) chain for incorporation into collagen trimers. This vector will serve as a useful tool to further explore gene therapy for Alport syndrome. PMID:12598321

Alport's syndrome with focal segmental glomerulosclerosis lesion - Pattern to recognize.

PubMed

Alsahli, Afnan A; Alshahwan, Sara I; Alotaibi, Amal O; Alsaad, Khaled O; Aloudah, Nourah; Farooqui, Mahfooz; Al Sayyari, Abdullah A

2018-01-01

The association between Alport's syndrome (AS) and focal segmental glomerulosclerosis (FSGS) in the same patient is complex and rarely reported. We report a case of a 42-year-old male presenting with proteinuria, microscopic hematuria, elevated serum creatinine and hypertension with unremarkable physical examination apart from obesity. The renal biopsy showed well-established FSGS pattern of injury with mild interstitial fibrosis and tubular atrophy, while the electron microscopic examination demonstrated glomerular basement membranes (GBM) changes compatible with AS. AS can be complicated by segmental glomerular scarring, which can mimic primary FSGS, while familial FSGS can result from mutations in collagen IV network of the GBM. This overlap can complicate histopathological interpretation of renal biopsy, which should be accompanied by mutational analysis for accurate diagnosis and proper therapeutic intervention.

Advances in Alport syndrome diagnosis using next-generation sequencing

PubMed Central

Artuso, Rosangela; Fallerini, Chiara; Dosa, Laura; Scionti, Francesca; Clementi, Maurizio; Garosi, Guido; Massella, Laura; Epistolato, Maria Carmela; Mancini, Roberta; Mari, Francesca; Longo, Ilaria; Ariani, Francesca; Renieri, Alessandra; Bruttini, Mirella

2012-01-01

Alport syndrome (ATS) is a hereditary nephropathy often associated with sensorineural hypoacusis and ocular abnormalities. Mutations in the COL4A5 gene cause X-linked ATS. Mutations in COL4A4 and COL4A3 genes have been reported in both autosomal recessive and autosomal dominant ATS. The conventional mutation screening, performed by DHPLC and/or Sanger sequencing, is time-consuming and has relatively high costs because of the absence of hot spots and to the high number of exons per gene: 51 (COL4A5), 48 (COL4A4) and 52 (COL4A3). Several months are usually necessary to complete the diagnosis, especially in cases with less informative pedigrees. To overcome these limitations, we designed a next-generation sequencing (NGS) protocol enabling simultaneous detection of all possible variants in the three genes. We used a method coupling selective amplification to the 454 Roche DNA sequencing platform (Genome Sequencer junior). The application of this technology allowed us to identify the second mutation in two ATS patients (p.Ser1147Phe in COL4A3 and p.Arg1682Trp in COL4A4) and to reconsider the diagnosis of ATS in a third patient. This study, therefore, illustrates the successful application of NGS to mutation screening of Mendelian disorders with locus heterogeneity. PMID:21897443

Structure of the human type IV collagen COL4A6 gene, which is mutated in Alport syndrome-associated leiomyomatosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Xu; Zhou, Jing; Reeders, S.T.

1996-05-01

Basement membrane (type IV) collagen, a subfamily of the collagen protein family, is encoded by six distinct genes in mammals. Three of those, COL4A3, COL4A4, and COL4A5, are linked with Alport syndrome (hereditary nephritis). Patients with leimoyomatosis associated with Alport syndrome have been shown to have deletions in the 5{prime} end of the COL4A6 gene, in addition to having deletions in COL4A6. The human COL4A6 gene is reported to be 425 kb as determined by mapping of overlapping YAC clones by probes for its 5{prime} and 3{prime} ends. In the present study we describe the complete exon/intron size pattern ofmore » the human COL4A6 gene. The 12 {lambda} phage clones characterized in the study spanned a total of 110 kb, including 85 kb of the actual gene and 25 kb of flanking sequences. The overlapping clones contained all 46 exons of the gene and all introns, except for intron 2. Since the total size of the exons and all introns except for intron 2 is about 85 kb, intron 2 must be about 340 kb. All exons of the gene were assigned to EcoRI restriction fragments to facilitate analysis of the gene in patients with leiomyomatosis associated with Alport syndrome. The exon size pattern of COL4A6 is highly homologous with that of the human and mouse COL4A2 genes, with 27 of the 46 exons of COL4A6 being identical in size between the genes. 42 refs., 2 figs., 3 tabs.« less

Characterization of contiguous gene deletions in COL4A6 and COL4A5 in Alport syndrome-diffuse leiomyomatosis.

PubMed

Nozu, Kandai; Minamikawa, Shogo; Yamada, Shiro; Oka, Masafumi; Yanagita, Motoko; Morisada, Naoya; Fujinaga, Shuichiro; Nagano, China; Gotoh, Yoshimitsu; Takahashi, Eihiko; Morishita, Takahiro; Yamamura, Tomohiko; Ninchoji, Takeshi; Kaito, Hiroshi; Morioka, Ichiro; Nakanishi, Koichi; Vorechovsky, Igor; Iijima, Kazumoto

2017-07-01

Alport syndrome-diffuse leiomyomatosis (AS-DL, OMIM: 308940) is a rare variant of the X-linked Alport syndrome that shows overgrowth of visceral smooth muscles in the gastrointestinal, respiratory and female reproductive tracts in addition to renal symptoms. AS-DL results from deletions that encompass the 5' ends of the COL4A5 and COL4A6 genes, but deletion breakpoints between COL4A5 and COL4A6 have been determined in only four cases. Here, we characterize deletion breakpoints in five AS-DL patients and show a contiguous COL4A6/COL4A5 deletion in each case. We also demonstrate that eight out of nine deletion alleles involved sequences homologous between COL4A5 and COL4A6. Most breakpoints took place in recognizable transposed elements, including long and short interspersed repeats, DNA transposons and long-terminal repeat retrotransposons. Because deletions involved the bidirectional promoter region in each case, we suggest that the occurrence of leiomyomatosis in AS-DL requires inactivation of both genes. Altogether, our study highlights the importance of homologous recombination involving multiple transposed elements for the development of this continuous gene syndrome and other atypical loss-of-function phenotypes.

αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

PubMed Central

Hahm, Kyungmin; Lukashev, Matvey E.; Luo, Yi; Yang, William J.; Dolinski, Brian M.; Weinreb, Paul H.; Simon, Kenneth J.; Chun Wang, Li; Leone, Diane R.; Lobb, Roy R.; McCrann, Donald J.; Allaire, Normand E.; Horan, Gerald S.; Fogo, Agnes; Kalluri, Raghu; Shield, Charles F.; Sheppard, Dean; Gardner, Humphrey A.; Violette, Shelia M.

2007-01-01

The transforming growth factor (TGF)-β-inducible integrin αvβ6 is preferentially expressed at sites of epithelial remodeling and has been shown to bind and activate latent precursor TGF-β. Herein, we show that αvβ6 is overexpressed in human kidney epithelium in membranous glomerulonephritis, diabetes mellitus, IgA nephropathy, Goodpasture’s syndrome, and Alport syndrome renal epithelium. To assess the potential regulatory role of αvβ6 in renal disease, we studied the effects of function-blocking αvβ6 monoclonal antibodies (mAbs) and genetic ablation of the β6 subunit on kidney fibrosis in Col4A3−/− mice, a mouse model of Alport syndrome. Expression of αvβ6 in Alport mouse kidneys was observed primarily in cortical tubular epithelial cells and in correlation with the progression of fibrosis. Treatment with αvβ6-blocking mAbs inhibited accumulation of activated fibroblasts and deposition of interstitial collagen matrix. Similar inhibition of renal fibrosis was observed in β6-deficient Alport mice. Transcript profiling of kidney tissues showed that αvβ6-blocking mAbs significantly inhibited disease-associated changes in expression of fibrotic and inflammatory mediators. Similar patterns of transcript modulation were produced with recombinant soluble TGF-β RII treatment, suggesting shared regulatory functions of αvβ6 and TGF-β. These findings demonstrate that αvβ6 can contribute to the regulation of renal fibrosis and suggest this integrin as a potential therapeutic target. PMID:17200187

[Immunohistochemistry contribution in Alport syndrome diagnosis].

PubMed

Krichen Makni, S; Kharrat, M; Ben Hmida, M; Chaker, H; Gubler, M-C; Antignac, C; Jlidi, R; Hachicha, J; Sellami Boudwara, T

2005-07-01

Alport syndrome (AS) is an hereditary disease characterised by the association of progressive hematuria nephritis. The diagnosis is based on clinical genetic and ultrastructural findings. Nowadays, immunohistochemical technique is of great interest. It enables us to analyze the distribution of the different chains of the type IV collagen in renal basement membrane (RBM) and epidermal basement membrane (EBM) which appeared to be abnormal in 70% of cases. We report a prospective study of five families affected with AS. Six patients were investigated by immunohistochemical studies of kidney (3 cases) and skin (6 cases) frozen specimens. Monoclonal antibodies recognizing the collagenous domain of alpha1 (MAB1), alpha3 (MAB3) and alpha5 (MAB5) chains of type IV collagen were used. Two methods were performed: direct immunofluorescence and immunohistochemical (ultravision) analysis. The different chains distribution of type IV collagen in the EBM and RBM was normal in four cases (4 men), abnormal in two patients (1 man and woman). Based on the clinical, genetical and immunohistochemical findings we established three transmission modes: autosomal recessive in two families, dominant X linked in two other familiales, and autosomal dominant in one family. Immunohistochemical studies is a simple technique of an easy interpretation accomplished on kidney frozen specimen, or even on a simple cutaneous biopsy. It could be very useful for the diagnosis and enables us in addition to determine the mode of transmission of AS.

RAAS inhibition and the course of Alport syndrome.

PubMed

Savva, Isavella; Pierides, Alkis; Deltas, Constantinos

2016-05-01

Alport syndrome (AS) is a hereditary progressive glomerulonephritis with a high life-time risk for end-stage renal disease (ESRD). Most patients will reach ESRD before the age of 30 years, while a subset of them with milder mutations will do so at older ages, even after 50 years. Frequent extrarenal manifestations are hearing loss and ocular abnormalities. AS is a genetically heterogeneous collagen IV nephropathy, with 85% of the cases caused by mutations in the X-linked COL4A5 gene and the rest by homozygous or compound heterozygous mutations in either the COL4A3 or the COL4A4 gene on chromosome 2q36-37. There is no radical cure for the disease and attempts to use various stem cell therapies in animal models have been met with ambiguous success. However, effective treatment has been accomplished with pharmacological intervention at the renin-angiotensin-aldosterone system (RAAS), first in animal models of AS and more recently in humans. Angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) have been shown to significantly delay the progression of chronic kidney disease and the onset of ESRD. Also, renin inhibitors and aldosterone blockade were used with positive results, while the combination of ACEis and ARBs was met with mixed success. An important study, the EARLY-PROTECT, aims at evaluating the efficacy of ACEis when administered very early on in children with AS. Novel therapies are also tested experimentally or are under design in animal models by several groups, including the use of amniotic fluid stem cells and synthetic chaperones. Copyright © 2016 Elsevier Ltd. All rights reserved.

Progression of Alport Kidney Disease in Col4a3 Knock Out Mice Is Independent of Sex or Macrophage Depletion by Clodronate Treatment

PubMed Central

Kim, Munkyung; Piaia, Alessandro; Shenoy, Neeta; Kagan, David; Gapp, Berangere; Kueng, Benjamin; Weber, Delphine; Dietrich, William; Ksiazek, Iwona

2015-01-01

Alport syndrome is a genetic disease of collagen IV (α3, 4, 5) resulting in renal failure. This study was designed to investigate sex-phenotype correlations and evaluate the contribution of macrophage infiltration to disease progression using Col4a3 knock out (Col4a3KO) mice, an established genetic model of autosomal recessive Alport syndrome. No sex differences in the evolution of body mass loss, renal pathology, biomarkers of tubular damage KIM-1 and NGAL, or deterioration of kidney function were observed during the life span of Col4a3KO mice. These findings confirm that, similar to human autosomal recessive Alport syndrome, female and male Col4a3KO mice develop renal failure at the same age and with similar severity. The specific contribution of macrophage infiltration to Alport disease, one of the prominent features of the disease in human and Col4a3KO mice, remains unknown. This study shows that depletion of kidney macrophages in Col4a3KO male mice by administration of clodronate liposomes, prior to clinical onset of disease and throughout the study period, does not protect the mice from renal failure and interstitial fibrosis, nor delay disease progression. These results suggest that therapy targeting macrophage recruitment to kidney is unlikely to be effective as treatment of Alport syndrome. PMID:26555339

Alport syndrome from bench to bedside: the potential of current treatment beyond RAAS blockade and the horizon of future therapies.

PubMed

Gross, Oliver; Perin, Laura; Deltas, Constantinos

2014-09-01

The hereditary type IV collagen disease Alport syndrome (AS) always leads to end-stage renal failure. Yesterday, for the past 90 years, this course was described as 'inevitable'. Today, RAAS blockade has changed the 'inevitable' course to a treatable disease. Tomorrow, researchers hope to erase the 'always' from 'always leads to renal failure' in the textbooks. This review elucidates therapeutic targets that evolve from research: (i) kidney embryogenesis and pathogenesis; (ii) phenotype-genotype correlation and the role of collagen receptors and podocytes; (iii) the malfunctioning Alport-GBM; (iv) tubulointerstitial fibrosis; (v) the role of proteinuria in pathogenesis and prognosis; and (vi) secondary events such as infections, hyperparathyroidism and hypercholesterolaemia. Therefore, moderate lifestyle, therapy of bacterial infections, Paricalcitol in adult patients with hyperparathyroidism and HMG-CoA-reductase inhibitors in adult patients with dyslipoproteinemia might contribute to a slower progression of AS and less cardiovascular events. In the future, upcoming treatments including stem cells, chaperon therapy, collagen receptor blockade and anti-microRNA therapy will expand our perspective in protecting the kidneys of Alport patients from further damage. This perspective on current and future therapies is naturally limited by our personal focus in research, but aims to motivate young scientists and clinicians to find a multimodal cure for AS. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Endothelin-1 Mediated Induction of Extracellular Matrix Genes in Strial Marginal Cells Underlies Strial Pathology in Alport Mice

PubMed Central

Meehan, Daniel T.; Delimont, Duane; Dufek, Brianna; Zallocchi, Marisa; Phillips, Grady; Gratton, Michael Anne; Cosgrove, Dominic

2016-01-01

Alport syndrome, a type IV collagen disorder, manifests as glomerular disease associated with hearing loss with thickening of the glomerular and strial capillary basement membranes (SCBMs). We have identified a role for endothelin-1 (ET-1) activation of endothelin A receptors (ETARs) in glomerular pathogenesis. Here we explore whether ET-1 plays a role in strial pathology. Wild type (WT) and Alport mice were treated with the ETAR antagonist, sitaxentan. The stria vascularis was analyzed for SCBM thickness and for extracellular matrix (ECM) proteins. Additional WT and Alport mice were exposed to noise or hypoxia and the stria analyzed for hypoxia-related and ECM genes. A strial marginal cell line cultured under hypoxic conditions, or stimulated with ET-1 was analyzed for expression of hypoxia-related and ECM transcripts. Noise exposure resulted in significantly elevated ABR thresholds in Alport mice relative to wild type littermates. Alport stria showed elevated expression of collagen α1(IV), laminin α2, and laminin α5 proteins relative to WT. SCBM thickening and elevated ECM protein expression was ameliorated by ETAR blockade. Stria from normoxic Alport mice and hypoxic WT mice showed upregulation of hypoxia-related, ECM, and ET-1 transcripts. Both ET-1 stimulation and hypoxia up-regulated ECM transcripts in cultured marginal cells. We conclude that ET-1 mediated activation of ETARs on strial marginal cells results in elevated expression of ECM genes and thickening of the SCBMs in Alport mice. SCBM thickening results in hypoxic stress further elevating ECM and ET-1 gene expression, exacerbating strial pathology. PMID:27553900

Female Patient with Alport Syndrome and Concomitant Membranous Nephropathy: Susceptibility or Association of Two Diseases?

PubMed

Veloso, Mariana P; Neves, Precil D M M; Jorge, Lectícia B; Dias, Cristiane B; Yu, Luis; Pinheiro, Rafaela B B; Testagrossa, Leonardo A; Malheiros, Denise M; Balbo, Bruno E P; Lerário, Antônio M; Onuchic, Luiz F; Woronik, Viktoria

2017-01-01

Alport syndrome (AS) is a disorder of collagen IV, a component of glomerular basement membrane (GBM). The association of AS and immunocomplex nephropathies is uncommon. This is a case of a 37-year-old woman with family history of X-linked AS, including 4 affected sons. This patient developed full-blown nephrotic syndrome along a 3-month period, a presentation not consistent with AS progression. This scenario suggested an alternative diagnosis. A kidney biopsy was therefore performed, showing membranous nephropathy (MN) in addition to GBM structural alterations compatible with AS. Whole exome sequencing also confirmed the diagnosis of X-linked AS, revealing a heterozygous pathogenic mutation in COL4A5. While a negative serum anti-phospholipase A2 receptor did not rule out a primary form of MN, it was also uncertain whether positive serologic tests for syphilis could represent a secondary factor. It is currently unknown whether this unusual association represents AS susceptibility to immunocomplex-mediated diseases or simply an association of 2 disorders. © 2017 S. Karger AG, Basel.

X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations

PubMed Central

Savige, Judith; Storey, Helen; Il Cheong, Hae; Gyung Kang, Hee; Park, Eujin; Hilbert, Pascale; Persikov, Anton; Torres-Fernandez, Carmen; Ars, Elisabet; Torra, Roser; Hertz, Jens Michael; Thomassen, Mads; Shagam, Lev; Wang, Dongmao; Wang, Yanyan; Flinter, Frances; Nagel, Mato

2016-01-01

Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher’s exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (p<10−41 and p<0.001 respectively). Gly>Ala substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal

X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.

PubMed

Savige, Judith; Storey, Helen; Il Cheong, Hae; Gyung Kang, Hee; Park, Eujin; Hilbert, Pascale; Persikov, Anton; Torres-Fernandez, Carmen; Ars, Elisabet; Torra, Roser; Hertz, Jens Michael; Thomassen, Mads; Shagam, Lev; Wang, Dongmao; Wang, Yanyan; Flinter, Frances; Nagel, Mato

2016-01-01

Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher's exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (p<10-41 and p<0.001 respectively). Gly>Ala substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal failure

Endothelin-1 mediated induction of extracellular matrix genes in strial marginal cells underlies strial pathology in Alport mice.

PubMed

Meehan, Daniel T; Delimont, Duane; Dufek, Brianna; Zallocchi, Marisa; Phillips, Grady; Gratton, Michael Anne; Cosgrove, Dominic

2016-11-01

Alport syndrome, a type IV collagen disorder, manifests as glomerular disease associated with hearing loss with thickening of the glomerular and strial capillary basement membranes (SCBMs). We have identified a role for endothelin-1 (ET-1) activation of endothelin A receptors (ET A Rs) in glomerular pathogenesis. Here we explore whether ET-1 plays a role in strial pathology. Wild type (WT) and Alport mice were treated with the ET A R antagonist, sitaxentan. The stria vascularis was analyzed for SCBM thickness and for extracellular matrix (ECM) proteins. Additional WT and Alport mice were exposed to noise or hypoxia and the stria analyzed for hypoxia-related and ECM genes. A strial marginal cell line cultured under hypoxic conditions, or stimulated with ET-1 was analyzed for expression of hypoxia-related and ECM transcripts. Noise exposure resulted in significantly elevated ABR thresholds in Alport mice relative to wild type littermates. Alport stria showed elevated expression of collagen α1(IV), laminin α2, and laminin α5 proteins relative to WT. SCBM thickening and elevated ECM protein expression was ameliorated by ET A R blockade. Stria from normoxic Alport mice and hypoxic WT mice showed upregulation of hypoxia-related, ECM, and ET-1 transcripts. Both ET-1 stimulation and hypoxia up-regulated ECM transcripts in cultured marginal cells. We conclude that ET-1 mediated activation of ET A Rs on strial marginal cells results in elevated expression of ECM genes and thickening of the SCBMs in Alport mice. SCBM thickening results in hypoxic stress further elevating ECM and ET-1 gene expression, exacerbating strial pathology. Copyright © 2016 Elsevier B.V. All rights reserved.

Genotype and Outcome After Kidney Transplantation in Alport Syndrome.

PubMed

Gillion, Valentine; Dahan, Karin; Cosyns, Jean-Pierre; Hilbert, Pascale; Jadoul, Michel; Goffin, Eric; Godefroid, Nathalie; De Meyer, Martine; Mourad, Michel; Pirson, Yves; Kanaan, Nada

2018-05-01

Alport syndrome (AS) is caused by mutations in α3/α4/α5 (IV) collagen genes, the severity of which determine the progression of AS. Posttransplantation outcome is good, although anti-glomerular basement membrane (anti-GBM) glomerulonephritis occurs in 3% to 5% of recipients, clustering in patients with a severe mutation. We assessed whether the severity of the underlying AS mutation affects graft and patients outcome after transplantation, including the occurrence of anti-GBM nephritis. We included 73 AS patients with an identified mutation (COL4A5, 57 patients; COL4A3, 9 patients; COL4A4, 6 patients; heterozygous composite COL4A3 and A4, 1 patient) who underwent transplantation between 1971 and 2014 and who had received a total of 93 kidney grafts. In all, 41 patients had a severe mutation (COL4A5, 30 patients; COL4A3, 6 patients; COL4A4, 5 patients), and 32 had a nonsevere mutation (COL4A5, 27 patients; COL4A3, 4 patients; COL4A4, 1 patient). Patient survival was similar in patients with severe and nonsevere mutations (89% vs. 84% at 5 years, 83% vs. 75% at 10, 15, and 20 years; P  = 0.46). Graft survival was not affected by the severity of mutation (77% vs. 63% at 5 years, 60% vs. 55% at 10 years, 55% vs. 55% at 15 years, and 55% vs. 50% at 20 years; P  = 0.65). Clinically significant anti-GBM glomerulonephritis occurred in 1 male patient with severe COL4A5 mutation 6 years after transplantation recurred in a subsequent graft, leading twice to graft loss. Although severe mutations affect the severity of AS, they do not have an impact on patient and graft survival after transplantation. De novo anti-GBM nephritis after transplantation was less frequent than previously reported, occurring in only 1.4% of AS patients, and in 2% of males with COL4A5 mutation.

Alport syndrome: impact of digenic inheritance in patients management.

PubMed

Fallerini, C; Baldassarri, M; Trevisson, E; Morbidoni, V; La Manna, A; Lazzarin, R; Pasini, A; Barbano, G; Pinciaroli, A R; Garosi, G; Frullanti, E; Pinto, A M; Mencarelli, M A; Mari, F; Renieri, A; Ariani, F

2017-07-01

Alport syndrome (ATS) is a genetically heterogeneous nephropathy with considerable phenotypic variability and different transmission patterns, including monogenic (X-linked/autosomal) and digenic inheritance (DI). Here we present a new series of families with DI and we discuss the consequences for genetic counseling and risk assessment. Out of five families harboring variants in more than one COL4 gene detected by next generation sequencing (NGS), minigene-splicing assay allowed us to identify four as true digenic. Two families showed COL4A3/A4 mutations in cis, mimicking an autosomal dominant inheritance with a more severe phenotype and one showed COL4A3/A4 mutations in trans, mimicking an autosomal recessive inheritance with a less severe phenotype. In a fourth family, a de novo mutation (COL4A5) combined with an inherited mutation (COL4A3) triggered a more severe phenotype. A fifth family, predicted digenic on the basis of silico tools, rather showed monogenic X-linked inheritance due to a hypomorphic mutation, in accordance with a milder phenotype. In conclusion, this study highlights the impact of DI in ATS and explains the associated atypical presentations. More complex inheritance should be therefore considered when reviewing prognosis and recurrence risks. On the other side, these findings emphasize the importance to accompany NGS with splicing assays in order to avoid erroneous identification of at risk members. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Toric multifocal intraocular lens implantation in a case of bilateral anterior and posterior lenticonus in Alport syndrome

PubMed Central

Ladi, Jeevan S; Shah, Nitant A

2016-01-01

We report the first case of toric multifocal intraocular lens (IOL) implantation in both the eyes of a young patient of Alport syndrome with anterior and posterior lenticonus with a successful outcome. An 18-year-old female patient presented with progressively blurred vision in both eyes since 4–5 years not improving with glasses. Refraction showed high myopia with astigmatism; however, the vision did not improve beyond 6/60 with glasses correction. Clinical examination on slit lamp showed anterior and posterior lenticonus bilaterally with a classical oil droplet appearance. We performed clear lens extraction by phacoemulsification with toric multifocal IOL implantation in both eyes. Postoperatively, the patient achieved an excellent refractive outcome with the unaided vision of 6/9, N6 in both eyes. PMID:27958211

Mutation analysis of COL4A3 and COL4A4 genes in a Chinese autosomal-dominant Alport syndrome family.

PubMed

Guo, Liwei; Li, Duan; Dong, Shuangshuang; Wan, Donghao; Yang, Baosheng; Huang, Yanmei

2017-06-01

Autosomal dominant Alport syndrome (ADAS) accounts for 5% of all cases of Alport syndrome (AS), a primary basement membrane disorder arising from mutations in genes encoding the type IV collagen protein family.Mutations in COL4A3 and COL4A4 genes were reported to be associated with ADAS. In this study, clinical data in a large consanguineous family with seven affected members were reviewed, and genomic DNA was extracted. For mutation screening, all exons of COL4A3 and COL4A4 genes were polymerase chain reaction-amplified and direct sequenced from genomic DNA, and the mutations were analyzed by comparing with members in this family, 100 ethnicitymatched controls and the sequence of COL4A3 and COL4A4 genes from GenBank. A novel mutation determining a nucleotide change was found, i.e. c.4195 A>T (p.Met1399Leu) at 44th exon of COL4A4 gene, and this mutation showed heterozygous in all patients of this family. Also a novel intron mutation (c.4127+11 C>T) was observed at COL4A4 gene. Thus the novel missense mutation c.4195 A>T (p.Met1399Leu) and the intron mutation (c.4127+11 C>T) at COL4A4 gene might be responsible for ADAS of this family. Our results broadened the spectrum of mutations in COL4A4 and had important implications in the diagnosis, prognosis, and genetic counselling of ADAS.

Phenotype variability in a large Spanish family with Alport syndrome associated with novel mutations in COL4A3 gene.

PubMed

Cervera-Acedo, C; Coloma, A; Huarte-Loza, E; Sierra-Carpio, M; Domínguez-Garrido, E

2017-10-31

Alport syndrome is an inherited renal disorder characterized by glomerular basement membrane lesions with hematuria, proteinuria and frequent hearing defects and ocular abnormalities. The disease is associated with mutations in genes encoding α3, α4, or α5 chains of type IV collagen, namely COL4A3 and COL4A4 in chromosome 2 and COL4A5 in chromosome X. In contrast to the well-known X-linked and autosomal recessive phenotypes, there is very little information about the autosomal dominant. In view of the wide spectrum of phenotypes, an exact diagnosis is sometimes difficult to achieve. We investigated a Spanish family with variable phenotype of autosomal dominant Alport syndrome using clinical, histological, and genetic analysis. Mutational analysis of COL4A3 and COL4A4 genes showed a novel heterozygous mutation (c. 998G > A; p.G333E) in exon 18 of the COL4A3 gene. Among relatives carrying the novel mutation, the clinical phenotype was variable. Two additional COL4A3 mutations were found, a Pro-Leu substitution in exon 48 (p.P1461L) and a Ser-Cys substitution in exon 49 (p.S1492C), non-pathogenics alone. Carriers of p.G333E and p.P1461L or p.S1492C mutations in COL4A3 gene appear to be more severely affected than carriers of only p.G333E mutation, and the clinical findings has an earlier onset. In this way, we could speculate on a synergistic effect of compound heterozygosity that could explain the different phenotype observed in this family.

STAT3 inhibition attenuates the progressive phenotypes of Alport syndrome mouse model.

PubMed

Yokota, Tsubasa; Omachi, Kohei; Suico, Mary Ann; Kamura, Misato; Kojima, Haruka; Fukuda, Ryosuke; Motomura, Keishi; Teramoto, Keisuke; Kaseda, Shota; Kuwazuru, Jun; Takeo, Toru; Nakagata, Naomi; Shuto, Tsuyoshi; Kai, Hirofumi

2018-02-01

Alport syndrome (AS) is a hereditary, progressive nephritis caused by mutation of type IV collagen. Previous studies have shown that activation of signal transducer and activator of transcription 3 (STAT3) exacerbates other renal diseases, but whether STAT3 activation exacerbates AS pathology is still unknown. Here we aim to investigate the involvement of STAT3 in the progression of AS. Phosphorylated STAT3 expression was assessed by immunoblotting analysis of kidneys and glomeruli of an AS mouse model (Col4a5 G5X mutant). To determine the effect of blocking STAT3 signaling, we treated AS mice with the STAT3 inhibitor stattic (10 mg/kg i.p., three times per week for 10 weeks; n = 10). We assessed the renal function [proteinuria, blood urea nitrogen (BUN), serum creatinine] and analyzed the glomerular injury score, fibrosis and inflammatory cell invasion by histological staining. Moreover, we analyzed the gene expression of nephritis-associated molecules. Phosphorylated STAT3 was upregulated in AS kidneys and glomeruli. Treatment with stattic ameliorated the progressive renal dysfunction, such as increased levels of proteinuria, BUN and serum creatinine. Stattic also significantly suppressed the gene expression levels of renal injury markers (Lcn2, Kim-1), pro-inflammatory cytokines (Il-6, KC), pro-fibrotic genes (Tgf-β, Col1a1, α-Sma) and Mmp9. Stattic treatment decreased the renal fibrosis congruently with the decrease of transforming growth factor beta (TGF-β) protein and increase of antifibrosis-associated markers p-Smad1, 5 and 8, which are negative regulators of TGF-β signaling. STAT3 inhibition significantly ameliorated the renal dysfunction in AS mice. Our finding identifies STAT3 as an important regulator in AS progression and provides a promising therapeutic target for AS. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Immunohistochemical diagnosis of Alport's syndrome in paraffin-embedded renal sections: antigen retrieval with autoclave heating.

PubMed

Naito, Ichiro; Ninomiya, Yoshifumi; Nomura, Shinsuke

2003-03-01

Alport's syndrome (AS) is a hereditary renal disease caused by mutations in the genes encoding collagen type IV. Immunohistochemical analysis of the alpha chains of collagen type IV has been found to be useful for the diagnosis of this disease. The monoclonal antibodies (mAbs) generated by us recognize alpha 1(IV) through alpha 6(IV) chains of collagen type IV on fresh-frozen sections but not on paraffin-embedded sections. Antigen retrieval by autoclave heating has been found to restore the epitopes recognized by the mAbs; however the heating conditions had not been well established. In this study, the heating conditions were carefully examined using renal sections obtained from AS and non-AS patients. The heating was performed in an autoclave, at 105 degrees -127 degrees C for 6-8 min. During the heating, the sections were immersed in 0.2 N HCl solution (pH 0.9). Then, the mAbs were applied for 30 min, and the bound mAbs were detected using the LSAB kit. The optimal temperature for the antigen retrieval varied among specimens, and was dependent on the type of basement membrane examined. Thus, it was considered that heating at two or three different temperatures could be helpful for the precise diagnosis of AS. Adopting the antigen retrieval method could extend the possibility of immunohistochemical diagnosis of AS to cases without using fresh-frozen sections.

Urine-derived podocytes-lineage cells: A promising tool for precision medicine in Alport Syndrome.

PubMed

Daga, Sergio; Baldassarri, Margherita; Lo Rizzo, Caterina; Fallerini, Chiara; Imperatore, Valentina; Longo, Ilaria; Frullanti, Elisa; Landucci, Elisa; Massella, Laura; Pecoraro, Carmine; Garosi, Guido; Ariani, Francesca; Mencarelli, Maria Antonietta; Mari, Francesca; Renieri, Alessandra; Pinto, Anna Maria

2018-02-01

Alport Syndrome (ATS) is a rare genetic disorder caused by collagen IV genes mutations, leading to glomerular basement membrane damage up to end-stage renal disease. Podocytes, the main component of the glomerular structure, are the only cells able to produce all the three collagens IV alpha chains associated with ATS and thus, they are key players in ATS pathogenesis. However, podocytes-targeted therapeutic strategies have been hampered by the difficulty of non-invasively isolating them and transcripts-based diagnostic approaches are complicated by the inaccessibility of other COL4 chains-expressing cells. We firstly isolated podocyte-lineage cells from ATS patients' urine samples, in a non-invasive way. RT-PCR analysis revealed COL4A3, COL4A4, and COL4A5 expression. Transcripts analysis on RNA extracted from patient's urine derived podocyte-lineage cells allowed defining the pathogenic role of intronic variants, namely one mutation in COL4A3 (c.3882+5G>A), three mutations in COL4A4 (c.1623+2T>A, c.3699_3706+1del, c.2545+143T>A), and one mutation in COL4A5 (c.3454+2T>C). Therefore, our cellular model represents a novel tool, essential to unequivocally prove the effect of spliceogenic intronic variants on transcripts expressed exclusively at a glomerular level. This process is a key step for providing the patient with a definite molecular diagnosis and with a proper recurrence risk. The established system also opens up the possibility of testing personalized therapeutic approaches on disease-relevant cells. © 2017 Wiley Periodicals, Inc.

Linkage approach and direct COL4A5 gene mutation screening in Alport syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Turco, A.E.; Rossetti, S.; Biasi, O.

1994-09-01

Alport Syndrome (AS) is transmitted as an X-linked dominant trait in the majority of families, the defective gene being COL4A5 at Xq22. In the remaining cases AS appears to be autosomally inherited. Recently, mutations in COL4A3 and COL4A4 genes at 2q35-q37 were identified in families with autosomal recessive AS. Mutation detection screening is being performed by non-radioactive single stand conformation polymorphism (SSCP), heteroduplex analysis, and automated DNA sequencing in over 170 AS patients enrolled in the ongoing Italian Multicenter Study on AS. So far twenty-five different mutations have been found, including missense, splicing, and frameshifts. Moreover, by using six tightlymore » linked COL4A5 informative makers, we have also typed two larger AS families, and have shown compatible sex-linked transmission in one other, suggesting autosomal recessive inheritance. In this latter three-generation COL4A5-unlinked family we are now looking for linkage and for mutations in the candidate COL4A3 and COL4A4 genes on chromosome 2q.« less

Prospective study on the potential of RAAS blockade to halt renal disease in Alport syndrome patients with heterozygous mutations.

PubMed

Stock, Johanna; Kuenanz, Johannes; Glonke, Niklas; Sonntag, Joseph; Frese, Jenny; Tönshoff, Burkhard; Höcker, Britta; Hoppe, Bernd; Feldkötter, Markus; Pape, Lars; Lerch, Christian; Wygoda, Simone; Weber, Manfred; Müller, Gerhard-Anton; Gross, Oliver

2017-01-01

Patients with autosomal or X-linked Alport syndrome (AS) with heterozygous mutations in type IV collagen genes have a 1-20 % risk of progressing to end-stage renal disease during their lifetime. We evaluated the long-term renal outcome of patients at risk of progressive disease (chronic kidney disease stages 1-4) with/without nephroprotective therapy. This was a prospective, non-interventional, observational study which included data from a 4-year follow-up of AS patients with heterozygous mutations whose datasets had been included in an analysis of the 2010 database of the European Alport Registry. Using Kaplan-Meier estimates and logrank tests, we prospectively analyzed the updated datasets of 52 of these patients and 13 new datasets (patients added to the Registry after 2011). The effects of therapy, extrarenal symptoms and inheritance pattern on renal outcome were analyzed. The mean prospective follow-up was 46 ± 10 months, and the mean time on therapy was 8.4 ± 4.4 (median 7; range 2-18) years. The time from the appearance of the first symptom to diagnosis was 8.1 ± 14.2 (range 0-52) years. At the time of starting therapy, 5.4 % of patients had an estimated glomerular filtration rate of <60 ml/min, 67.6 % had proteinuria and 27.0 % had microalbuminuria. Therapeutic strategies included angiotensin-converting enzymer inhibitors (97.1 %), angiotensin receptor antagonists (1 patient), dual therapy (11.8 %) and statins (8.8 %). Among patients included in the prospective dataset, prevented the need for dialysis. Among new patients, no patient at risk for renal failure progressed to the next disease stage after 4 years follow-up; three patients even regressed to a lower stage during therapy. Treatment with blockers of the renin-angiotensin-aldosterone system prevents progressive renal failure in AS patients with heterozygous mutations in the genes causing AS. Considerable numbers of aging AS patients on dialysis may have heterozygous mutations in these

Upregulated Expression of Integrin α1 in Mesangial Cells and Integrin α3 and Vimentin in Podocytes of Col4a3-Null (Alport) Mice

PubMed Central

Steenhard, Brooke M.; Vanacore, Roberto; Friedman, David; Zelenchuk, Adrian; Stroganova, Larysa; Isom, Kathryn; St. John, Patricia L.; Hudson, Billy G.; Abrahamson, Dale R.

2012-01-01

Alport disease in humans, which usually results in proteinuria and kidney failure, is caused by mutations to the COL4A3, COL4A4, or COL4A5 genes, and absence of collagen α3α4α5(IV) networks found in mature kidney glomerular basement membrane (GBM). The Alport mouse harbors a deletion of the Col4a3 gene, which also results in the lack of GBM collagen α3α4α5(IV). This animal model shares many features with human Alport patients, including the retention of collagen α1α2α1(IV) in GBMs, effacement of podocyte foot processes, gradual loss of glomerular barrier properties, and progression to renal failure. To learn more about the pathogenesis of Alport disease, we undertook a discovery proteomics approach to identify proteins that were differentially expressed in glomeruli purified from Alport and wild-type mouse kidneys. Pairs of cy3- and cy5-labeled extracts from 5-week old Alport and wild-type glomeruli, respectively, underwent 2-dimensional difference gel electrophoresis. Differentially expressed proteins were digested with trypsin and prepared for mass spectrometry, peptide ion mapping/fingerprinting, and protein identification through database searching. The intermediate filament protein, vimentin, was upregulated ∼2.5 fold in Alport glomeruli compared to wild-type. Upregulation was confirmed by quantitative real time RT-PCR of isolated Alport glomeruli (5.4 fold over wild-type), and quantitative confocal immunofluorescence microscopy localized over-expressed vimentin specifically to Alport podocytes. We next hypothesized that increases in vimentin abundance might affect the basement membrane protein receptors, integrins, and screened Alport and wild-type glomeruli for expression of integrins likely to be the main receptors for GBM type IV collagen and laminin. Quantitative immunofluorescence showed an increase in integrin α1 expression in Alport mesangial cells and an increase in integrin α3 in Alport podocytes. We conclude that overexpression of

Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy.

PubMed

Weber, Stefanie; Strasser, Katja; Rath, Sabine; Kittke, Achim; Beicht, Sonja; Alberer, Martin; Lange-Sperandio, Bärbel; Hoyer, Peter F; Benz, Marcus R; Ponsel, Sabine; Weber, Lutz T; Klein, Hanns-Georg; Hoefele, Julia

2016-06-01

Alport syndrome (ATS) is a progressive hereditary nephropathy characterized by hematuria and proteinuria. It can be associated with extrarenal manifestations. In contrast, thin basement membrane nephropathy (TBMN) is characterized by microscopic hematuria, is largely asymptomatic, and is rarely associated with proteinuria and end-stage renal disease. Mutations have been identified in the COL4A5 gene in ATS and in the COL4A3 and COL4A4 genes in ATS and TBMN. To date, more than 1000 different mutations in COL4A5, COL4A3, and COL4A4 are known. In this study mutational analysis by exon sequencing and multiplex ligation-dependent probe amplification was performed in a large European cohort of families with ATS and TBMN. Molecular diagnostic testing of 216 individuals led to the detection of 47 novel mutations, thereby expanding the spectrum of known mutations causing ATS and TBMN by up to 10 and 6%, respectively, depending on the database. Remarkably, a high number of ATS patients with only single mutations in COL4A3 and COL4A4 were identified. Additionally, three ATS patients presented with synonymous sequence variants that possible affect correct mRNA splicing, as suggested by in silico analysis. The results of this study clearly broaden the genotypic spectrum of known mutations for ATS and TBMN, which will in turn now facilitate future studies into genotype-phenotype correlations. Further studies should also examine the significance of single heterozygous mutations in COL4A3 and COL4A4 and of synonymous sequence variants associated with ATS.

The Chemical Chaperone, PBA, Reduces ER Stress and Autophagy and Increases Collagen IV α5 Expression in Cultured Fibroblasts From Men With X-Linked Alport Syndrome and Missense Mutations.

PubMed

Wang, Dongmao; Mohammad, Mardhiah; Wang, Yanyan; Tan, Rachel; Murray, Lydia S; Ricardo, Sharon; Dagher, Hayat; van Agtmael, Tom; Savige, Judy

2017-07-01

X-linked Alport syndrome (OMIM 301050) is caused by COL4A5 missense variants in 40% of families. This study examined the effects of chemical chaperone treatment (sodium 4-phenylbutyrate) on fibroblast cell lines derived from men with missense mutations. Dermal fibroblast cultures were established from 2 affected men and 3 normals. Proliferation rates were examined, the collagen IV α5 chain localized with immunostaining, and levels of the intra- and extracellular chains quantitated with an in-house enzyme-linked immunosorbent assay. COL4A5 mRNA was measured using quantitative reverse transcriptase polymerase chain reaction. Endoplasmic reticulum (ER) size was measured on electron micrographs and after HSP47 immunostaining. Markers of ER stress (ATF6, HSPA5, DDIT3), autophagy (ATG5, BECN1, ATG7), and apoptosis (CASP3, BAD, BCL 2 ) were also quantitated by quantitative reverse transcriptase polymerase chain reaction. Measurements were repeated after 48 hours of incubation with 10 mM sodium 4-phenylbutyrate acid. Both COL4A5 missense variants were associated with reduced proliferation rates on day 6 ( P  = 0.01 and P  = 0.03), ER enlargement, and increased mRNA for ER stress and autophagy (all P values < 0.05) when compared with normal. Sodium 4-phenylbutyrate treatment increased COL4A5 transcript levels ( P  < 0.01), and reduced ER size ( P  < 0.01 by EM and P  < 0.001 by immunostaining), ER stress (p HSPA5 and DDIT3, all P values < 0.01) and autophagy (ATG7, P  < 0.01). Extracellular collagen IV α5 chain was increased in the M1 line only ( P  = 0.06). Sodium 4-phenylbutyrate increases collagen IV α5 mRNA levels, reduces ER stress and autophagy, and possibly facilitates collagen IV α5 extracellular transport. Whether these actions delay end-stage renal failure in men with X-linked Alport syndrome and missense mutations will only be determined with clinical trials.

Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease

PubMed Central

Dufek, Brianna; Meehan, Daniel; Delimont, Duane; Cheung, Linda; Gratton, Michael Anne; Phillips, Grady; Song, Wenping; Liu, Shiguang; Cosgrove, Dominic

2016-01-01

Recent work demonstrates that Alport glomerular disease is mediated through a biomechanical strain-sensitive activation of mesangial actin dynamics. This occurs through a Rac1/CDC42 cross-talk mechanism that results in the invasion of the sub-capillary spaces by mesangial filopodia. The filopodia deposit mesangial matrix proteins in the glomerular basement membrane, including laminin 211, which activates focal adhesion kinase in podocytes culminating in the up-regulation of pro-inflammatory cytokines and metalloproteinases. These events drive the progression of glomerulonephritis. Here we test whether endothelial cell-derived endothelin-1 is upregulated in Alport glomeruli, and further elevated by hypertension. Treatment of cultured mesangial cells with endothelin-1 activates the formation of drebrin-positive actin microspikes. These microspikes do not form when cells are treated with the endothelin A receptor antagonist sitaxentan, or under conditions of siRNA knockdown of endothelin A receptor mRNA. Treatment of Alport mice with sitaxentan results in delayed onset of proteinuria, normalized glomerular basement membrane morphology, inhibition of mesangial filopodial invasion of the glomerular capillaries, normalization of glomerular expression of metalloproteinases and pro-inflammatory cytokines, increased lifespan, and prevention of glomerulosclerosis and interstitial fibrosis. Thus endothelin A receptor activation on mesangial cells is a key event in initiation of Alport glomerular disease in this model. PMID:27165837

Long-term treatment with EGFR inhibitor erlotinib attenuates renal inflammatory cytokines but not nephropathy in Alport syndrome mouse model.

PubMed

Omachi, Kohei; Miyakita, Rui; Fukuda, Ryosuke; Kai, Yukari; Suico, Mary Ann; Yokota, Tsubasa; Kamura, Misato; Shuto, Tsuyoshi; Kai, Hirofumi

2017-12-01

Alport syndrome (AS) is a hereditary kidney disease caused by mutation of type IV collagen. Loss of collagen network induces collapse of glomerular basement membrane (GBM) structure. The previous studies showed that upregulation of some tyrosine kinase receptors signaling accompanied GBM disorder in AS mouse model. EGFR signaling is one of the well-known receptor kinase signaling that is involved in glomerular diseases. However, whether EGFR signaling is relevant to AS progression is still uninvestigated. Here, we determined the involvement of EGFR in AS and the effect of suppressing EGFR signaling by erlotinib treatment on AS progression. Phosphorylated EGFR expression was investigated by Western blotting analysis and immunostaining of kidney tissues of Col4a5 mutant mice (a mouse model of X-linked AS). To check the effect of blocking EGFR signaling in AS, we administered erlotinib to AS mice once a day (10 mg/kg/day) orally for 18 weeks. Renal function parameters (proteinuria, serum creatinine, and BUN) and renal histology were assessed, and the gene expressions of inflammatory cytokines were analyzed in renal tissues. Phosphorylated EGFR expression was upregulated in AS mice kidney tissues. Erlotinib slightly reduced the urinary protein and suppressed the expression of renal injury markers (Lcn2, Lysozyme) and inflammatory cytokines (Il-6, Il-1β and KC). Erlotinib did not improve renal pathology, such as glomerular sclerosis and fibrosis. These findings suggest that EGFR signaling is upregulated in kidney, but although inhibiting this signaling pathway suppressed renal inflammatory cytokines, it did not ameliorate renal dysfunction in AS mouse model.

Laminin α2-Mediated Focal Adhesion Kinase Activation Triggers Alport Glomerular Pathogenesis

PubMed Central

Delimont, Duane; Dufek, Brianna M.; Meehan, Daniel T.; Zallocchi, Marisa; Gratton, Michael Anne; Phillips, Grady; Cosgrove, Dominic

2014-01-01

It has been known for some time that laminins containing α1 and α2 chains, which are normally restricted to the mesangial matrix, accumulate in the glomerular basement membranes (GBM) of Alport mice, dogs, and humans. We show that laminins containing the α2 chain, but not those containing the α1 chain activates focal adhesion kinase (FAK) on glomerular podocytes in vitro and in vivo. CD151-null mice, which have weakened podocyte adhesion to the GBM rendering these mice more susceptible to biomechanical strain in the glomerulus, also show progressive accumulation of α2 laminins in the GBM, and podocyte FAK activation. Analysis of glomerular mRNA from both models demonstrates significant induction of MMP-9, MMP-10, MMP-12, MMPs linked to GBM destruction in Alport disease models, as well as the pro-inflammatory cytokine IL-6. SiRNA knockdown of FAK in cultured podocytes significantly reduced expression of MMP-9, MMP-10 and IL-6, but not MMP-12. Treatment of Alport mice with TAE226, a small molecule inhibitor of FAK activation, ameliorated fibrosis and glomerulosclerosis, significantly reduced proteinuria and blood urea nitrogen levels, and partially restored GBM ultrastructure. Glomerular expression of MMP-9, MMP-10 and MMP-12 mRNAs was significantly reduced in TAE226 treated animals. Collectively, this work identifies laminin α2-mediated FAK activation in podocytes as an important early event in Alport glomerular pathogenesis and suggests that FAK inhibitors, if safe formulations can be developed, might be employed as a novel therapeutic approach for treating Alport renal disease in its early stages. PMID:24915008

Ultrastructural Characterization of the Glomerulopathy in Alport Mice by Helium Ion Scanning Microscopy (HIM).

PubMed

Tsuji, Kenji; Suleiman, Hani; Miner, Jeffrey H; Daley, James M; Capen, Diane E; Păunescu, Teodor G; Lu, Hua A Jenny

2017-09-15

The glomerulus exercises its filtration barrier function by establishing a complex filtration apparatus consisting of podocyte foot processes, glomerular basement membrane and endothelial cells. Disruption of any component of the glomerular filtration barrier leads to glomerular dysfunction, frequently manifested as proteinuria. Ultrastructural studies of the glomerulus by transmission electron microscopy (TEM) and conventional scanning electron microscopy (SEM) have been routinely used to identify and classify various glomerular diseases. Here we report the application of newly developed helium ion scanning microscopy (HIM) to examine the glomerulopathy in a Col4a3 mutant/Alport syndrome mouse model. Our study revealed unprecedented details of glomerular abnormalities in Col4a3 mutants including distorted podocyte cell bodies and disorganized primary processes. Strikingly, we observed abundant filamentous microprojections arising from podocyte cell bodies and processes, and presence of unique bridging processes that connect the primary processes and foot processes in Alport mice. Furthermore, we detected an altered glomerular endothelium with disrupted sub-endothelial integrity. More importantly, we were able to clearly visualize the complex, three-dimensional podocyte and endothelial interface by HIM. Our study demonstrates that HIM provides nanometer resolution to uncover and rediscover critical ultrastructural characteristics of the glomerulopathy in Col4a3 mutant mice.

Alport Syndrome

MedlinePlus

... in your genes (mutations) to a protein called collagen. Collagen is important to the normal structure and function of the kidneys. Changes to collagen can also cause problems with the eyes and ...

Genes and Syndromic Hearing Loss.

ERIC Educational Resources Information Center

Keats, Bronya J. B.

2002-01-01

This article provides a description of the human genome and patterns of inheritance and discusses genes that are associated with some of the syndromes for which hearing loss is a common finding, including: Waardenburg, Stickler, Jervell and Lange-Neilsen, Usher, Alport, mitochondrial encephalomyopathy, and sensorineural hearing loss. (Contains…

Bromide supplementation exacerbated the renal dysfunction, injury and fibrosis in a mouse model of Alport syndrome.

PubMed

Yokota, Tsubasa; Omachi, Kohei; Suico, Mary Ann; Kojima, Haruka; Kamura, Misato; Teramoto, Keisuke; Kaseda, Shota; Kuwazuru, Jun; Shuto, Tsuyoshi; Kai, Hirofumi

2017-01-01

A seminal study recently demonstrated that bromide (Br-) has a critical function in the assembly of type IV collagen in basement membrane (BM), and suggested that Br- supplementation has therapeutic potential for BM diseases. Because salts of bromide (KBr and NaBr) have been used as antiepileptic drugs for several decades, repositioning of Br- for BM diseases is probable. However, the effects of Br- on glomerular basement membrane (GBM) disease such as Alport syndrome (AS) and its impact on the kidney are still unknown. In this study, we administered daily for 16 weeks 75 mg/kg or 250 mg/kg (within clinical dosage) NaBr or NaCl (control) via drinking water to 6-week-old AS mice (mouse model of X-linked AS). Treatment with 75 mg/kg NaBr had no effect on AS progression. Surprisingly, compared with 250 mg/kg NaCl, 250 mg/kg NaBr exacerbated the progressive proteinuria and increased the serum creatinine and blood urea nitrogen in AS mice. Histological analysis revealed that glomerular injury, renal inflammation and fibrosis were exacerbated in mice treated with 250 mg/kg NaBr compared with NaCl. The expressions of renal injury markers (Lcn2, Lysozyme), matrix metalloproteinase (Mmp-12), pro-inflammatory cytokines (Il-6, Il-8, Tnf-α, Il-1β) and pro-fibrotic genes (Tgf-β, Col1a1, α-Sma) were also exacerbated by 250 mg/kg NaBr treatment. Notably, the exacerbating effects of Br- were not observed in wild-type mice. These findings suggest that Br- supplementation needs to be carefully evaluated for real positive health benefits and for the absence of adverse side effects especially in GBM diseases such as AS.

A patient with MEN1 and end-stage chronic kidney disease due to Alport syndrome: Decision making on the eligibility of transplantation.

PubMed

Matrone, Antonio; Brancatella, Alessandro; Marchetti, Piero; Vasile, Enrico; Boggi, Ugo; Elisei, Rossella; Cetani, Filomena; Marcocci, Claudio; Vitti, Paolo; Latrofa, Francesco

2018-03-01

Absence of neoplastic disease in the organ-recipient is required in order to allow organ transplantation. Due to its rarity, no data regarding management of patients with Multiple endocrine neoplasia type 1 (MEN1) and end-stage renal failure candidates for kidney transplantation are available. A 36 year-old man was referred to the present hospital with MEN1, with a neuroendocrine pancreatic tumor and primary hyperparathyroidism and associated Alport syndrome with end stage renal failure. The present study aimed to establish the eligibility of the patient for a kidney transplantation. The neuroendocrine tumor had been treated with duodenopancreatectomy two years earlier and hyperparathyroidism by parathyroidectomy. The review of the literature did not provide data regarding the eligibility for kidney transplantation of patients harboring a neuroendocrine pancreatic tumor in the context of MEN1. Due to the end-stage renal failure, neuroendocrine markers were unreliable and the investigation therefore relied on imaging studies, which were unremarkable. Young age, low-grade tumor, low expression of Ki67, absence of metastatic lymph nodes, onset in the setting of a MEN1 were all positive prognostic factors of the neuroendocrine tumor. Normal serum calcium ruled out persistent primary hyperparathyroidism. Overall, hemodyalisis is known to significantly reduce life expectancy. Benefits of kidney transplantation overcome the risk of neuroendocrine tumor recurrence in a young patient bearing MEN1.

Genetic diagnosis of polycystic kidney disease, Alport syndrome, and thalassemia minor in a large Chinese family.

PubMed

Miao, Yun; Xiong, Jun; Zhang, Xuelian; Huang, Huajie; Yu, Lixin; Chen, Jianfan; Deng, Wenfeng; Xu, Huiling; Liu, Rumin; Xiang, Chenglin; Xu, Xiangmin; Xiong, Fu

2017-10-01

Polycystic kidney disease (PKD) and Alport syndrome (AS) are serious inherited disorders associated with renal disease, and thalassemia is a hereditary blood disease with a high prevalence in south China. Here, we report an exceptional PKD coincidence of thalassemia minor and AS (diagnosed genetically) in a large Chinese family. Whole genome next-generation sequencing (NGS) was performed on the proband, and all family members underwent clinical evaluation. Sanger sequencing was used to validate the mutations distinguished by NGS. The pathogenic potential of the variants were evaluated by Polymorphism Phenotyping v2 (PolyPhen-2), Sorting Intolerant From Tolerant (SIFT) algorithm, and MutationTaster. Immunohistochemical, Western blot, immunofluorescent, and TdT-mediated dUTP nick-end labeling (TUNEL) analyses were performed to investigate polycystin 1 (PC1) expression, and cell proliferation and apoptosis in kidney tissues from the proband and normal control. A novel frameshift polycystic kidney disease 1 ( PKD1 ) mutation (c.3903delC, p.A1302Pfs) was identified to be responsible for renal disease in this family. PC1 expression, and cell proliferation and apoptosis were significantly increased in the kidney tissues of the proband. Moreover, a deletion of approximately 19.3 kb of DNA with α-globin genes ( _ _SEA ) was associated with thalassemia minor in the family. In addition, a collagen type IV α 5 chain ( COL4A5 ) variant (c.2858G>T, rs78972735), annotated as a pathogenic mutation in dbSNP and human gene mutation database (HGMD), was found in four family members with no clinical traits of AS. A novel pathogenic PKD1 mutation (c.3903delC) and ( _ _SEA ) thalassemia deletion were found to be responsible for the clinical symptoms in this family. The reported pathogenic COL4a5 variant (c.2858G>T, rs78972735) was not pathogenic alone. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

X-linked Alport syndrome: An SSCP-based mutation survey over all 51 exons of the COL4A5 gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Renieri, A.; Bruttini, M.; Galli, L.

1996-06-01

The COL4A5 gene encodes the {alpha}5 (type IV) collagen chain and is defective in X-linked Alport syndrome (AS). Here, we report the first systematic analysis of all 51 exons of COL4A5 gene in a series of 201 Italian AS patients. We have previously reported nine major rearrangements, as well as 18 small mutations identified in the same patient series by SSCP analysis of several exons. After systematic analysis of all 51 exons of COL4A5, we have now identified 30 different mutations: 10 glycine substitutions in the triple helical domain of the protein, 9 frameshift mutations, 4 in-frame deletions, 1 startmore » codon, 1 nonsense, and 5 splice-site mutations. These mutations were either unique or found in two unrelated families, thus excluding the presence of a common mutation in the coding part of the gene. Overall, mutations were detected in only 45% of individuals with a certain or likely diagnosis of X-linked AS. This finding suggests that mutations in noncoding segments of COL4A5 account for a high number of X-linked AS cases. An alternative hypothesis is the presence of locus heterogeneity, even within the X-linked form of the disease. A genotype/phenotype comparison enabled us to better substantiate a significant correlation between the degree of predicted disruption of the {alpha}5 chain and the severity of phenotype in affected male individuals. Our study has significant implications in the diagnosis and follow-up of AS patients. 44 refs., 3 figs., 4 tabs.« less

Control of Mammary Differentiation by Ras-Dependent Signal Transduction Pathways

DTIC Science & Technology

2005-05-01

NM_007607 carbonic anhydrase 4 2.399 NM_011361 serum/glucocorticoid regulated kinase 2.05575 NM_019496 Alport syndrome , mental retardation, mid...oxidase NM_013515 erythrocyte protein band 7.2 NM_011338 small inducible cytokine A9, chemokine NM 007607 carbonic anhydrase 4 NM_019496 Alport syndrome

Acute compartment syndrome caused by uncontrolled hypothyroidism.

PubMed

Modi, Anar; Amin, Hari; Salzman, Matthew; Morgan, Farah

2017-06-01

Acute compartment syndrome is increased tissue pressure exceeding perfusion pressure in a closed compartment resulting in nerve and muscle ischemia. Common precipitating causes are crush injuries, burns, substance abuse, osseous or vascular limb trauma. This is a case of 42year old female with history of hypothyroidism who presented to emergency room with acute onset of severe pain and swelling in right lower extremity. Physical examination was concerning for acute compartment syndrome of right leg which was confirmed by demonstration of elevated compartmental pressures. No precipitating causes were readily identified. Further laboratory testing revealed uncontrolled hypothyroidism. Management included emergent fasciotomy and initiating thyroid hormone replacement. This case represents a rare association between acute compartment syndrome and uncontrolled hypothyroidism. We also discuss the pathogenesis of compartment syndrome in hypothyroid patients and emphasize the importance of evaluating for less common causes, particularly in setting of non-traumatic compartment syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

[Multiple bladder diverticula caused by occipital horn syndrome].

PubMed

Legros, L; Revencu, N; Nassogne, M-C; Wese, F-X; Feyaerts, A

2015-11-01

We report on the case of a child who presented with recurrent, multiple, and voluminous bladder diverticula. Bladder diverticula are defined as a herniation of the mucosa through the bladder muscle or the detrusor. Causes are numerous and diverticula can be classified into primary congenital diverticula (para-ureteral - or Hutch diverticula - and posterolateral diverticula); secondary diverticula (resulting from chronic mechanical obstruction or from neurological disease; and diverticula secondary to connective tissue or muscle fragility. The latter is seen in disease entities such as prune belly syndrome, Ehlers-Danlos syndrome, cutis laxa syndrome, OHS (occipital horn syndrome), Menkes disease, and Williams-Beuren syndrome. In this patient, the cause of these diverticula was OHS, a genetic, recessive X-chromosome-linked syndrome, responsible for abnormal tissue caused by a disorder in copper metabolism. This case reminds us of the importance of pushing the diagnostic workup when presented with multiple and/or large bladder diverticula, and in particular to search for rare malformation syndromes after exclusion of an obstacle. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Hantavirus pulmonary syndrome: encephalitis caused by virus Andes.

PubMed

Talamonti, Lionel; Padula, Paula J; Canteli, María Sol; Posner, Federico; Marczeski, Fanny Pires; Weller, Carlos

2011-04-01

Hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome (HPS) are rodent-borne emerging diseases caused by members of the genus Hantavirus, family Bunyaviridae. Some species of hantavirus may cause encephalitis, but this is the first report in Andes virus associated to HPS.

Neuroleptic malignant syndrome possibly caused by molindone hydrochloride.

PubMed

Gradon, J D

1991-10-01

The case of a patient who developed neuroleptic malignant syndrome (NMS) on three separate occasions is presented. Her third bout of this syndrome possibly was caused by molindone hydrochloride. This medication has been reported only once previously to cause NMS. The pharmacology of molindone is reviewed and a complicating factor in this case--the recent onset of hypothyroidism--is discussed together with its implication in the development of the clinical manifestations of this syndrome.

Ectopic ACTH syndrome caused by pulmonary carcinoid tumourlets.

PubMed

Povedano, S T; Pastor, C V; Seoane, C P; Reina, L J; Moreno, M A; Ortega, R P; López-Rubio, F; López, P B

2001-06-01

The differential diagnosis of Cushing's syndrome is a major challenge to clinical endocrinologists, especially those infrequent cases referred to as occult ectopic ACTH syndromes. Although bronchial carcinoids are well known to be a cause of Cushing's syndrome due to ectopic ACTH secretion, very few cases of carcinoid tumourlets causing an ACTH ectopic syndrome have been reported, and their origin remains controversial. For some authors, tumourlets and typical carcinoids represent distinct pathological entities, whilst others hold that tumourlets are merely microscopic carcinoid tumours. We report a patient with an aggressive Cushing's syndrome that required bilateral adrenalectomy, diagnosed 22 years before a 3-cm lung nodule became apparent on routine chest X-ray. The biopsy after lung surgery revealed a typical peripheral bronchial carcinoid surrounded by tumourlets. Both tumourlets and carcinoid tumour showed strongly positive ACTH immunostaining. Recently, Arioglu et al. (1998) reported a case of Cushing's syndrome caused by pulmonary carcinoid tumourlets, concluding that this entity should be considered in the differential diagnosis of occult ectopic ACTH syndrome. Furthermore, we consider that the carcinoid tumourlets found in our patient, were the initial source of ACTH, leading to Cushing's syndrome with a rapid onset, and that a loss of cell proliferation control in one of such tumourlets many years later, could have resulted in the development of a typical carcinoid tumour, reinforcing the theory of a common origin of these lesions.

Negative Staining for COL4A5 Correlates With Worse Prognosis and More Severe Ultrastructural Alterations in Males With Alport Syndrome.

PubMed

Said, Samar M; Fidler, Mary E; Valeri, Anthony M; McCann, Brooke; Fiedler, Wade; Cornell, Lynn D; Alexander, Mariam Priya; Alkhunaizi, Ahmed M; Sullivan, Anne; Cramer, Carl H; Hogan, Marie C; Nasr, Samih H

2017-01-01

Alport syndrome (AS) is a genetic disorder characterized by progressive hematuric nephropathy with or without sensorineural hearing loss and ocular lesions. Previous studies on AS included mostly children. To determine the prognostic value of loss of staining for collagen type IV alpha 5 (COL4A5) and its relationship with the ultrastructural glomerular basement membrane alterations, we performed direct immunofluorescence using a mixture of fluorescein isothiocyanate-conjugated and Texas-red conjugated antibodies against COL4A5 and COL4A2, respectively, on renal biopsies of 25 males with AS (including 16 who were diagnosed in adulthood). All patients showed normal positive staining of glomerular basement membranes and tubular basement membranes for COL4A2. Of the 25 patients, 10 (40%) patients showed loss of staining for COL4A5 (including 89% of children and 13% of adults) and the remaining 15 (60%) had intact staining for COL4A5. Compared with patients with intact staining for COL4A5, those with loss of staining had more prominent ultrastructural glomerular basement membrane alterations and were younger at the time of biopsy. By Kaplan-Meier survival analysis and Cox regression analysis, loss of staining for COL4A5 predicted earlier progression to overt proteinuria and stage 2 chronic kidney disease or worse. By multivariate Cox regression analysis, loss of staining for COL4A5 was an independent predictor of the development of overt proteinuria and stage 2 chronic kidney disease or worse. Thus, the COL4A5 expression pattern has an important prognostic value and it correlates with the severity of ultrastructural glomerular basement membrane alterations in males with AS. Loss of COL4A5 staining is uncommon in patients with AS diagnosed in their adulthood.

Break-dance: an unusual cause of hammer syndrome.

PubMed

Schneider, Frédéric; Milesi, Ilaria; Haesler, Erik; Wicky, Stephan; Schnyder, P; Denys, Alban

2002-01-01

We report the case of a young break-dancer presenting with hammer syndrome. This syndrome has been correlated with many professional and recreational activities but this is, to our knowledge, the first description of hammer syndrome caused by break-dancing. The etiology, diagnosis and treatment modalities of this rare syndrome are considered.

Break-Dance: An Unusual Cause of Hammer Syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schneider, Frederic; Milesi, Ilaria; Haesler, Erik

2002-08-15

We report the case of a young break-dancer presenting with hammer syndrome. This syndrome has been correlated with many professional and recreational activities but this is, to our knowledge, the first description of hammer syndrome caused by break-dancing. The etiology, diagnosis and treatment modalities of this rare syndrome are considered.

Nakalanga Syndrome: Clinical Characteristics, Potential Causes, and Its Relationship with Recently Described Nodding Syndrome

PubMed Central

Föger, Kathrin; Gora-Stahlberg, Gina; Sejvar, James; Ovuga, Emilio; Jilek-Aall, Louise; Schmutzhard, Erich

2017-01-01

Nakalanga syndrome is a condition that was described in Uganda and various other African countries decades ago. Its features include growth retardation, physical deformities, endocrine dysfunction, mental impairment, and epilepsy, amongst others. Its cause remains obscure. Nodding syndrome is a neurological disorder with some features in common with Nakalanga syndrome, which has been described mainly in Uganda, South Sudan, and Tanzania. It has been considered an encephalopathy affecting children who, besides head nodding attacks, can also present with stunted growth, delayed puberty, and mental impairment, amongst other symptoms. Despite active research over the last years on the pathogenesis of Nodding syndrome, to date, no convincing single cause of Nodding syndrome has been reported. In this review, by means of a thorough literature search, we compare features of both disorders. We conclude that Nakalanga and Nodding syndromes are closely related and may represent the same condition. Our findings may provide new directions in research on the cause underlying this neurological disorder. PMID:28182652

Stage-Specific Action of Matrix Metalloproteinases Influences Progressive Hereditary Kidney Disease

PubMed Central

Zeisberg, Michael; Khurana, Mona; Rao, Velidi H; Cosgrove, Dominic; Rougier, Jean-Philippe; Werner, Michelle C; Shield, Charles F; Werb, Zena; Kalluri, Raghu

2006-01-01

Background Glomerular basement membrane (GBM), a key component of the blood-filtration apparatus in the in the kidney, is formed through assembly of type IV collagen with laminins, nidogen, and sulfated proteoglycans. Mutations or deletions involving α3(IV), α4(IV), or α5(IV) chains of type IV collagen in the GBM have been identified as the cause for Alport syndrome in humans, a progressive hereditary kidney disease associated with deafness. The pathological mechanisms by which such mutations lead to eventual kidney failure are not completely understood. Methods and Findings We showed that increased susceptibility of defective human Alport GBM to proteolytic degradation is mediated by three different matrix metalloproteinases (MMPs)—MMP-2, MMP-3, and MMP-9—which influence the progression of renal dysfunction in α3(IV) −/− mice, a model for human Alport syndrome. Genetic ablation of either MMP-2 or MMP-9, or both MMP-2 and MMP-9, led to compensatory up-regulation of other MMPs in the kidney glomerulus. Pharmacological ablation of enzymatic activity associated with multiple GBM-degrading MMPs, before the onset of proteinuria or GBM structural defects in the α3(IV) −/− mice, led to significant attenuation in disease progression associated with delayed proteinuria and marked extension in survival. In contrast, inhibition of MMPs after induction of proteinuria led to acceleration of disease associated with extensive interstitial fibrosis and early death of α3(IV) −/− mice. Conclusions These results suggest that preserving GBM/extracellular matrix integrity before the onset of proteinuria leads to significant disease protection, but if this window of opportunity is lost, MMP-inhibition at the later stages of Alport disease leads to accelerated glomerular and interstitial fibrosis. Our findings identify a crucial dual role for MMPs in the progression of Alport disease in α3(IV) −/− mice, with an early pathogenic function and a later protective

X-Linked Glomerulopathy Due to COL4A5 Founder Variant.

PubMed

Barua, Moumita; John, Rohan; Stella, Lorenzo; Li, Weili; Roslin, Nicole M; Sharif, Bedra; Hack, Saidah; Lajoie-Starkell, Ginette; Schwaderer, Andrew L; Becknell, Brian; Wuttke, Matthias; Köttgen, Anna; Cattran, Daniel; Paterson, Andrew D; Pei, York

2018-03-01

Alport syndrome is a rare hereditary disorder caused by rare variants in 1 of 3 genes encoding for type IV collagen. Rare variants in COL4A5 on chromosome Xq22 cause X-linked Alport syndrome, which accounts for ∼80% of the cases. Alport syndrome has a variable clinical presentation, including progressive kidney failure, hearing loss, and ocular defects. Exome sequencing performed in 2 affected related males with an undefined X-linked glomerulopathy characterized by global and segmental glomerulosclerosis, mesangial hypercellularity, and vague basement membrane immune complex deposition revealed a COL4A5 sequence variant, a substitution of a thymine by a guanine at nucleotide 665 (c.T665G; rs281874761) of the coding DNA predicted to lead to a cysteine to phenylalanine substitution at amino acid 222, which was not seen in databases cataloguing natural human genetic variation, including dbSNP138, 1000 Genomes Project release version 01-11-2004, Exome Sequencing Project 21-06-2014, or ExAC 01-11-2014. Review of the literature identified 2 additional families with the same COL4A5 variant leading to similar atypical histopathologic features, suggesting a unique pathologic mechanism initiated by this specific rare variant. Homology modeling suggests that the substitution alters the structural and dynamic properties of the type IV collagen trimer. Genetic analysis comparing members of the 3 families indicated a distant relationship with a shared haplotype, implying a founder effect. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

An uncommon cause of anaemia: Sheehan's syndrome.

PubMed

Melchardt, Thomas; Namberger, Konrad; Weiss, Lukas; Egle, Alexander; Faber, Viktoria; Greil, Richard

2010-12-01

Ischemic pituitary necrosis due to severe postpartum haemorrhage called Sheehan's syndrome is a rare cause of hypopituitarism in the western world, but much more common in developing countries. A 45-year-old female patient being a war refugee from Chechnya with severe anaemia and fatigue was diagnosed at our outpatient department with Sheehan's syndrome after severe postpartum haemorrhage and emergency hysterectomy 15 years ago. Panhypopituitarism was adequately treated with substitution of hydrocortisone, thyroxine and transdermal oestrogen which resulted in haemoglobin increase to nearly normal levels and symptoms improved immediately. Severe anaemia caused by panhypopituitarism shows the importance of the hormonal system for erythropoiesis. Clinical and basic scientific evidence indicates thyroidal hormones to be the main cause.

Polymyositis-like syndrome caused by hypothyroidism, presenting as camptocormia.

PubMed

Kim, Ji Min; Song, Eun Joo; Seo, Jae Seok; Nam, Eon Jeong; Kang, Young Mo

2009-01-01

Polymyositis-like syndrome characterized by proximal muscle weakness and elevation of muscle enzymes may be a presenting manifestation of hypothyroidism. Camptocormia, which can be caused by myopathy of the paraspinal muscles, is an involuntary truncal flexion of the thoracolumbar spine while standing or walking. Among various neuromuscular disorders, hypothyroidism has not been reported in the literature as a cause of camptocormia. This is the first report of polymyositis-like syndrome with camptocormia caused by hypothyroidism.

A Rare Cause of Hypothalamic Obesity, Rohhad Syndrome: 2 Cases.

PubMed

Şiraz, Ülkü Gül; Okdemir, Deniz; Direk, Gül; Akın, Leyla; Hatipoğlu, Nihal; Kendırcı, Mustafa; Kurtoğlu, Selim

2018-03-19

Rapid-onset obesity with hypoventilation, hypothalamic dysfunction and autonomic dysregulation (ROHHAD) syndrome is a rare disease that is difficult to diagnosis and distinguish from genetic obesity syndromes. The underlying causes of the disease has not been fully explained. Hypothalamic dysfunction causes endocrine problems, respiratory dysfunction and autonomic alterations. There are around 80 reported patients due to lack of recognition. We present two female patient suspected of ROHHAD due to weight gain since early childhood. The presented symptoms, respiratory and circulatory dysfunction, hypothalamic hypernatremia, hypothalamo-pituitary hormonal disorders such as santral hypothyrodism, hyperprolactinemia and santral early puberty are completely matched the criteria of ROHHAD syndrome. ROHHAD syndrome should be considered in differential diagnosis since it is difficult to distinguish from causes of monogenic obesity. Early identification of the disease reduces morbidity of the syndrome and patients require regular follow-up by a multidisciplinary approach.

Causes of infertility in men with Down syndrome.

PubMed

Stefanidis, K; Belitsos, P; Fotinos, A; Makris, N; Loutradis, D; Antsaklis, A

2011-10-01

Men with Down syndrome are considered as infertile although the causes of infertility are not known in detail yet. Although this constitutes a general rule there are three confirmed cases of parenting by fathers with Down syndrome. Many investigators have addressed the causes of infertility and their studies indicate that the causes may be hormonal deficits, morphological alterations of the gonads, abnormal spermatogenesis, psychological and social factors related to the mental retardation. It is obvious that the extra chromosome 21 has a detrimental direct and indirect effect on the reproductive capacity of the affected male patient. But the definite cause of the insufficient and inadequate spermatogenesis remains to be discovered. © 2011 Blackwell Verlag GmbH.

Alport syndrome

MedlinePlus

... deafness; Hemorrhagic familial nephritis; Hereditary deafness and nephropathy Images Male urinary system References Appel GB, Radhakrishnan J, D'Agati V. Secondary glomerular disease. In: Skorecki ...

SKIV2L Mutations Cause Syndromic Diarrhea, or Trichohepatoenteric Syndrome

PubMed Central

Fabre, Alexandre; Charroux, Bernard; Martinez-Vinson, Christine; Roquelaure, Bertrand; Odul, Egritas; Sayar, Ersin; Smith, Hilary; Colomb, Virginie; Andre, Nicolas; Hugot, Jean-Pierre; Goulet, Olivier; Lacoste, Caroline; Sarles, Jacques; Royet, Julien; Levy, Nicolas; Badens, Catherine

2012-01-01

Syndromic diarrhea (or trichohepatoenteric syndrome) is a rare congenital bowel disorder characterized by intractable diarrhea and woolly hair, and it has recently been associated with mutations in TTC37. Although databases report TTC37 as being the human ortholog of Ski3p, one of the yeast Ski-complex cofactors, this lead was not investigated in initial studies. The Ski complex is a multiprotein complex required for exosome-mediated RNA surveillance, including the regulation of normal mRNA and the decay of nonfunctional mRNA. Considering the fact that TTC37 is homologous to Ski3p, we explored a gene encoding another Ski-complex cofactor, SKIV2L, in six individuals presenting with typical syndromic diarrhea without variation in TTC37. We identified mutations in all six individuals. Our results show that mutations in genes encoding cofactors of the human Ski complex cause syndromic diarrhea, establishing a link between defects of the human exosome complex and a Mendelian disease. PMID:22444670

Infrasellar pituitary gangliocytoma causing Cushing's syndrome.

PubMed

Domingue, Marie-Eve; Marbaix, Etienne; Do Rego, Jean-Luc; Col, Vincent; Raftopoulos, Christian; Duprez, Thierry; Vaudry, Hubert; Maiter, Dominique

2015-10-01

Pituitary gangliocytomas are uncommon neuronal tumours that may present with endocrine disorders, the most frequent being acromegaly caused by growth hormone hypersecretion. Cushing's syndrome is very rarely seen with gangliocytomas. We report the unique case of a 62 year-old woman whose clinical picture and endocrine testing clearly demonstrated adrenocorticotropin (ACTH)-dependent Cushing's syndrome. Pituitary magnetic resonance imaging showed a 12-mm homogeneous, infra- and retrosellar mass first diagnosed as pituitary macroadenoma. Transsphenoidal surgery was performed and allowed complete resection of the tumour with sparing of normal anterior pituitary. Very low postoperative serum cortisol and ACTH levels were observed in the early postoperative period and the patient is still in remission 18 months after surgery, thus demonstrating that the resected lesion was entirely responsible for the clinical picture. Histological and immunocytochemical analyses demonstrated a benign tumour composed of mature neuronal cells suggestive of a gangliocytoma, expressing both ACTH and corticotropin-releasing hormone (CRH). The tumour was surrounded by a rim of pituitary tissue containing ACTH-producing endocrine cells. Careful analysis of the resected lesion did not reveal any pituitary microadenoma. We search literature for similar cases and retraced only nine cases of gangliocytomas associated with Cushing's syndrome. In most of them, the tumour was combined with either pituitary corticotroph adenoma or hyperplasia. Our case represents a unique case of an infrasellar pituitary gangliocytoma which was able to cause Cushing's syndrome by both direct ACTH production and CRH-induced stimulation of neighbour normal corticotroph cells.

Dysphagia caused by a lateral medullary infarction syndrome (Wallenberg's syndrome)

PubMed Central

El Mekkaoui, Amine; Irhoudane, Hanane; Ibrahimi, Adil; El Yousfi, Mounia

2012-01-01

A 68-year-old man was referred to our hospital for a dysphagia evolving for 10 days. Clinical examination had found neurological signs as contralateral Horner's syndrome, ipsilateral palatal paresis, gait ataxia and hoarseness. Video-fluoroscopy showed a lack of passage of contrast medium to the distal esophagus. Esogastroduodenoscopy was normal. The cranial MRI had shown an acute ischemic stroke in the left lateral medullar region and the diagnosis of Wallenberg syndrome (WS) was established. WS remains an unknown cause of dysphagia in the clinical practice of the gastroenterologist. PMID:23077713

The Role of Fatty Acid Metabolism in Estrogen Receptor Negative Breast Cancer

DTIC Science & Technology

2015-11-01

6):529-541. 10 5. Curtis C, Shah SP, Chin S-F, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y et al: The genomic and...triacylglycerol synthesis [45]. Deletion of the human ACSL4 gene has been associated with Alport syndrome , ellipto- cytosis, and mental retardation [46], and a...synthetase 4, is deleted in a family with Alport syndrome , elliptocytosis, and mental retardation. Genomics 47, 350–358. [47] Meloni I, Muscettola M

Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus.

PubMed

Rasmuson, J; Andersson, C; Norrman, E; Haney, M; Evander, M; Ahlm, C

2011-05-01

Hantaviruses have previously been recognised to cause two separate syndromes: hemorrhagic fever with renal syndrome in Eurasia, and hantavirus pulmonary syndrome (HPS) in the Americas. However, increasing evidence suggests that this dichotomy is no longer fruitful when recognising human hantavirus disease and understanding the pathogenesis. Herein are presented three cases of severe European Puumala hantavirus infection that meet the HPS case definition. The clinical and pathological findings were similar to those found in American hantavirus patients. Consequently, hantavirus infection should be considered as a cause of acute respiratory distress in all endemic areas worldwide.

Morvan syndrome: a rare cause of syndrome of inappropriate antidiuretic hormone secretion.

PubMed

Demirbas, Seref; Aykan, Musa Baris; Zengin, Haydar; Mazman, Semir; Saglam, Kenan

2017-01-01

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) accounts for an important part of hyponatremia cases. The causes of SIADH can be detected almost always. As a rare disorder, Morvan Syndrome can be defined by the sum of peripheral nerve hyperexcitability, autonomic instability and neuropsychiatric features. Antibodies to voltage-gated potassium channels (Anti - VGKC-Ab) including contactin associated protein-like 2 antibodies (CASPR2-Ab) and leucine-rich glioma inactivated protein 1 antibodies (LGI1-Ab) were previously known for the potential association with this condition. We present a Morvan Syndrome in a patient who presented with various neuropsychiatric symptoms and SIADH.

Iatrogenic Cushing's syndrome caused by intranasal steroid use.

PubMed

Dursun, Fatma; Kirmizibekmez, Heves

2017-01-01

Cushing's syndrome (CS) is common after oral steroid use and has also been reported following topical or inhaled use, but it is extremely uncommon after intranasal administration. This is the case of a 6-year-old child who developed Cushing's syndrome after intranasal application of dexamethasone sodium phosphate for a period of 6 months. Pediatricians and other clinical practitioners should be aware that high-dose and long-term nasal steroid administration may cause iatrogenic Cushing's syndrome characterized by complications of glucocorticoid excess as well as serious and even life-threatening complications of adrenal insufficiency.

Chronic Fatigue Syndrome: Searching for the Cause and Treatment.

ERIC Educational Resources Information Center

Eichner, Edward R.

1989-01-01

Chronic fatigue syndrome became known nationally in l985 with a pseudoepidemic in a Nevada resort community. Initially and erroneously linked to the Epstein-Barr virus, the cause of this puzzling syndrome and the mind-body connection are areas of controversy and research. (Author/SM)

Genetic, chromosomal, and syndromic causes of neural tube defects.

PubMed

Seidahmed, Mohammed Z; Abdelbasit, Omer B; Shaheed, Meeralebbae M; Alhussein, Khalid A; Miqdad, Abeer M; Samadi, Abdulmohsen S; Khalil, Mohammed I; Al-Mardawi, Elham; Salih, Mustafa A

2014-12-01

To ascertain the incidence, and describe the various forms of neural tube defects (NTDs) due to genetic, chromosomal, and syndromic causes. We carried out a retrospective analysis of data retrieved from the medical records of newborn infants admitted to the Neonatal Intensive Care Unit with NTDs and their mothers spanning 14 years (1996-2009) at the Security Forces Hospital, Riyadh, Saudi Arabia. The cases were ascertained by a perinatologist, neonatologist, geneticist, radiologist, and neurologist. The literature was reviewed via a MEDLINE search. Only liveborn babies were included. Permission from the Educational Committee at the Security Forces Hospital was obtained prior to the collection of data. Out of 103 infants with NTDs admitted during this period, 20 (19.4%) were found to have an underlying genetic syndromic, chromosomal and/or other anomalies. There were 5 cases of Meckel-Gruber syndrome, 2 Joubert syndrome, one Waardenburg syndrome, one Walker-Warburg syndrome, 2 chromosomal disorders, 2 caudal regression, one amniotic band disruption sequence, one associated with omphalocele, one with diaphragmatic hernia, and 4 with multiple congenital anomalies. There is a high rate of underlying genetic syndromic and/or chromosomal causes of NTDs in the Saudi Arabian population due to the high consanguinity rate. Identification of such association can lead to more accurate provisions of genetic counseling to the family including preimplantation genetic diagnosis or early termination of pregnancies associated with lethal conditions.

Morvan syndrome: a rare cause of syndrome of inappropriate antidiuretic hormone secretion

PubMed Central

DEMIRBAS, SEREF; AYKAN, MUSA BARIS; ZENGIN, HAYDAR; MAZMAN, SEMIR; SAGLAM, KENAN

2017-01-01

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) accounts for an important part of hyponatremia cases. The causes of SIADH can be detected almost always. As a rare disorder, Morvan Syndrome can be defined by the sum of peripheral nerve hyperexcitability, autonomic instability and neuropsychiatric features. Antibodies to voltage-gated potassium channels (Anti – VGKC-Ab) including contactin associated protein-like 2 antibodies (CASPR2-Ab) and leucine-rich glioma inactivated protein 1 antibodies (LGI1-Ab) were previously known for the potential association with this condition. We present a Morvan Syndrome in a patient who presented with various neuropsychiatric symptoms and SIADH. PMID:28781533

Mutations in the G6PC3 gene cause Dursun syndrome.

PubMed

Banka, Siddharth; Newman, William G; Ozgül, R Koksal; Dursun, Ali

2010-10-01

Dursun syndrome is a triad of familial primary pulmonary hypertension, leucopenia, and atrial septal defect. Here we demonstrate that mutations in G6PC3 cause Dursun syndrome. Mutations in G6PC3 are known to also cause severe congenital neutropenia type 4. Identification of the genetic basis of Dursun syndrome expands the pre-existing knowledge about the phenotypic effects of mutations in G6PC3. We propose that Dursun syndrome should now be considered as a subset of severe congenital neutropenia type 4 with pulmonary hypertension as an important clinical feature. Copyright © 2010 Wiley-Liss, Inc.

An overview of hereditary hearing loss.

PubMed

Bayazit, Yildirim A; Yilmaz, Metin

2006-01-01

Understanding the genetic basis of hearing loss is important because almost 50% of profound hearing loss are caused by genetic factors and more than 120 independent genes have been identified. In this review, after a brief explanation of some genetic terms (allele, heterozygosis, homozygosis, polymorphism, genotype and phenotype), classification of genetic hearing loss (syndromic versus nonsyndromic, and recessive dominant, X-linked and mitochondrial) was performed. Some of the most common syndromes (Usher, Pendred, Jervell and Lange-Nielsen, Waardenburg, branchio-oto-renal, Stickler, Treacher Collins and Alport syndromes, biotinidase deficiency and Norrie disease) causing genetic hearing loss were also explained briefly. The genes involved in hearing loss and genetic heterogeneity were presented. Copyright 2006 S. Karger AG, Basel.

[Case of posterior reversible encephalopathy syndrome caused by Fisher syndrome].

PubMed

Yokoi, Katsunori; Ando, Tetsuo; Kawakami, Osamu

2018-01-26

This report presents a case of a 71-year-old woman with Fisher syndrome who had posterior reversible encephalopathy syndrome (PRES) before the initiation of intravenous immunoglobulin (IVIg) treatment. She had symptoms of common cold 2 weeks before the onset of PRES. On the day of the onset, she began to stagger while walking. On day 2, she developed hypertension, vision impairment, and limb weakness and was admitted to the hospital. On day 3, she was provided steroid pulse therapy. On day 4, she developed convulsions and right imperfection single paralysis and was transferred to the our hospital. During the transfer, the patient was conscious. Her blood pressure was high at 198/107 mmHg. She had mild weakness in her limbs and face, light perception in both eyes, dilation of both pupils, total external ophthalmoplegia, no tendon reflexes, and limb and trunk ataxia. We diagnosed PRES because of the high signal intensities observed on T 2 -weighted MRI on both sides of the parietal and occipital lobes. We also diagnosed Fisher syndrome because of a positive anti-GQ1b immunoglobulin G antibody test and albuminocytologic dissociation in the cerebrospinal fluid. PRES showed prompt improvement with antihypertensive therapy, whereas Fisher syndrome slowly improved over a course of 2 months. This case is the first report of PRES without IVIg suggesting that Fisher syndrome induces hypertension and causes PRES.

Etiology of chronic renal failure in Jenin district, Palestine.

PubMed

Abumwais, Jamal Qasem

2012-01-01

A study was conducted on chronic renal failure patients treated by medications or by hemodialysis at The Martyr Dr. Khalil Sulaiman Hospital in Jenin city, Palestine, from 1/8/2005 to 1/8/2006 to know the underlying etiology of chronic renal failure. The subjects included were 84 patients. The information was obtained from files of the patients. The diagnosis was based on medical history, laboratory tests, X-rays, CT scans, ultrasound and renal biopsies. The results showed that the three most common causes of chronic renal failure in Jenin district were diabetes mellitus (33.32%), hypertension (16.7%), and chronic glomerulonephritis (13.1%). Inherited kidney diseases formed an important percentage (17.85%) and included primary hyperoxaluria (10.71%), Alport's syndrome (5.95%), and adult polycystic kidney disease (1.19%). These results differ from what is found in most developing countries including many Arab countries where the principal causes of chronic renal failure are chronic glomerulonephritis and interstitial nephritis. The high prevalence of inherited kidney diseases in some families (primary hyperoxaluria and Alport's) syndrome may be explained by the very high prevalence of consanguineous marriage especially among cousins in these families.

Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome

PubMed Central

Boyden, Lynn M.; Kam, Chen Y.; Hernández-Martín, Angela; Zhou, Jing; Craiglow, Brittany G.; Sidbury, Robert; Mathes, Erin F.; Maguiness, Sheilagh M.; Crumrine, Debra A.; Williams, Mary L.; Hu, Ronghua; Lifton, Richard P.; Elias, Peter M.; Green, Kathleen J.; Choate, Keith A.

2016-01-01

Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin. PMID:26604139

Lumbar vertebral hemangioma causing cauda equina syndrome: a case report.

PubMed

Ahn, Henry; Jhaveri, Subir; Yee, Albert; Finkelstein, Joel

2005-11-01

Case report. To report a case of lumbar hemangioma causing neurogenic claudication and early cauda equina, managed with hemostatic vertebroplasty and posterior decompression. This is the first report to our knowledge of a lumbar hemangioma causing neurogenic claudication and early cauda equina syndrome. Most hemangiomas causing neurologic symptoms occur in thoracic spine and cause spinal cord compression. Vertebroplasty as a method of hemostasis and for providing mechanical stability in this situation has not been discussed previously in the literature. L4 hemangioma was diagnosed in a 64-year-old woman with severe neurogenic claudication and early cauda equina syndrome. Preoperative angiograms showed no embolizable vessels. Posterior decompression was performed followed by bilateral transpedicular vertebroplasty. The patient received postoperative radiation to prevent recurrence. Complete relief of neurogenic claudication and cauda equina with less than 100 mL of blood loss. A lumbar hemangioma of the vertebral body, although rare, can cause neurogenic claudication and cauda equina syndrome. Intraoperative vertebroplasty can be an effective method of hemostasis and provide stability of the vertebra following posterior decompression.

Genetic, chromosomal, and syndromic causes of neural tube defects

PubMed Central

Seidahmed, Mohammed Z.; Abdelbasit, Omer B.; Shaheed, Meeralebbae M.; Alhussein, Khalid A.; Miqdad, Abeer M.; Samadi, Abdulmohsen S.; Khalil, Mohammed I.; Al-Mardawi, Elham; Salih, Mustafa A.

2014-01-01

Objective: To ascertain the incidence, and describe the various forms of neural tube defects (NTDs) due to genetic, chromosomal, and syndromic causes. Methods: We carried out a retrospective analysis of data retrieved from the medical records of newborn infants admitted to the Neonatal Intensive Care Unit with NTDs and their mothers spanning 14 years (1996-2009) at the Security Forces Hospital, Riyadh, Saudi Arabia. The cases were ascertained by a perinatologist, neonatologist, geneticist, radiologist, and neurologist. The literature was reviewed via a MEDLINE search. Only liveborn babies were included. Permission from the Educational Committee at the Security Forces Hospital was obtained prior to the collection of data. Results: Out of 103 infants with NTDs admitted during this period, 20 (19.4%) were found to have an underlying genetic syndromic, chromosomal and/or other anomalies. There were 5 cases of Meckel-Gruber syndrome, 2 Joubert syndrome, one Waardenburg syndrome, one Walker-Warburg syndrome, 2 chromosomal disorders, 2 caudal regression, one amniotic band disruption sequence, one associated with omphalocele, one with diaphragmatic hernia, and 4 with multiple congenital anomalies. Conclusions: There is a high rate of underlying genetic syndromic and/or chromosomal causes of NTDs in the Saudi Arabian population due to the high consanguinity rate. Identification of such association can lead to more accurate provisions of genetic counseling to the family including preimplantation genetic diagnosis or early termination of pregnancies associated with lethal conditions. PMID:25551112

Unilateral facial paralysis caused by Ramsay Hunt syndrome.

PubMed

Pereira, Flávia P; Guskuma, Marcos H; Luvizuto, Eloá R; Faco, Eduardo F S; Magro-Filho, Osvaldo; Hochuli-Vieira, Eduardo

2011-09-01

The Ramsay Hunt syndrome is a rare disease caused by an infection of the geniculate ganglion by the varicella-zoster virus. The main clinical features of the syndrome are as follows: Bell palsy unilateral or bilateral, vesicular eruptions on the ears, ear pain, dizziness, preauricular swelling, tingling, tearing, loss of taste sensation, and nystagmus. We describe a 23-year-old white woman, who presented with facial paralysis on the left side of the face, pain, fever, ear pain, and swelling in the neck and auricular region on the left side. She received appropriate treatment with acyclovir, vitamin B complex, and CMP nucleus. After 30 days after presentation, the patient did not show any signs or symptoms of the syndrome. At follow-up at 1 year, she showed no relapse of the syndrome.

Munchausen syndrome by proxy caused by ipecac poisoning.

PubMed

Carter, Kathryn Elizabeth; Izsak, Eugene; Marlow, James

2006-09-01

To present a case of Munchausen syndrome by proxy caused by ipecac poisoning to increase the awareness of their warning signs and symptoms so that they may be recognized and diagnosed earlier. Report of one case of a child who was determined to be a victim of Munchausen syndrome by proxy by ipecac poisoning who was hospitalized multiple times over a 4-year period at 2 different hospitals before an accurate diagnosis was made.

Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome.

PubMed

Boyden, Lynn M; Kam, Chen Y; Hernández-Martín, Angela; Zhou, Jing; Craiglow, Brittany G; Sidbury, Robert; Mathes, Erin F; Maguiness, Sheilagh M; Crumrine, Debra A; Williams, Mary L; Hu, Ronghua; Lifton, Richard P; Elias, Peter M; Green, Kathleen J; Choate, Keith A

2016-01-15

Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Gain-of-Function Mutations in RIT1 Cause Noonan Syndrome, a RAS/MAPK Pathway Syndrome

PubMed Central

Aoki, Yoko; Niihori, Tetsuya; Banjo, Toshihiro; Okamoto, Nobuhiko; Mizuno, Seiji; Kurosawa, Kenji; Ogata, Tsutomu; Takada, Fumio; Yano, Michihiro; Ando, Toru; Hoshika, Tadataka; Barnett, Christopher; Ohashi, Hirofumi; Kawame, Hiroshi; Hasegawa, Tomonobu; Okutani, Takahiro; Nagashima, Tatsuo; Hasegawa, Satoshi; Funayama, Ryo; Nagashima, Takeshi; Nakayama, Keiko; Inoue, Shin-ichi; Watanabe, Yusuke; Ogura, Toshihiko; Matsubara, Yoichi

2013-01-01

RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes. PMID:23791108

Guillain-Barré syndrome: causes, immunopathogenic mechanisms and treatment.

PubMed

Jasti, Anil K; Selmi, Carlo; Sarmiento-Monroy, Juan C; Vega, Daniel A; Anaya, Juan-Manuel; Gershwin, M Eric

2016-11-01

Guillain-Barré syndrome is a rare disease representing the most frequent cause of acute flaccid symmetrical weakness of the limbs and areflexia usually reaching its peak within a month. The etiology and pathogenesis remain largely enigmatic and the syndrome results in death or severe disability in 9-17% of cases despite immunotherapy. Areas covered: In terms of etiology, Guillain-Barré syndrome is linked to Campylobacter infection but less than 0.1% of infections result in the syndrome. In terms of pathogenesis, activated macrophages and T cells and serum antibodies against gangliosides are observed but their significance is unclear. Expert commentary: Guillain-Barré syndrome is a heterogeneous condition with numerous subtypes and recent data point towards the role of ganglioside epitopes by immunohistochemical methods. Ultimately, the syndrome results from a permissive genetic background on which environmental factors, including infections, vaccination and the influence of aging, lead to disease.

A Double Selection Approach to Achieve Specific Expression of Toxin Genes for Ovarian Cancer Gene Therapy

DTIC Science & Technology

2005-11-01

biological properties. CAV-1 is known to cause allergic two knobs may in fact be distinct based on our uveitis, called the ’blue eye syndrome ’ and rarely...system - first steps towards gene therapy of Alport syndrome . Gene Ther 3(1), 2 1-7. Hemminki, A., and Alvarez, R. D. 2002. Adenoviruses in oncology: a...Ad-IX- Ad-IX-imRFPI or Ad-IX-tdimer2(12) (10000 viral particles/ tdimer2(12) with plX modifications, and wild-type El/E3 cell) were added to the

Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome.

PubMed

Aoki, Yoko; Niihori, Tetsuya; Banjo, Toshihiro; Okamoto, Nobuhiko; Mizuno, Seiji; Kurosawa, Kenji; Ogata, Tsutomu; Takada, Fumio; Yano, Michihiro; Ando, Toru; Hoshika, Tadataka; Barnett, Christopher; Ohashi, Hirofumi; Kawame, Hiroshi; Hasegawa, Tomonobu; Okutani, Takahiro; Nagashima, Tatsuo; Hasegawa, Satoshi; Funayama, Ryo; Nagashima, Takeshi; Nakayama, Keiko; Inoue, Shin-Ichi; Watanabe, Yusuke; Ogura, Toshihiko; Matsubara, Yoichi

2013-07-11

RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

LRIG2 Mutations Cause Urofacial Syndrome

PubMed Central

Stuart, Helen M.; Roberts, Neil A.; Burgu, Berk; Daly, Sarah B.; Urquhart, Jill E.; Bhaskar, Sanjeev; Dickerson, Jonathan E.; Mermerkaya, Murat; Silay, Mesrur Selcuk; Lewis, Malcolm A.; Olondriz, M. Beatriz Orive; Gener, Blanca; Beetz, Christian; Varga, Rita E.; Gülpınar, Ömer; Süer, Evren; Soygür, Tarkan; Özçakar, Zeynep B.; Yalçınkaya, Fatoş; Kavaz, Aslı; Bulum, Burcu; Gücük, Adnan; Yue, Wyatt W.; Erdogan, Firat; Berry, Andrew; Hanley, Neil A.; McKenzie, Edward A.; Hilton, Emma N.; Woolf, Adrian S.; Newman, William G.

2013-01-01

Urofacial syndrome (UFS) (or Ochoa syndrome) is an autosomal-recessive disease characterized by congenital urinary bladder dysfunction, associated with a significant risk of kidney failure, and an abnormal facial expression upon smiling, laughing, and crying. We report that a subset of UFS-affected individuals have biallelic mutations in LRIG2, encoding leucine-rich repeats and immunoglobulin-like domains 2, a protein implicated in neural cell signaling and tumorigenesis. Importantly, we have demonstrated that rare variants in LRIG2 might be relevant to nonsyndromic bladder disease. We have previously shown that UFS is also caused by mutations in HPSE2, encoding heparanase-2. LRIG2 and heparanase-2 were immunodetected in nerve fascicles growing between muscle bundles within the human fetal bladder, directly implicating both molecules in neural development in the lower urinary tract. PMID:23313374

Dyke-Davidoff-Masson Syndrome. An unusual cause of status epilepticus.

PubMed

Zawar, Ifrah; Khan, Ashfa A; Sultan, Tipu; Rathore, Ahsan W

2015-10-01

The Dyke-Davidoff-Masson Syndrome (DDMS) results from an insult to the growing brain in utero or early infancy, which lead to loss of neurons compromising the growth of the brain. Clinical presentation includes seizures, hemiparesis, facial asymmetry, and learning disability. Radiological findings include cerebral atrophy on one side. Here, we present a case with status epilepticus who had underlying DDMS. It is a rare syndrome and uncommon cause for status epilepticus. Infections of CNS, hypoxic ischemic encephalopathy, intracranial bleed, trauma, congenital vascular malformations are the common causes of this syndrome. Diagnosis is established after clinical history, examination, and MRI. Intractable seizures can be controlled with appropriate anticonvulsants. Subsequently, these children may require physiotherapy, speech therapy, and occupational therapy in addition to the anticonvulsant medication. Outcome is better if the seizures are controlled.

Preterm labor: one syndrome, many causes.

PubMed

Romero, Roberto; Dey, Sudhansu K; Fisher, Susan J

2014-08-15

Preterm birth is associated with 5 to 18% of pregnancies and is a leading cause of infant morbidity and mortality. Spontaneous preterm labor, a syndrome caused by multiple pathologic processes, leads to 70% of preterm births. The prevention and the treatment of preterm labor have been long-standing challenges. We summarize the current understanding of the mechanisms of disease implicated in this condition and review advances relevant to intra-amniotic infection, decidual senescence, and breakdown of maternal-fetal tolerance. The success of progestogen treatment to prevent preterm birth in a subset of patients at risk is a cause for optimism. Solving the mystery of preterm labor, which compromises the health of future generations, is a formidable scientific challenge worthy of investment. Copyright © 2014, American Association for the Advancement of Science.

Alport Syndrome Foundation

MedlinePlus

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Intronic splicing mutations in PTCH1 cause Gorlin syndrome.

PubMed

Bholah, Zaynab; Smith, Miriam J; Byers, Helen J; Miles, Emma K; Evans, D Gareth; Newman, William G

2014-09-01

Gorlin syndrome is an autosomal dominant disorder characterized by multiple early-onset basal cell carcinoma, odontogenic keratocysts and skeletal abnormalities. It is caused by heterozygous mutations in the tumour suppressor PTCH1. Routine clinical genetic testing, by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to confirm a clinical diagnosis of Gorlin syndrome, identifies a mutation in 60-90 % of cases. We undertook RNA analysis on lymphocytes from ten individuals diagnosed with Gorlin syndrome, but without known PTCH1 mutations by exonic sequencing or MLPA. Two altered PTCH1 transcripts were identified. Genomic DNA sequence analysis identified an intron 7 mutation c.1068-10T>A, which created a strong cryptic splice acceptor site, leading to an intronic insertion of eight bases; this is predicted to create a frameshift p.(His358Alafs*12). Secondly, a deep intronic mutation c.2561-2057A>G caused an inframe insertion of 78 intronic bases in the cDNA transcript, leading to a premature stop codon p.(Gly854fs*3). The mutations are predicted to cause loss of function of PTCH1, consistent with its tumour suppressor function. The findings indicate the importance of RNA analysis to detect intronic mutations in PTCH1 not identified by routine screening techniques.

[Auto-immune disorders as a possible cause of neuropsychiatric syndromes].

PubMed

Martinez-Martinez, P; Molenaar, P C; Losen, M; Hoffmann, C; Stevens, J; de Witte, L D; van Amelsvoort, T; van Os, J; Rutten, B P F

2015-01-01

Changes that occur in the behaviour of voltage-gated ion channels and ligand-gated receptor channels due to gene mutations or auto-immune attack are the cause of channelopathies in the central and peripheral nervous system. Although the relation between molecular channel defects and clinical symptoms has been explained in the case of many neuromuscular channelopathies, the pathophysiology of auto-immunity in neuropsychiatric syndromes is still unclear. To review recent findings regarding neuronal auto-immune reactions in severe neuropsychiatric syndromes. Using PubMed, we consulted the literature published between 1990 and August 2014 relating to the occurrence of auto-immune antibodies in severe and persistent neuropsychiatric syndromes. Auto-antibodies have only limited access to the central nervous system, but if they do enter the system they can, in some cases, cause disease. We discuss recent findings regarding the occurrence of auto-antibodies against ligand-activated receptor channels and potassium channels in neuropsychiatric and neurological syndromes, including schizophrenia and limbic encephalitis. Although the occurrence of several auto-antibodies in schizophrenia has been confirmed, there is still no proof of a causal relationship in the syndrome. We still have no evidence of the prevalence of auto-immunity in neuropsychiatric syndromes. The discovery that an antibody against an ion channel is associated with some neuropsychiatric disorders may mean that in future it will be possible to treat patients by means of immunosuppression, which could lead to an improvement in a patient's cognitive abilities.

A molecular and clinical study of Larsen syndrome caused by mutations in FLNB.

PubMed

Bicknell, Louise S; Farrington-Rock, Claire; Shafeghati, Yousef; Rump, Patrick; Alanay, Yasemin; Alembik, Yves; Al-Madani, Navid; Firth, Helen; Karimi-Nejad, Mohammad Hassan; Kim, Chong Ae; Leask, Kathryn; Maisenbacher, Melissa; Moran, Ellen; Pappas, John G; Prontera, Paolo; de Ravel, Thomy; Fryns, Jean-Pierre; Sweeney, Elizabeth; Fryer, Alan; Unger, Sheila; Wilson, L C; Lachman, Ralph S; Rimoin, David L; Cohn, Daniel H; Krakow, Deborah; Robertson, Stephen P

2007-02-01

Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected relatives were evaluated for mutations in FLNB and their phenotypes studied. Probands were screened for mutations in FLNB using a combination of denaturing high-performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and radiographical features of the patients were evaluated. The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. Three mutations are recurrent, with one mutation, 5071G-->A, observed in 6 of 20 subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate clustering of causative mutations in FLNB.

LRIG2 mutations cause urofacial syndrome.

PubMed

Stuart, Helen M; Roberts, Neil A; Burgu, Berk; Daly, Sarah B; Urquhart, Jill E; Bhaskar, Sanjeev; Dickerson, Jonathan E; Mermerkaya, Murat; Silay, Mesrur Selcuk; Lewis, Malcolm A; Olondriz, M Beatriz Orive; Gener, Blanca; Beetz, Christian; Varga, Rita E; Gülpınar, Omer; Süer, Evren; Soygür, Tarkan; Ozçakar, Zeynep B; Yalçınkaya, Fatoş; Kavaz, Aslı; Bulum, Burcu; Gücük, Adnan; Yue, Wyatt W; Erdogan, Firat; Berry, Andrew; Hanley, Neil A; McKenzie, Edward A; Hilton, Emma N; Woolf, Adrian S; Newman, William G

2013-02-07

Urofacial syndrome (UFS) (or Ochoa syndrome) is an autosomal-recessive disease characterized by congenital urinary bladder dysfunction, associated with a significant risk of kidney failure, and an abnormal facial expression upon smiling, laughing, and crying. We report that a subset of UFS-affected individuals have biallelic mutations in LRIG2, encoding leucine-rich repeats and immunoglobulin-like domains 2, a protein implicated in neural cell signaling and tumorigenesis. Importantly, we have demonstrated that rare variants in LRIG2 might be relevant to nonsyndromic bladder disease. We have previously shown that UFS is also caused by mutations in HPSE2, encoding heparanase-2. LRIG2 and heparanase-2 were immunodetected in nerve fascicles growing between muscle bundles within the human fetal bladder, directly implicating both molecules in neural development in the lower urinary tract. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Germinal mosaicism of PAX3 mutation caused Waardenburg syndrome type I.

PubMed

Chen, Kaitian; Zhan, Yuan; Wu, Xuan; Zong, Ling; Jiang, Hongyan

2018-01-01

Waardenburg syndrome mutations are most often recurrent or de novo. The rate of familial recurrence is low and families with several affected children are extremely rare. In this study, we aimed to clarify the underlying hereditary cause of Waardenburg syndrome type I in two siblings in a Chinese family, with a mother affected by prelingual mild hearing loss and a father who was negative for clinical symptoms of Waardenburg syndrome and had a normal hearing threshold. Complete characteristic features of the family members were recorded and genetic sequencing and parent-child relationship analyses were performed. The two probands were found to share double mutations in the PAX3/GJB2 genes that caused concurrent hearing loss in Waardenburg syndrome type I. Their mother carried the GJB2 c.109G > A homozygous mutation; however, neither the novel PAX3 c.592delG mutation, nor the Waardenburg syndrome phenotype, was observed in either parent. These previously unreported digenic mutations in PAX3/GJB2 resulted in deafness associated with Waardenburg syndrome type I in this family. To our knowledge, this is the first report describing germinal mosaicism in Waardenburg syndrome. This concept is important because it complicates genetic counseling of this family regarding the risk of recurrence of the mutations in subsequent pregnancies. Copyright © 2017 Elsevier B.V. All rights reserved.

[Toxic shock syndrome caused by pyogenic bacteria].

PubMed

Gábor, Zsuzsa; Szekeres, Sándor; Gacs, Mária

2003-01-12

Case reports and review of the literature. Severe toxic shock syndrome caused by invasive infection with pyogenic bacteria Staphylococcus aureus or group A Streptococcus pyogenes, with high mortality rates in cases of the latter, remained one of the most problematic chapters of critical care medicine to date. To give an overview on the epidemiology, clinical manifestations, the complex therapeutical approaches of the syndrome and, on the role and mechanisms of action of bacterial superantigens in the pathophysiological processes as well. Literary data, and some illustrative selected cases demonstrate that, the incidence of TSS shows increasing tendency worldwide and, that otherwise healthy, younger people are the most frequently affected. As for prognosis: early diagnosis and treatment with sufficient radicality are of decisive importance.

Recent advances in bulbar syndromes: genetic causes and disease mechanisms.

PubMed

Manole, Andreea; Fratta, Pietro; Houlden, Henry

2014-10-01

With advances in next-generation gene sequencing, progress in deep phenotyping and a greater understanding of the pathogenesis of motor neuron disease, our knowledge of the progressive bulbar syndromes has significantly increased in recent years. This group of heterogeneous conditions, in which the primary disorder is focused around degeneration of the lower cranial nerves, can occur in children or adults and form a spectrum of severity, based around the common feature of bulbar dysfunction. Early genetic diagnosis may allow treatment in some bulbar syndromes. Brown-Vialetto-Van Laere and Fazio-Londe syndromes are the most recent childhood forms of progressive bulbar palsy to be genetically defined. The clinical phenotype of this group of childhood disorders was first reported over 120 years ago. Recently, it was demonstrated that in a third of these patients Brown-Vialetto-Van Laere is caused by mutations in the SLC52A2 and SLC52A3 genes, both of which encode riboflavin transporters. Importantly, supplementation of riboflavin can lead to significant clinical improvement if started early in the disease process. Here, we outline the clinical features, management and an update on the disease mechanisms and genetic causes of the progressive bulbar syndromes.

Long-term survival in pseudo-Meigs' syndrome caused by ovarian metastases from colon cancer.

PubMed

Tajima, Yosuke; Kameyama, Hitoshi; Yamada, Saki; Yagi, Ryoma; Nakano, Masato; Nagahashi, Masayuki; Shimada, Yoshifumi; Sakata, Jun; Kobayashi, Takashi; Umezu, Hajime; Wakai, Toshifumi

2016-11-14

Meigs' syndrome is defined as the co-existence of benign ovarian fibroma or fibroma-like tumor, ascites, and pleural effusion. In contrast, pseudo-Meigs' syndrome is defined as the co-existence of other ovarian or pelvic tumors, ascites, and pleural effusion. In Meigs' and pseudo-Meigs' syndromes, ascites and pleural effusion resolve promptly after the complete resection of the ovarian or pelvic tumor(s). Secondary ovarian tumors from colorectal gastrointestinal metastases rarely cause pseudo-Meigs' syndrome; only 11 cases of pseudo-Meigs' syndrome secondary to colorectal cancers have been reported in the literature. Therefore, the prognosis and etiology of pseudo-Meigs' syndrome caused by ovarian metastasis from colorectal cancers remain unclear. We report here a rare case of pseudo-Meigs' syndrome caused by ovarian metastases from sigmoid colon cancer with long-term survival. A 47-year-old woman presented with abdominal distention of 1-month duration. She developed acute dyspnea 2 weeks after the initial presentation. Colonoscopy and computed tomography revealed sigmoid colon cancer with an ovarian metastasis, along with massive ascites and bilateral pleural effusion. Emergency operation, including bilateral oophorectomy and sigmoidectomy, was performed. Subsequently, ascites and bilateral pleural effusion resolved rapidly. Curative hepatic resection was performed for liver metastases 29 months after the first operation, and as of this writing, the patient is alive with no evidence of a disease 78 months after the first operation. In general, colorectal cancer with ovarian metastasis is hard to cure, and long-term survival in patients with colorectal cancer with pseudo-Meigs' syndrome is rare. Our experience suggests that curative resection for pseudo-Meigs' syndrome caused by ovarian metastasis from colorectal cancer may offer long-term survival. Our experience suggests that pseudo-Meigs' syndrome can occur in a patient with colorectal cancer after metastasis

Primary CNS lymphoma as a cause of Korsakoff syndrome.

PubMed

Toth, Cory; Voll, Chris; Macaulay, Robert

2002-01-01

Korsakoff syndrome presents with memory dysfunction with retrograde amnesia, anterograde amnesia, limited insight into dysfunction, and confabulation. The most common etiology of Korsakoff syndrome is thiamine deficiency secondary to alcoholism. There are limited case reports of structural lesions causing Korsakoff syndrome. A 46-year-old male with a long history of alcoholism presented with a history of confusion, amnesia, and confabulation with no localizing features on neurological examination. The patient showed no clinical change with intravenous thiamine. Computed tomography of the brain revealed a heterogenous, enhancing mass lesion centered within the third ventricle, with other lesions found throughout cortical and subcortical regions. The patient was given dexamethasone i.v. without noticeable clinical improvement but with marked radiological improvement with mass reduction. Stereotactic biopsy revealed a diagnosis of primary central nervous system (CNS) lymphoma. Most patients presenting with Korsakoff syndrome have thiamine deficiency; however, mass lesions can produce an identical clinical picture. This is the first case report of a patient with primary CNS lymphoma presenting as Korsakoff syndrome.

Maternally inherited Leigh syndrome: an unusual cause of infantile apnea.

PubMed

Shuk-kuen Chau, Christy; Kwok, Ka-li; Ng, Daniel K; Lam, Ching-Wan; Tong, Sui-Fan; Chan, Yan-Wo; Siu, Wai-Kwan; Yuen, Yuet-Ping

2010-06-01

Leigh Syndrome is an uncommon cause of infantile apnea. We report a 5-month-old girl with sudden respiratory arrest followed by episodic hyper- and hypo-ventilation, encephalopathy, and persistent lactic acidosis. Computed tomography of the brain revealed symmetric low densities over the basal ganglia, internal capsule, thalami, and midbrain. Cardiac echocardiogram was suggestive of hypertrophic cardiomyopathy. Diagnosis of Leigh syndrome due to T8993G mutation was confirmed with polymerase chain reaction and direct DNA sequencing of mitochondrial genome. To our knowledge, this is the first report of proven maternally inherited Leigh syndrome in Hong Kong.

Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality survey.

PubMed

Butler, Merlin G; Manzardo, Ann M; Heinemann, Janalee; Loker, Carolyn; Loker, James

2017-06-01

Prader-Willi syndrome (PWS) is a rare, complex, neurodevelopmental genetic disorder that is associated with hyperphagia and morbid obesity in humans and leads to a shortened life expectancy. This report summarizes the primary causes of death and evaluates mortality trends in a large cohort of individuals with PWS. The US Prader-Willi Syndrome Association (PWSA (USA)) syndrome-specific database of death reports was collected through a cursory bereavement program for PWSA (USA) families using a brief survey created in 1999. Causes of death were descriptively characterized and statistically examined using Cox proportional hazards. A total of 486 deaths were reported (263 males, 217 females, 6 unknown) between 1973 and 2015, with mean age of 29.5 ± 16 years (2 months-67 years); 70% occurred in adulthood. Respiratory failure was the most common cause, accounting for 31% of all deaths. Males were at increased risk for presumed hyperphagia-related accidents/injuries and cardiopulmonary factors compared to females. PWS maternal disomy 15 genetic subtype showed an increased risk of death from cardiopulmonary factors compared to the deletion subtype. These findings highlight the heightened vulnerability to obesity and hyperphagia-related mortality in PWS. Future research is needed to address critical vulnerabilities such as gender and genetic subtype in the cause of death in PWS.Genet Med advance online publication 17 November 2016.

Prader-Willi Syndrome: Causes, Characteristics, Interventions, Long-Term Consequences.

ERIC Educational Resources Information Center

Otto, Tracy L.; Barber, William H.

1992-01-01

An overview of Prader-Willi syndrome, the most common form of dysmorphic genetic obesity associated with mental retardation, is presented, with an emphasis on associated causes, characteristics, diagnosis and counseling, intervention, and long-term consequences. (Author/DB)

Frontal mucocele with intracranial extension causing frontal lobe syndrome.

PubMed

Weidmayer, Sara

2015-06-01

Mucoceles are mucus-containing cysts that form in paranasal sinuses; although mucoceles themselves are benign, this case report highlights the extensive damage they can cause as their expansion may lead to bony erosion and extension of the mucocele into the orbit and cranium; it also presents a rarely reported instance of frontal sinus mucocele leading to frontal lobe syndrome. A thorough discussion and review of mucoceles is included. A 68-year-old white man presented with intermittent diplopia and a pressure sensation in the right eye. He had a history of chronic sinusitis and had had endoscopic sinus surgery 5 years prior. A maxillofacial computed tomography scan revealed a large right frontal sinus mucocele, which had caused erosion along the medial wall of the right orbit and the outer and inner tables of the right frontal sinus. The mucocele had protruded both into the right orbit and intracranially, causing mass effect on the frontal lobe, which led to frontal lobe syndrome. The patient was successfully treated with endoscopic right ethmoidectomy, radial frontal sinusotomy, marsupialization of the mucocele, and transcutaneous irrigation. Paranasal sinus mucoceles may expand and lead to bony erosion and can become very invasive in surrounding structures such as the orbit and cranium. This case not only exhibits a very rare presentation of frontal sinus mucocele with intracranial extension and frontal lobe mass effect causing a frontal lobe syndrome but also demonstrates many of the ocular and visual complications commonly associated with paranasal sinus mucoceles. Early identification and surgical intervention is vital for preventing and reducing morbidity associated with invasive mucoceles, and the patient must be followed regularly to monitor for recurrence.

Locked-in syndrome caused by a solitary pontine abscess.

PubMed Central

Murphy, M J; Brenton, D W; Aschenbrener, C A; Van Gilder, J C

1979-01-01

The clinical and pathological findings in a patient with locked-in syndrome caused by a solitary pontine abscess are reported for the first time. Successful treatment of brainstem abscess rests on early and accurate diagnosis. Images PMID:501372

[Currarino syndrome a rare cause of recurrent purulent meningitis].

PubMed

Fitouri, Z; Ben Slima, S; Matoussi, N; Aloui, N; Bellagha, I; Kechrid, A; Ben Becher, S

2007-12-01

The authors report a case of partial Currarino syndrome in a three and a half year old child with a left hemisacrum agenesis and a presacral mature teratoma. The special aspect of the observation was the apparition of repetitive polymicrobial purulent meningitis (Escherichia coli, Streptococcus B, Haemophilus influenzae) treated several times with non-specific antibiotics without normalization of CSF, particularly the CSF glucose, which remained low, justifying the use of an antimycobacterial treatment, especially since there was no local or general cause explaining the relapse. During a relapse of meningitis after ten months of antituberculosis treatment, the teratoma was discovered by a spine MRI done to detect any cerebrospinal defect. The authors insist on the fact that the Currarino syndrome must be investigated in case of repetitive purulent meningitis after ruling out the usual causes of meningitis.

Sudden infant death syndrome caused by poliomyelitis.

PubMed

Dunne, J W; Harper, C G; Hilton, J M

1984-07-01

Most seemingly well infants who die suddenly and unexpectedly have no adequate cause of death found on thorough postmortem examination. Respiratory and enteric viruses are often present, especially in the upper respiratory tract, but the infective process seems, of itself, insufficient to cause death. In the remainder of the cases, a variety of lesions will be discovered, including viral myocarditis, bronchiolitis, and sepsis. We report a case of sudden and unexpected death in a 5-week-old male infant due to acute anterior poliomyelitis. This case illustrates the importance of a thorough postmortem examination, including histologic studies of the brain stem and spinal cord in cases of sudden infant death syndrome.

Causes of death in 2877 patients with myelodysplastic syndromes.

PubMed

Nachtkamp, Kathrin; Stark, Romina; Strupp, Corinna; Kündgen, Andrea; Giagounidis, Aristoteles; Aul, Carlo; Hildebrandt, Barbara; Haas, Rainer; Gattermann, Norbert; Germing, Ulrich

2016-05-01

Patients with myelodysplastic syndromes face a poor prognosis. The exact causes of death have not been described properly in the past. We performed a retrospective analysis of causes of death using data of 3792 patients in the Düsseldorf registry who have been followed up for a median time of 21 months. Medical files as well as death certificates were screened and primary care physicians were contacted. Death after AML evolution, infection, and bleeding was considered to be clearly disease-related. Further categories of causes of death were heart failure, other possibly disease-related reasons, such as hemochromatosis, disease-independent reasons as well as cases with unclear causes of death. Median age at the time of diagnosis was 71 years. At the time of analysis, 2877 patients (75.9 %) had deceased. In 1212 cases (42.1 %), the exact cause of death could not be ascertained. From 1665 patients with a clearly documented cause of death, 1388 patients (83.4 %) succumbed directly disease-related (AML (46.6 %), infection (27.0 %), bleeding (9.8 %)), whereas 277 patients (16.6 %) died for reasons not directly related with myelodysplastic syndromes (MDS), including 132 patients with cardiac failure, 77 non-disease-related reasons, 23 patients with solid tumors, and 45 patients with possibly disease-related causes like hemochromatosis. Correlation with IPSS, IPSS-R, and WPSS categories showed a proportional increase of disease-related causes of death with increasing IPSS/IPSS-R/WPSS risk category. Likewise, therapy-related MDS were associated with a higher percentage of disease-related causes of death than primary MDS. This reflects the increasing influence of the underlying disease on the cause of death with increasing aggressiveness of the disease.

[Orbital compartment syndrome. The most frequent cause of blindness following facial trauma].

PubMed

Klenk, Gusztáv; Katona, József; Kenderfi, Gábor; Lestyán, János; Gombos, Katalin; Hirschberg, Andor

2017-09-01

Although orbital compartment syndrome is a rare condition, it is still the most common cause of blindness following simple or complicated facial fractures. Its pathomechanism is similar to the compartment syndrome in the limb. Little extra fluid (blood, oedema, brain, foreign body) in a non-space yielding space results with increasingly higher pressures within a short period of time. Unless urgent surgical intervention is performed the blocked circulation of the central retinal artery will result irreversible ophthalmic nerve damage and blindness. Aim, material and method: A retrospective analysis of ten years, 2007-2017, in our hospital among those patients referred to us with facial-head trauma combined with blindness. 571 patients had fractures involving the orbit. 23 patients become blind from different reasons. The most common cause was orbital compartment syndrome in 17 patients; all had retrobulbar haematomas as well. 6 patients with retrobulbar haematoma did not develop compartment syndrome. Compartment syndrome was found among patient with extensive and minimal fractures such as with large and minimal haematomas. Early lateral canthotomy and decompression saved 7 patients from blindness. We can not predict and do not know why some patients develop orbital compartment syndrome. Compartment syndrome seems independent from fracture mechanism, comminution, dislocation, amount of orbital bleeding. All patients are in potential risk with midface fractures. We have a high suspicion that orbital compartment syndrome has been somehow missed out in the recommended textbooks of our medical universities and in the postgraduate trainings. Thus compartment syndrome is not recognized. Teaching, training and early surgical decompression is the only solution to save the blind eye. Orv Hetil. 2017; 158(36): 1410-1420.

What Causes Rett Syndrome?

MedlinePlus

... early-onset seizure variant of Rett syndrome. Human Molecular Genetics , Jul 15;14(14), 1935–1946. Retrieved June ... Dragich, J., & Schanen, C. (2003). Rett Syndrome: Clinical-Molecular Correlates. In G. Fisch (Ed.), Genetics and neurobehavioral disorders (pp. 391–418). Totowa, NJ: ...

3M syndrome: an easily recognizable yet underdiagnosed cause of proportionate short stature.

PubMed

Al-Dosari, Mohammed S; Al-Shammari, Muneera; Shaheen, Ranad; Faqeih, Eissa; Alghofely, Mohammed A; Boukai, Ahmad; Alkuraya, Fowzan S

2012-07-01

To characterize, via clinical and molecul criteria, a cohort of patients with 3M syndrome and thereby increase awareness of this syndrome as a recognizable cause of proportionate short stature. We conducted a case series of patients referred to clinical genetics for proportionate short stature. CUL7, OBSL1, and CCDC8 genes were clinically phenotyped and sequenced. In 6 Saudi families with 3M syndrome, we identified three CUL7, one OBSL1, and one CCDC8 novel mutations, which we show result in a remarkably similar clinical phenotype. Despite their typical and easily discernible clinical phenotype, all these patients have been extensively investigated for alternative causes of their short stature and received erroneous diagnoses. Increased awareness about this syndrome among pediatricians and endocrinologists is needed to avoid a costly and unnecessary diagnostic odyssey. Copyright © 2012 Mosby, Inc. All rights reserved.

Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome.

PubMed

Woods, C G; Stricker, S; Seemann, P; Stern, R; Cox, J; Sherridan, E; Roberts, E; Springell, K; Scott, S; Karbani, G; Sharif, S M; Toomes, C; Bond, J; Kumar, D; Al-Gazali, L; Mundlos, S

2006-08-01

Fuhrmann syndrome and the Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome are considered to be distinct limb-malformation disorders characterized by various degrees of limb aplasia/hypoplasia and joint dysplasia in humans. In families with these syndromes, we found homozygous missense mutations in the dorsoventral-patterning gene WNT7A and confirmed their functional significance in retroviral-mediated transfection of chicken mesenchyme cell cultures and developing limbs. The results suggest that a partial loss of WNT7A function causes Fuhrmann syndrome (and a phenotype similar to mouse Wnt7a knockout), whereas the more-severe limb truncation phenotypes observed in Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome result from null mutations (and cause a phenotype similar to mouse Shh knockout). These findings illustrate the specific and conserved importance of WNT7A in multiple aspects of vertebrate limb development.

Mutations in WNT7A Cause a Range of Limb Malformations, Including Fuhrmann Syndrome and Al-Awadi/Raas-Rothschild/Schinzel Phocomelia Syndrome

PubMed Central

Woods, C. G.; Stricker, S.; Seemann, P.; Stern, R.; Cox, J.; Sherridan, E.; Roberts, E.; Springell, K.; Scott, S.; Karbani, G.; Sharif, S. M.; Toomes, C.; Bond, J.; Kumar, D.; Al-Gazali, L.; Mundlos, S.

2006-01-01

Fuhrmann syndrome and the Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome are considered to be distinct limb-malformation disorders characterized by various degrees of limb aplasia/hypoplasia and joint dysplasia in humans. In families with these syndromes, we found homozygous missense mutations in the dorsoventral-patterning gene WNT7A and confirmed their functional significance in retroviral-mediated transfection of chicken mesenchyme cell cultures and developing limbs. The results suggest that a partial loss of WNT7A function causes Fuhrmann syndrome (and a phenotype similar to mouse Wnt7a knockout), whereas the more-severe limb truncation phenotypes observed in Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome result from null mutations (and cause a phenotype similar to mouse Shh knockout). These findings illustrate the specific and conserved importance of WNT7A in multiple aspects of vertebrate limb development. PMID:16826533

[A rare cause of oral pain: The pterygoid hamulus syndrome].

PubMed

Bandini, M; Corre, P; Huet, P; Khonsari, R H

2015-12-01

Pterygoid hamulus syndrome (PHS) is a rare cause of orofacial and oropharyngeal pain. PHS can be associated with a hamulus hypertrophy or with a bursitis of the palatosalpingeus but it has not always an anatomic cause. A 36-year-old woman was seen for a constant posterior palatal pain spreading towards oropharynx, increasing during swallowing and lasting for more than 6 months. Physical examination showed an erythema of the soft palate, medially to the hamulus. Hamulus palpation was painful and revealed hamulus hypertrophia on both sides. A bilateral PHS was evocated. This observation is typical of a PHS. We propose a review of the literature of this little-known syndrome. Treatment is initially conservative (corticosteroids) but surgery can be proposed in case of morphological anomalies of the hamulus. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Iliac Vein Compression Syndrome due to Bladder Distention Caused by Urethral Calculi

PubMed Central

Ikegami, Akiko; Kondo, Takeshi; Tsukamoto, Tomoko; Ohira, Yoshiyuki; Ikusaka, Masatomi

2015-01-01

We report a rare case of iliac vein compression syndrome caused by urethral calculus. A 71-year-old man had a history of urethral stenosis. He complained of bilateral leg edema and dysuria for 1 week. Physical examination revealed bilateral distention of the superficial epigastric veins, so obstruction of both common iliac veins or the inferior vena cava was suspected. Plain abdominal computed tomography showed a calculus in the pendulous urethra, distention of the bladder (as well as the right renal pelvis and ureter), and compression of the bilateral common iliac veins by the distended bladder. Iliac vein compression syndrome was diagnosed. Bilateral iliac vein compression due to bladder distention (secondary to neurogenic bladder, benign prostatic hyperplasia, or urethral calculus as in this case) is an infrequent cause of acute bilateral leg edema. Detecting distention of the superficial epigastric veins provides a clue for diagnosis of this syndrome. PMID:25802794

The infundibulo-tuberal syndrome caused by craniopharyngiomas: clinicopathological evidence from an historical French cohort (1705-1973).

PubMed

Castro-Dufourny, Inés; Carrasco, Rodrigo; Prieto, Ruth; Barrios, Laura; Pascual, José M

2015-10-01

Infundibulo-tuberal syndrome groups endocrine, metabolic and behavioral disturbances caused by lesions involving the upper neurohypophysis (median eminence) and adjacent basal hypothalamus (tuber cinereum). It was originally described by Henri Claude and Jean Lhermitte in 1917, in a patient with a craniopharyngioma. This study investigates the clinical, pathological and surgical evidence verifying the infundibulo-tuberal syndrome caused by craniopharyngiomas (CPs). A systematic retrospective review of craniopharyngiomas reported in French literature between 1705 and 1973 was conducted. A total of 128 well described reports providing a comprehensive clinical and pathological description of the tumors were selected. This series represents the historical French cohort of CPs reported in the pre-CT/MRI era. Three major syndromes caused by CPs were categorized: pituitary syndrome (35%), infundibulo-tuberal syndrome (52%) and hypothalamic syndrome (49%). CP topography was significantly related to the type of syndrome described (p < 0.001). Infundibulo-tuberal syndrome occurred in CPs which replaced or invaded the third ventricle floor. In contrast, the majority of sellar/suprasellar CPs growing below the third ventricle showed a pituitary syndrome (82%). Cases with hypothalamic syndrome were characterized by anatomical integrity of the pituitary gland and stalk (p = 0.033) and occurred predominantly in adults older than 41 years old (p < 0.005). Among infundibulo-tuberal symptoms, abnormal somnolence was not related with the presence of hydrocephalus. All squamous-papillary CPs presented psychiatric disturbances (p < 0.001). This historical CP cohort evidences a clinical-topographical correlation between the patient's type of syndrome and the anatomical structures involved by the tumor along the hypophysial-hypothalamic axis.

A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome.

PubMed

Oud, Machteld M; Bonnard, Carine; Mans, Dorus A; Altunoglu, Umut; Tohari, Sumanty; Ng, Alvin Yu Jin; Eskin, Ascia; Lee, Hane; Rupar, C Anthony; de Wagenaar, Nathalie P; Wu, Ka Man; Lahiry, Piya; Pazour, Gregory J; Nelson, Stanley F; Hegele, Robert A; Roepman, Ronald; Kayserili, Hülya; Venkatesh, Byrappa; Siu, Victoria M; Reversade, Bruno; Arts, Heleen H

2016-01-01

Endocrine-cerebro-osteodysplasia (ECO) syndrome [MIM:612651] caused by a recessive mutation (p.R272Q) in Intestinal cell kinase (ICK) shows significant clinical overlap with ciliary disorders. Similarities are strongest between ECO syndrome, the Majewski and Mohr-Majewski short-rib thoracic dysplasia (SRTD) with polydactyly syndromes, and hydrolethalus syndrome. In this study, we present a novel homozygous ICK mutation in a fetus with ECO syndrome and compare the effect of this mutation with the previously reported ICK variant on ciliogenesis and cilium morphology. Through homozygosity mapping and whole-exome sequencing, we identified a second variant (c.358G > T; p.G120C) in ICK in a Turkish fetus presenting with ECO syndrome. In vitro studies of wild-type and mutant mRFP-ICK (p.G120C and p.R272Q) revealed that, in contrast to the wild-type protein that localizes along the ciliary axoneme and/or is present in the ciliary base, mutant proteins rather enrich in the ciliary tip. In addition, immunocytochemistry revealed a decreased number of cilia in ICK p.R272Q-affected cells. Through identification of a novel ICK mutation, we confirm that disruption of ICK causes ECO syndrome, which clinically overlaps with the spectrum of ciliopathies. Expression of ICK-mutated proteins result in an abnormal ciliary localization compared to wild-type protein. Primary fibroblasts derived from an individual with ECO syndrome display ciliogenesis defects. In aggregate, our findings are consistent with recent reports that show that ICK regulates ciliary biology in vitro and in mice, confirming that ECO syndrome is a severe ciliopathy.

Guillain Barre syndrome: the leading cause of acute flaccid paralysis in Hazara division.

PubMed

Anis-ur-Rehman; Idris, Muhammad; Elahi, Manzoor; Jamshed; Arif, Adeel

2007-01-01

Acute flaccid paralysis (AFP) can be caused by a number of conditions. A common preventable cause is poliomyelitis which is still being reported in Pakistan, Guillain Barre Syndrome (GBS), also known as Acute Inflammatory Demyelinating Polyneuropathy, is another common cause of acute flaccid paralysis. It is important to recognize GBS in childhood as parents consider all acute flaccid paralysis to be due to poliomyelitis. The present study was designed to know the frequency of different causes of acute flaccid paralysis in Hazara division. This is a retrospective analysis of cases of acute flaccid paralysis reported from various districts of Hazara division during the period January 2003 to December 2004. Acute flaccid paralysis was diagnosed clinically through history and clinical examination. The underlying cause of acute flaccid paralysis was investigated by appropriate laboratory tests, such as serum electrolytes, cerebrospinal fluid analysis, electromyogram, nerve conduction study and stool culture for polio virus and other enteroviruses. Diagnosis of Poliomyelitis was confirmed by stool testing for poliovirus. 74 patients presented with AFP during the study period. 36 were male and 38 were female. Guillain Barre syndrome and enteroviral encephalopathy were the two leading causes of acute flaccid paralysis. Majority of the cases were reported from Mansehra district. Children of age groups 12 to 24 months and > 96 months constituted the majority (20% each). Guillian Barre syndrome was the leading cause of acute flaccid paralysis reported from various parts of Hazara division.

A Rare Cause of Obstructive Sleep Apnea Syndrome: Retropharyngeal Lipoma

PubMed Central

Dilek, Okan; Yilmaz, Cengiz; Gulek, Bozkurt; Akin, Mehmet Ali

2017-01-01

Lipoma is the most common benign mesenchymal neoplasm. About 16% of lipomas arise in the head and neck region, especially in the posterior neck. Large lipomas that originate from the retropharyngeal space may cause dyspnea, dysphagia, and snoring and occasionally may lead to obstructive sleep apnea syndrome (OSAS). Herein, we report a 45-year-old male patient with OSAS caused by a giant retropharyngeal lipoma with emphasis on CT findings. PMID:28912996

A Rare Cause of Cyanosis: Hepatopulmonary Syndrome Caused by Congenital Extrahepatic Portosystemic Shunt

PubMed Central

Ding, Xue-Yan; Chen, Feng; Zhao, Xian-Xian; Wu, Hong; Chen, Shao-Ping; Qin, Yong-Wen

2011-01-01

A 19-year-old male patient presented cyanosis and dyspnoea because of the presence of multiple pulmonary arteriovenous fistulas resulting in oxygen desaturation. The CTA revealed that intestinal and splenic venous blood bypasses the liver and drains into the inferior vena cava. This is the first reported case of hepatopulmonary syndrome caused by congenital extrahepatic portosystemic shunt in which intestinal and splenic venous blood bypasses the liver and drains into the inferior vena cava. PMID:22937464

Bertolotti's syndrome. A cause of back pain in young people.

PubMed

Quinlan, J F; Duke, D; Eustace, S

2006-09-01

Bertolotti's syndrome is characterised by anomalous enlargement of the transverse process(es) of the most caudal lumbar vertebra which may articulate or fuse with the sacrum or ilium and cause isolated L4/5 disc disease. We analysed the elective MR scans of the lumbosacral spine of 769 consecutive patients with low back pain taken between July 2003 and November 2004. Of these 568 showed disc degeneration. Bertolotti's syndrome was present in 35 patients with a mean age of 32.7 years (15 to 60). This was a younger age than that of patients with multiple disc degeneration, single-level disease and isolated disc degeneration at the L4/5 level (p syndrome in our study was 4.6% (35 of 769). It was present in 11.4% (20 patients) of the under-30 age group. Our findings suggest that Bertolotti's syndrome must form part of a list of differential diagnoses in the investigation of low back pain in young people.

Mutations in CDK5RAP2 cause Seckel syndrome.

PubMed

Yigit, Gökhan; Brown, Karen E; Kayserili, Hülya; Pohl, Esther; Caliebe, Almuth; Zahnleiter, Diana; Rosser, Elisabeth; Bögershausen, Nina; Uyguner, Zehra Oya; Altunoglu, Umut; Nürnberg, Gudrun; Nürnberg, Peter; Rauch, Anita; Li, Yun; Thiel, Christian Thomas; Wollnik, Bernd

2015-09-01

Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152.

Mutations in CDK5RAP2 cause Seckel syndrome

PubMed Central

Yigit, Gökhan; Brown, Karen E; Kayserili, Hülya; Pohl, Esther; Caliebe, Almuth; Zahnleiter, Diana; Rosser, Elisabeth; Bögershausen, Nina; Uyguner, Zehra Oya; Altunoglu, Umut; Nürnberg, Gudrun; Nürnberg, Peter; Rauch, Anita; Li, Yun; Thiel, Christian Thomas; Wollnik, Bernd

2015-01-01

Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152. PMID:26436113

Causes of Death in Prader-Willi Syndrome: Prader-Willi Syndrome Association (USA) 40-Year Mortality Survey

PubMed Central

Butler, Merlin G.; Manzardo, Ann M.; Heinemann, Janalee; Loker, Carolyn; Loker, James

2016-01-01

Background Prader-Willi syndrome (PWS) is a rare complex neurodevelopmental genetic disorder that is associated with hyperphagia and morbid obesity in humans leading to a shortened life expectancy. This report summarizes the primary causes of death and evaluates mortality trends in a large cohort of individuals with PWS. Methods PWSA (USA) mortality syndrome-specific database of death reports was collected through a cursory bereavement program for PWSA(USA) families using a brief survey created in 1999. Causes of death were descriptively characterized and statistically examined using Cox Proportional Hazards. Results A total of 486 deaths were reported (263 males, 217 females, 6 unknown) between 1973 and 2015 with mean age of 29.5 ± 16 years (2mo–67yrs), 70% occurring in adulthood. Respiratory failure was the most common cause accounting for 31% of all deaths. Males were at increased risk for presumed hyperphagia-related accidents/injuries compared to females and cardiopulmonary factors. PWS maternal disomy 15 genetic subtype showed an increased risk of death from cardiopulmonary factors compared to the deletion subtype. Conclusions These findings highlight the heightened vulnerability towards obesity and hyperphagia-related mortality in PWS. Future research is needed to address critical vulnerabilities such as gender and genetic subtype in the cause of death in PWS. PMID:27854358

Determining the Amount, Timing and Causes of Mortality among Infants with Down Syndrome

ERIC Educational Resources Information Center

Goldman, S. E.; Urbano, R. C.; Hodapp, R. M.

2011-01-01

Objective: To examine the amount, timing and causes/correlates of infant mortality among newborns with Down syndrome. Methods: Using the Tennessee Department of Health Birth, Hospital Discharge and Death records, infants were identified who were born with Down syndrome from 1990 to 2006. Those who died during the first year were separated into…

Association of metabolic syndrome and its components with all-cause and cardiovascular mortality in the elderly

PubMed Central

Ju, Sang-Yhun; Lee, June-Young; Kim, Do-Hoon

2017-01-01

Abstract There is increasing evidence regarding the relationship between metabolic syndrome and mortality. However, previous research examining metabolic syndrome and mortality in older populations has produced mixed results. In addition, there is a clear need to identify and manage individual components of metabolic syndrome to decrease cardiovascular disease (CVD) mortality. In this meta-analysis, we searched the MEDLINE databases using PubMed, Cochrane Library, and EMBASE databases. Based on 20 prospective cohort studies, metabolic syndrome was associated with a higher risk of all-cause mortality [relative risk (RR), 1.23; 95% confidence interval (CI), 1.15–1.32; I2 = 55.9%] and CVD mortality (RR, 1.24; 95% CI, 1.11–1.39; I2 = 58.1%). The risk estimates of all-cause mortality for single components of metabolic syndrome were significant for higher values of waist circumference or body mass index (RR, 0.94; 95% CI, 0.88–1.00), higher values of blood glucose (RR, 1.19; 95% CI, 1.05–1.34), and lower values of high-density lipoprotein (HDL) cholesterol (RR, 1.11; 95% CI, 1.02–1.21). In the elderly population, metabolic syndrome was associated with an increased risk of all-cause and CVD mortality. Among the individual components of metabolic syndrome, increased blood glucose and HDL cholesterol levels were significantly associated with increased mortality. However, older obese or overweight individuals may have a decreased mortality risk. Thus, the findings of the current meta-analysis raise questions about the utility of the definition of metabolic syndrome in predicting all-cause mortality and CVD mortality in the elderly population. PMID:29137039

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease.

PubMed

Nabhani, Schafiq; Ginzel, Sebastian; Miskin, Hagit; Revel-Vilk, Shoshana; Harlev, Dan; Fleckenstein, Bernhard; Hönscheid, Andrea; Oommen, Prasad T; Kuhlen, Michaela; Thiele, Ralf; Laws, Hans-Jürgen; Borkhardt, Arndt; Stepensky, Polina; Fischer, Ute

2015-09-01

Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20-30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon γ production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease. Copyright© Ferrata Storti

Piriformis syndrome: a cause of nondiscogenic sciatica.

PubMed

Cass, Shane P

2015-01-01

Piriformis syndrome is a nondiscogenic cause of sciatica from compression of the sciatic nerve through or around the piriformis muscle. Patients typically have sciatica, buttocks pain, and worse pain with sitting. They usually have normal neurological examination results and negative straight leg raising test results. Flexion, adduction, and internal rotation of the hip, Freiberg sign, Pace sign, and direct palpation of the piriformis cause pain and may reproduce symptoms. Imaging and neurodiagnostic studies are typically normal and are used to rule out other etiologies for sciatica. Conservative treatment, including medication and physiotherapy, is usually helpful for the majority of patients. For recalcitrant cases, corticosteroid and botulinum toxin injections may be attempted. Ultrasound and other imaging modalities likely improve accuracy of injections. Piriformis tenotomy and decompression of the sciatic nerve can be done for those who do not respond.

Mutations causing syndromic autism define an axis of synaptic pathophysiology.

PubMed

Auerbach, Benjamin D; Osterweil, Emily K; Bear, Mark F

2011-11-23

Tuberous sclerosis complex and fragile X syndrome are genetic diseases characterized by intellectual disability and autism. Because both syndromes are caused by mutations in genes that regulate protein synthesis in neurons, it has been hypothesized that excessive protein synthesis is one core pathophysiological mechanism of intellectual disability and autism. Using electrophysiological and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2(+/-) and Fmr1(-/y) mice, here we show that synaptic dysfunction caused by these mutations actually falls at opposite ends of a physiological spectrum. Synaptic, biochemical and cognitive defects in these mutants are corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions, and deficits in the mutants disappear when the mice are bred to carry both mutations. Thus, normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate-receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioural impairments.

Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome.

PubMed

Bénit, P; Slama, A; Cartault, F; Giurgea, I; Chretien, D; Lebon, S; Marsac, C; Munnich, A; Rötig, A; Rustin, P

2004-01-01

Respiratory chain complex I deficiency represents a genetically heterogeneous group of diseases resulting from mutations in mitochondrial or nuclear genes. Mutations have been reported in 13 of the 14 subunits encoding the core of complex I (seven mitochondrial and six nuclear genes) and these result in Leigh or Leigh-like syndromes or cardiomyopathy. In this study, a combination of denaturing high performance liquid chromatography and sequence analysis was used to study the NDUFS3 gene in a series of complex I deficient patients. Mutations found in this gene (NADH dehydrogenase iron-sulphur protein 3), coding for the seventh and last subunit of complex I core, were shown to cause late onset Leigh syndrome, optic atrophy, and complex I deficiency. A biochemical diagnosis of complex I deficiency on cultured amniocytes from a later pregnancy was confirmed through the identification of disease causing NDUFS3 mutations in these cells. While mutations in the NDUFS3 gene thus result in Leigh syndrome, a dissimilar clinical phenotype is observed in mutations in the NDUFV2 and NDUFS2 genes, resulting in encephalomyopathy and cardiomyopathy. The reasons for these differences are uncertain.

Hyperthyroidism due to thyroid-stimulating hormone secretion after surgery for Cushing's syndrome: a novel cause of the syndrome of inappropriate secretion of thyroid-stimulating hormone.

PubMed

Tamada, Daisuke; Onodera, Toshiharu; Kitamura, Tetsuhiro; Yamamoto, Yuichi; Hayashi, Yoshitaka; Murata, Yoshiharu; Otsuki, Michio; Shimomura, Iichiro

2013-07-01

Hyperthyroidism with the syndrome of inappropriate secretion of TSH (SITSH) occurred by a decrease in hydrocortisone dose after surgery for Cushing's syndrome. This is a novel cause of SITSH. The aim of this study was to describe and discuss 2 cases of SITSH patients that were found after surgery for Cushing's syndrome. We also checked whether SITSH occurred in 7 consecutive patients with Cushing's syndrome after surgery. A 45-year-old Japanese woman with ACTH-independent Cushing's syndrome and a 37-year-old Japanese man with ACTH-dependent Cushing's syndrome presented SITSH caused by insufficient replacement of hydrocortisone for postoperative adrenal insufficiency. When the dose of hydrocortisone was reduced to less than 20 mg/d within 18 days after surgery, SITSH occurred in both cases. We examined whether the change of the hydrocortisone dose induced the secretion of TSH. Free T₃ and TSH were normalized by the hydrocortisone dose increase of 30 mg/d, and these were elevated by the dose decrease of 10 mg/d. We also checked TSH and thyroid hormone levels of the 7 consecutive patients with Cushing's syndrome after surgery. Six (66.6 %) of 9 patients showed SITSH. This is the first report that insufficient replacement of hydrocortisone after surgery for Cushing's syndrome caused SITSH. Hyperthyroidism by SITSH as well as adrenal insufficiency can contribute to withdrawal symptoms of hydrocortisone replacement. We need to consider the possibility of SITSH for the pathological evaluation of withdrawal syndrome of hydrocortisone replacement.

Anticholinergic Toxic Syndrome Caused by Atropa Belladonna Fruit (Deadly Nightshade): A Case Report

PubMed Central

Demirhan, Abdullah; Tekelioğlu, Ümit Yaşar; Yıldız, İsa; Korkmaz, Tanzer; Bilgi, Murat; Akkaya, Akcan; Koçoğlu, Hasan

2013-01-01

Atropa Belladonna poisoning may lead to anticholinergic syndrome. Ingestion of high amounts of the plant may cause lethargy, coma, and even a serious clinical picture leading to death. In this case report, we aimed to present a case with anticholinergic syndrome that developed after ingestion of the fruit called “Deadly Nightshade” in our country. PMID:27366377

Hypertensive Cerebral Hemorrhage in a Patient with Turner Syndrome Caused by Deletion in the Short Arm of the X Chromosome.

PubMed

Hori, Yusuke S; Ohkura, Takahiro; Ebisudani, Yuki; Umakoshi, Michiari; Ishi, Masato; Oda, Kazunori; Aoi, Mizuho; Inoue, Takushi; Furujo, Mahoko; Tanaka, Hiroyuki; Fukuhara, Toru

2018-01-01

Turner syndrome is a chromosomal disorder usually caused by complete deletion of an X chromosome, with deletion in the short arm of the X chromosome being a rare cause of the condition. Patients with Turner syndrome commonly develop hypertension, and associated vascular complications such as aortic dissection or cerebral hemorrhage have been reported. Cerebral hemorrhage in Turner syndrome is a rare complication, and only a few reports have been published. In these reports, all patients have XO karyotypes or a mosaic type as the cause of Turner syndrome, while no other Turner syndrome types have been documented. In this report, we present for the first time a patient with Turner syndrome caused by deletion in the short arm of the X chromosome who experienced hypertensive hemorrhage as a late complication. © 2017 S. Karger AG, Basel.

NDUFS4 mutations cause Leigh syndrome with predominant brainstem involvement.

PubMed

Leshinsky-Silver, E; Lebre, Anne-Sophie; Minai, Limor; Saada, Ann; Steffann, Julie; Cohen, Sarit; Rötig, Agnes; Munnich, Arnold; Lev, Dorit; Lerman-Sagie, Tally

2009-07-01

Complex I deficiency is a frequent cause of Leigh syndrome. We describe a non-consanguineous Ashkenazi-Sephardic Jewish patient with Leigh syndrome due to complex I deficiency. The clinical and neuroradiological presentation showed predominant brainstem involvement. Blue native polyacrylamide gel electrophoresis analysis revealed an impaired assembly of complex I. The patient was found to be compound heterozygous of two mutations in the NDUFS4 gene: p.Asp119His (a novel mutation) and p.Lys154fs (recently described in an Ashkenazi Jewish family). These findings support the suggestion that the p.Lys154fs mutation in NDUFS4 should be evaluated in Ashkenazi Jewish patients presenting with early onset Leigh syndrome even before enzymatic studies. Our results further demonstrated that NDUFS4 presents a hotspot of mutations in the genetic apparatus of oxidative phosphorylation and the correct assembly of the subunit it encodes is essential for completion of the assembly of complex I.

De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy?

PubMed

Caro-Llopis, Alfonso; Rosello, Monica; Orellana, Carmen; Oltra, Silvestre; Monfort, Sandra; Mayo, Sonia; Martinez, Francisco

2016-12-01

Mutations in the X-linked gene MED12 cause at least three different, but closely related, entities of syndromic intellectual disability. Recently, a new syndrome caused by MED13L deleterious variants has been described, which shows similar clinical manifestations including intellectual disability, hypotonia, and other congenital anomalies. Genotyping of 1,256 genes related with neurodevelopment was performed by next-generation sequencing in three unrelated patients and their healthy parents. Clinically relevant findings were confirmed by conventional sequencing. Each patient showed one de novo variant not previously reported in the literature or databases. Two different missense variants were found in the MED12 or MED13L genes and one nonsense mutation was found in the MED13L gene. The phenotypic consequences of these mutations are closely related and/or have been previously reported in one or other gene. Additionally, MED12 and MED13L code for two closely related partners of the mediator kinase module. Consequently, we propose the concept of a common MED12/MED13L clinical spectrum, encompassing Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, MED13L haploinsufficiency syndrome, and others.

[A commonly seen cause of abdominal pain: abdominal cutaneous nerve entrapment syndrome].

PubMed

Solmaz, Ilker; Talay, Mustafa; Tekindur, Şükrü; Kurt, Ercan

2012-01-01

Although abdominal cutaneous nerve entrapment syndrome (ACNES) is accepted as a rare condition, it is a syndrome that should be diagnosed more commonly when the clinical signs cannot explain the cause of abdominal pain. Abdominal pain is commonly considered by physicians to be based on intra-abdominal causes. Consequently, redundant tests and consultations are requested for these patients, and unnecessary surgical procedures may be applied. Patients with this type of pain are consulted to many clinics, and because their definitive diagnoses cannot be achieved, they are assessed as psychiatric patients. Actually, a common cause of abdominal wall pain is nerve entrapment on the lateral edge of the rectus abdominis muscle. In this paper, we would like to share information about the diagnosis and treatment of a patient who, prior to presenting to us, had applied to different clinics for chronic abdominal pain and had undergone many tests and consultations; abdominal surgery was eventually decided.

[Vertical retraction syndrome caused by anomalous orbital structures].

PubMed

Yang, Qiong; Jiao, Yong-hong; Man, Feng-yuan; Wang, Zhen-chang; Chang, Qing-lin; Lu, Wei; Wang, Jing-hui; Zhao, Kan-xing

2011-11-01

To described the clinical feature and MRI imaging of six children with vertical retraction syndrome. Six children with unilateral vertical retraction syndrome between 15 months and 8 years of age, mean age was (5.01 ± 1.27) years old. Strabismus examination included diopter, prism diopters, eye movement examination, binocular vision and fundus examination. Imaging of the ocular motor nerves at the brainstem was performed in 0.8 mm thickness image planes using 3D-FIESTA sequence, the orbits were imaged with FSE T1, T2WI using surface coils, and within 2.0 mm thick planes. Four children showed hypertropia, characterized by limited depression, a light retraction of the globe during downward gaze and eyelid lag. The MRI imaging showed anomalous orbital structure in the superonasal quadrant that between medial rectus and superior rectus or adjacent to the superior rectus. Two children showed intermittent exotropia, characterized by limited elevation, retraction of the globe and narrowing of the palpebral fissure during upward gaze. The MRI imaging showed anomalous orbital structure was present in the inferotemporal quadrant, one originate in inferior rectus and another close to the lateral rectus. Anomalous orbital structures are a main cause of vertical retraction syndrome. The presence of specific unusual eye movement and MRI imaging may assist in diagnosis. When the eyelid lag was found since the early age, anomalous orbital structures were implied.

Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects

PubMed Central

Runtuwene, Vincent; van Eekelen, Mark; Overvoorde, John; Rehmann, Holger; Yntema, Helger G.; Nillesen, Willy M.; van Haeringen, Arie; van der Burgt, Ineke; Burgering, Boudewijn; den Hertog, Jeroen

2011-01-01

SUMMARY Noonan syndrome is a relatively common developmental disorder that is characterized by reduced growth, wide-set eyes and congenital heart defects. Noonan syndrome is associated with dysregulation of the Ras–mitogen-activated-protein-kinase (MAPK) signaling pathway. Recently, two mutations in NRAS were reported to be associated with Noonan syndrome, T50I and G60E. Here, we report a mutation in NRAS, resulting in an I24N amino acid substitution, that we identified in an individual bearing typical Noonan syndrome features. The I24N mutation activates N-Ras, resulting in enhanced downstream signaling. Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V, which we included as a positive control, results in developmental defects in zebrafish embryos, demonstrating that these activating N-Ras mutants are sufficient to induce developmental disorders. The defects in zebrafish embryos are reminiscent of symptoms in individuals with Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated genes induce in zebrafish embryos. MEK inhibition completely rescued the activated N-Ras-induced phenotypes, demonstrating that these defects are mediated exclusively by Ras-MAPK signaling. In conclusion, mutations in NRAS from individuals with Noonan syndrome activated N-Ras signaling and induced developmental defects in zebrafish embryos, indicating that activating mutations in NRAS cause Noonan syndrome. PMID:21263000

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome.

PubMed

Wiseman, Frances K; Al-Janabi, Tamara; Hardy, John; Karmiloff-Smith, Annette; Nizetic, Dean; Tybulewicz, Victor L J; Fisher, Elizabeth M C; Strydom, André

2015-09-01

Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP)--an Alzheimer disease risk factor--although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

PubMed Central

Wiseman, Frances K.; Al-Janabi, Tamara; Hardy, John; Karmiloff-Smith, Annette; Nizetic, Dean; Tybulewicz, Victor L. J.; Fisher, Elizabeth M. C.; Strydom, André

2015-01-01

Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) — an Alzheimer disease risk factor — although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population. PMID:26243569

Review Recent progress in identification and characterization of loci associated with sex-linked congenital cataract.

PubMed

Zhang, D D; Du, J Z; Topolewski, J; Wang, X M

2016-07-29

Congenital cataract is a common cause of blindness in children; however, its pathogenesis remains unclear. Genetic factors have been shown to play an important role in the pathogenesis of congenital cataract. The current genetic models of congenital cataract include autosomal dominant, autosomal recessive, and sex-linked inheritance. Sex-linked congenital cataract could be inherited through the X or Y chromosome. Congenital cataract is a symptom associated with several X-linked disorders, including Nance-Horan syndrome, Lowe syndrome, Conradi-Hünermann-Happle syndrome, oculo-facio-cardio-dental syndrome, and Alport syndrome. On the other hand, the mechanism and characteristics of Y-linked congenital cataract remains to be identified. Despite its rarity, sex-linked congenital cataract has been known to seriously affect the quality of life of patients. In this review, we present our current understanding of the genes and loci associated with sex-linked congenital cataract. This could help identify novel approaches for the prevention, early diagnosis, and comprehensive disease treatment.

A homozygous mutation in the stem II domain of RNU4ATAC causes typical Roifman syndrome.

PubMed

Dinur Schejter, Yael; Ovadia, Adi; Alexandrova, Roumiana; Thiruvahindrapuram, Bhooma; Pereira, Sergio L; Manson, David E; Vincent, Ajoy; Merico, Daniele; Roifman, Chaim M

2017-01-01

Roifman syndrome (OMIM# 616651) is a complex syndrome encompassing skeletal dysplasia, immunodeficiency, retinal dystrophy and developmental delay, and is caused by compound heterozygous mutations involving the Stem II region and one of the other domains of the RNU4ATAC gene. This small nuclear RNA gene is essential for minor intron splicing. The Canadian Centre for Primary Immunodeficiency Registry and Repository were used to derive patient information as well as tissues. Utilising RNA sequencing methodologies, we analysed samples from patients with Roifman syndrome and assessed intron retention. We demonstrate that a homozygous mutation in Stem II is sufficient to cause the full spectrum of features associated with typical Roifman syndrome. Further, we demonstrate the same pattern of aberration in minor intron retention as found in cases with compound heterozygous mutations.

Proteus syndrome: A rare cause of gigantic limb.

PubMed

Chakrabarti, Nandini; Chattopadhyay, Chandan; Bhuban, Majhi; Pal, Salil Kumar

2014-04-01

A congenital disorder with variable manifestations, including partial gigantism of the hands and feet with hypertrophy of soles, nevi, hemihypertrophy, gynecomastia, macrocephaly and other skull abnormalities, and abdominal lipomatosis. The cause is unknown, although a genetic origin, generally of autosomal-dominant transmission, has been conjectured. Symptoms can be treated, but there is no known cure. We present the case of a young male with grotesque overgrowth of the right lower limb, splenomegaly and multiple nevi. Angiography revealed venous malformation within the limb. The findings are in conformity to the criteria for the Proteus syndrome.

Refeeding syndrome as an unusual cause of anion gap metabolic acidosis.

PubMed

Singla, Manish; Perry, Alexandra; Lavery, Eric

2012-11-01

Refeeding syndrome is characterized by hypophosphatemia in the setting of malnutrition. It is commonly seen in patients with anorexia, alcoholism, or malignancy, and it is often a missed diagnosis. Because of the potential morbidity associated with missing the diagnosis of refeeding syndrome, it is important to monitor for this disease in any malnourished patient. We present a case of a 49-year-old male with chronic alcohol abuse who presented for alcohol detoxification and was found to have low phosphate, potassium, and magnesium on presentation, in addition to an elevated anion gap of unclear etiology. After extensive workup to evaluate the cause of his elevated anion gap and worsening of his electrolyte abnormalities despite replenishment, it was felt his symptoms were a result of refeeding syndrome. After oral intake was held and aggressive electrolyte replenishment was performed for 24 hours, the patient's anion gap closed and his electrolyte levels stabilized. This case demonstrates a unique presentation of refeeding syndrome given the patient's profound metabolic acidosis that provided a clue toward his eventual diagnosis. The standard workup for an anion gap metabolic acidosis was negative, and it was not until his refeeding syndrome had been treated that the anion gap closed.

Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1

PubMed Central

Slavotinek, Anne M; Baranzini, Sergio E; Schanze, Denny; Labelle-Dumais, Cassandre; Short, Kieran M; Chao, Ryan; Yahyavi, Mani; Bijlsma, Emilia K; Chu, Catherine; Musone, Stacey; Wheatley, Ashleigh; Kwok, Pui-Yan; Marles, Sandra; Fryns, Jean-Pierre; Maga, A Murat; Hassan, Mohamed G; Gould, Douglas B; Madireddy, Lohith; Li, Chumei; Cox, Timothy C; Smyth, Ian; Chudley, Albert E; Zenker, Martin

2014-01-01

Background Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare condition defined by eyelid colobomas, cryptophthalmos and anophthalmia/ microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance had been assumed because of consanguinity in the Oji-Cre population of Manitoba and reports of affected siblings, but no locus or cytogenetic aberration had previously been described. Methods and results This study shows that MOTA syndrome is caused by mutations in FREM1, a gene previously mutated in bifid nose, renal agenesis, and anorectal malformations (BNAR) syndrome. MOTA syndrome and BNAR syndrome can therefore be considered as part of a phenotypic spectrum that is similar to, but distinct from and less severe than, Fraser syndrome. Re-examination of Frem1bat/bat mutant mice found new evidence that Frem1 is involved in anal and craniofacial development, with anal prolapse, eyelid colobomas, telecanthus, a shortened snout and reduced philtral height present in the mutant mice, similar to the human phenotype in MOTA syndrome. Conclusions The milder phenotypes associated with FREM1 deficiency in humans (MOTA syndrome and BNAR syndrome) compared to that resulting from FRAS1 and FREM2 loss of function (Fraser syndrome) are also consistent with the less severe phenotypes resulting from Frem1 loss of function in mice. Together, Fraser, BNAR and MOTA syndromes constitute a clinically overlapping group of FRAS–FREM complex diseases. PMID:21507892

Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly.

PubMed

Braun, Daniela A; Rao, Jia; Mollet, Geraldine; Schapiro, David; Daugeron, Marie-Claire; Tan, Weizhen; Gribouval, Olivier; Boyer, Olivia; Revy, Patrick; Jobst-Schwan, Tilman; Schmidt, Johanna Magdalena; Lawson, Jennifer A; Schanze, Denny; Ashraf, Shazia; Ullmann, Jeremy F P; Hoogstraten, Charlotte A; Boddaert, Nathalie; Collinet, Bruno; Martin, Gaëlle; Liger, Dominique; Lovric, Svjetlana; Furlano, Monica; Guerrera, I Chiara; Sanchez-Ferras, Oraly; Hu, Jennifer F; Boschat, Anne-Claire; Sanquer, Sylvia; Menten, Björn; Vergult, Sarah; De Rocker, Nina; Airik, Merlin; Hermle, Tobias; Shril, Shirlee; Widmeier, Eugen; Gee, Heon Yung; Choi, Won-Il; Sadowski, Carolin E; Pabst, Werner L; Warejko, Jillian K; Daga, Ankana; Basta, Tamara; Matejas, Verena; Scharmann, Karin; Kienast, Sandra D; Behnam, Babak; Beeson, Brendan; Begtrup, Amber; Bruce, Malcolm; Ch'ng, Gaik-Siew; Lin, Shuan-Pei; Chang, Jui-Hsing; Chen, Chao-Huei; Cho, Megan T; Gaffney, Patrick M; Gipson, Patrick E; Hsu, Chyong-Hsin; Kari, Jameela A; Ke, Yu-Yuan; Kiraly-Borri, Cathy; Lai, Wai-Ming; Lemyre, Emmanuelle; Littlejohn, Rebecca Okashah; Masri, Amira; Moghtaderi, Mastaneh; Nakamura, Kazuyuki; Ozaltin, Fatih; Praet, Marleen; Prasad, Chitra; Prytula, Agnieszka; Roeder, Elizabeth R; Rump, Patrick; Schnur, Rhonda E; Shiihara, Takashi; Sinha, Manish D; Soliman, Neveen A; Soulami, Kenza; Sweetser, David A; Tsai, Wen-Hui; Tsai, Jeng-Daw; Topaloglu, Rezan; Vester, Udo; Viskochil, David H; Vatanavicharn, Nithiwat; Waxler, Jessica L; Wierenga, Klaas J; Wolf, Matthias T F; Wong, Sik-Nin; Leidel, Sebastian A; Truglio, Gessica; Dedon, Peter C; Poduri, Annapurna; Mane, Shrikant; Lifton, Richard P; Bouchard, Maxime; Kannu, Peter; Chitayat, David; Magen, Daniella; Callewaert, Bert; van Tilbeurgh, Herman; Zenker, Martin; Antignac, Corinne; Hildebrandt, Friedhelm

2017-10-01

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

Sanfilippo syndrome: causes, consequences, and treatments

PubMed Central

Fedele, Anthony O

2015-01-01

Sanfilippo syndrome, or mucopolysaccharidosis (MPS) type III, refers to one of five autosomal recessive, neurodegenerative lysosomal storage disorders (MPS IIIA to MPS IIIE) whose symptoms are caused by the deficiency of enzymes involved exclusively in heparan sulfate degradation. The primary characteristic of MPS III is the degeneration of the central nervous system, resulting in mental retardation and hyperactivity, typically commencing during childhood. The significance of the order of events leading from heparan sulfate accumulation through to downstream changes in the levels of biomolecules within the cell and ultimately the (predominantly neuropathological) clinical symptoms is not well understood. The genes whose deficiencies cause the MPS III subtypes have been identified, and their gene products, as well as a selection of disease-causing mutations, have been characterized to varying degrees with respect to both frequency and direct biochemical consequences. A number of genetic and biochemical diagnostic methods have been developed and adopted by diagnostic laboratories. However, there is no effective therapy available for any form of MPS III, with treatment currently limited to clinical management of neurological symptoms. The availability of animal models for all forms of MPS III, whether spontaneous or generated via gene targeting, has contributed to improved understanding of the MPS III subtypes, and has provided and will deliver invaluable tools to appraise emerging therapies. Indeed, clinical trials to evaluate intrathecally-delivered enzyme replacement therapy in MPS IIIA patients, and gene therapy for MPS IIIA and MPS IIIB patients are planned or underway. PMID:26648750

A rare cause of acute coronary syndrome: Kounis syndrome.

PubMed

Almeida, João; Ferreira, Sara; Malheiro, Joana; Fonseca, Paulo; Caeiro, Daniel; Dias, Adelaide; Ribeiro, José; Gama, Vasco

2016-12-01

Kounis syndrome is an acute coronary syndrome in the context of a hypersensitivity reaction. The main pathophysiological mechanism appears to be coronary vasospasm. We report the case of a patient with a history of allergy to quinolones, who was given ciprofloxacin before an elective surgical procedure and during drug administration developed symptoms and electrocardiographic changes suggestive of ST-segment elevation acute coronary syndrome. The drug was suspended and coronary angiography excluded epicardial coronary disease. Two hours after withdrawal of the drug the symptoms and ST elevation had resolved completely. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

A novel NHS mutation causes Nance-Horan Syndrome in a Chinese family.

PubMed

Tian, Qi; Li, Yunping; Kousar, Rizwana; Guo, Hui; Peng, Fenglan; Zheng, Yu; Yang, Xiaohua; Long, Zhigao; Tian, Runyi; Xia, Kun; Lin, Haiying; Pan, Qian

2017-01-07

Nance-Horan Syndrome (NHS) (OMIM: 302350) is a rare X-linked developmental disorder characterized by bilateral congenital cataracts, with occasional dental anomalies, characteristic dysmorphic features, brachymetacarpia and mental retardation. Carrier females exhibit similar manifestations that are less severe than in affected males. Here, we report a four-generation Chinese family with multiple affected individuals presenting Nance-Horan Syndrome. Whole-exome sequencing combined with RT-PCR and Sanger sequencing was used to search for a genetic cause underlying the disease phenotype. Whole-exome sequencing identified in all affected individuals of the family a novel donor splicing site mutation (NM_198270: c.1045 + 2T > A) in intron 4 of the gene NHS, which maps to chromosome Xp22.13. The identified mutation results in an RNA processing defect causing a 416-nucleotide addition to exon 4 of the mRNA transcript, likely producing a truncated NHS protein. The donor splicing site mutation NM_198270: c.1045 + 2T > A of the NHS gene is the causative mutation in this Nance-Horan Syndrome family. This research broadens the spectrum of NHS gene mutations, contributing to our understanding of the molecular genetics of NHS.

Prehospital Dextrose Extravasation Causing Forearm Compartment Syndrome: A Case Report.

PubMed

Chinn, Matthew; Colella, M Riccardo

2017-01-01

A 57-year-old woman was found at home by paramedics to be hypoglycemic with altered mental status. She had multiple attempts at IV access and eventually a 22G IV was established and D50 was infused into her right forearm. Extravasation of the dextrose was noted after approximately 12 g of the medication was infused. She was given a dose of glucagon intramuscularly and her mental status improved. Shortly after her arrival to the emergency department, she was noted to have findings of compartment syndrome of her forearm at the site of the dextrose extravasation. She was evaluated by plastic surgery and taken to the operating room for emergent fasciotomy. She recovered well from the operation. D50 is well known to cause phlebitis and local skin necrosis as a complication. This case illustrates the danger of compartment syndrome after D50 extravasation. It is the first documented case of prehospital dextrose extravasation leading to compartment syndrome. There may be safer alternatives to D50 administration and providers must be acutely aware to monitor for D50 infusion complications.

Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3.

PubMed

Brouillard, Pascal; Dupont, Laura; Helaers, Raphael; Coulie, Richard; Tiller, George E; Peeden, Joseph; Colige, Alain; Vikkula, Miikka

2017-11-01

Primary lymphedema is due to developmental and/or functional defects in the lymphatic system. It may affect any part of the body, with predominance for the lower extremities. Twenty-seven genes have already been linked to primary lymphedema, either isolated, or as part of a syndrome. The proteins that they encode are involved in VEGFR3 receptor signaling. They account for about one third of all primary lymphedema cases, underscoring the existence of additional genetic factors. We used whole-exome sequencing to investigate the underlying cause in a non-consanguineous family with two children affected by lymphedema, lymphangiectasia and distinct facial features. We discovered bi-allelic missense mutations in ADAMTS3. Both were predicted to be highly damaging. These amino acid substitutions affect well-conserved residues in the prodomain and in the peptidase domain of ADAMTS3. In vitro, the mutant proteins were abnormally processed and sequestered within cells, which abolished proteolytic activation of pro-VEGFC. VEGFC processing is also affected by CCBE1 mutations that cause the Hennekam lymphangiectasia-lymphedema syndrome syndrome type1. Our data identifies ADAMTS3 as a novel gene that can be mutated in individuals affected by the Hennekam syndrome. These patients have distinctive facial features similar to those with mutations in CCBE1. Our results corroborate the recent in vitro and murine data that suggest a close functional interaction between ADAMTS3 and CCBE1 in triggering VEGFR3 signaling, a cornerstone for the differentiation and function of lymphatic endothelial cells. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[Sleep apnea syndrome -- cause of resistance to treatment of arterial hypertension].

PubMed

Frenţ, Stefan; Tudorache, Voicu; Ardelean, Carmen; Dimitriu, Diana; Lighezan, Daniel; Gaiţă, Dan; Mihăicuţă, Stefan

2011-01-01

The prevalence of sleep apnea syndrome is relatively high in population (5%). The mortality is significantly higher in those with apnea-hypopnea index >20. There is an increased rate of car accidents in the subjects with OSA compared to those who don't have this syndrome (31% versus 6%). The impact of OSA on mortality is also given by its association with a significant number of cardiovascular diseases. The association between OSA and hypertension has been much debated. The prevalence of hypertension among patients with OSA varies between 50-58%, while the prevalence of OSA in hypertensive patients is 30%. A particular association is OSA and resistant hypertension, i.e. blood pressure that remains above goal in spite of the concurrent use of three antihypertensive agents of different classes, one to be a diuretic and all pharmacological agents being prescribed at recommended doses. Secondary causes of hypertension are common in patients with resistant hypertension. Among these causes, one of the most frequent is sleep apnea syndrome. Some of the mechanisms by which sleep apnea contributes to the development of hypertension are intermittent hypoxia and/or increased upper airway resistance associated with sleep apnea that induces a sustained increase in sympathetic nervous system activity. Treatment of sleep apnea with continuous positive airway pressure devices (CPAP) improves blood pressure control, although the benefit of CPAP evaluated in clinical trials is variable.

Hypomorphic Temperature-Sensitive Alleles of NSDHL Cause CK Syndrome

PubMed Central

McLarren, Keith W.; Severson, Tesa M.; du Souich, Christèle; Stockton, David W.; Kratz, Lisa E.; Cunningham, David; Hendson, Glenda; Morin, Ryan D.; Wu, Diane; Paul, Jessica E.; An, Jianghong; Nelson, Tanya N.; Chou, Athena; DeBarber, Andrea E.; Merkens, Louise S.; Michaud, Jacques L.; Waters, Paula J.; Yin, Jingyi; McGillivray, Barbara; Demos, Michelle; Rouleau, Guy A.; Grzeschik, Karl-Heinz; Smith, Raffaella; Tarpey, Patrick S.; Shears, Debbie; Schwartz, Charles E.; Gecz, Jozef; Stratton, Michael R.; Arbour, Laura; Hurlburt, Jane; Van Allen, Margot I.; Herman, Gail E.; Zhao, Yongjun; Moore, Richard; Kelley, Richard I.; Jones, Steven J.M.; Steiner, Robert D.; Raymond, F. Lucy; Marra, Marco A.; Boerkoel, Cornelius F.

2010-01-01

CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development. PMID:21129721

Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training

PubMed Central

Roberts, Christian K.; Hevener, Andrea L.; Barnard, R. James

2014-01-01

Metabolic syndrome (MS) is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Regardless of the true definition, based on current population estimates, nearly 100 million have MS. It is often characterized by insulin resistance, which some have suggested is a major underpinning link between physical inactivity and MS. The purpose of this review is to: (i) provide an overview of the history, causes and clinical aspects of MS, (ii) review the molecular mechanisms of insulin action and the causes of insulin resistance, and (iii) discuss the epidemiological and intervention data on the effects of exercise on MS and insulin sensitivity. PMID:23720280

Cervical neuro-muscular syndrome: discovery of a new disease group caused by abnormalities in the cervical muscles.

PubMed

Matsui, Takayoshi; Ii, Kunio; Hojo, Shuntaro; Sano, Keiji

2012-01-01

Our previous study of whiplash injury found that abnormalities in the cervical muscles cause autonomic dystonia. Further research has found that abnormalities in the cervical muscles cause headache, chronic fatigue syndrome, vertigo, and dizziness. We named this group of diseases cervical neuro-muscular syndrome. Patients treated within a 2-year period from April 1, 2002 to March 31, 2004 reported good outcomes in 83.8% for headache, 88.4% for vertigo and dizziness, 84.5% for chronic fatigue syndrome, 88.0% for autonomic dystonia, and 83.7% for whiplash-associated disorder. A large number of outpatients present with general malaise, including many general physical complaints without identifiable cause. We propose that treatment of the cervical muscle is effective for general malaise.

Streptococcal Toxic Shock Syndrome Caused by Group G Streptococcus, United Kingdom.

PubMed

Baxter, Melissa; Morgan, Marina

2017-01-01

We describe successful management of 3 patients with streptococcal toxic shock syndrome (STSS) attributable to group G Streptococcus infection. This small series supports recognition of group G Streptococcus in the etiology of STSS. We propose intravenous immunoglobulin be used in treatment as it is for STSS caused by group A Streptococcus.

Gastric invagination in adults as a rare cause of constitutional syndrome.

PubMed

Dávila Arias, Cristina; Milena Muñoz, Ana; Valero González, María Ángeles; Céspedes Mas, Mariano

2017-02-01

This article describes and illustrates the case of an adult patient with clinical symptoms of constitutional syndrome, postprandial discomfort and a mass in the left lateral abdominal region caused by a gastric intussusception with a fundal adenoma as the head of the invagination. The intussusception was diagnosed by MRI (magnetic resonance imaging).

Air Swallowing Caused Recurrent Ileus in Tourette’s Syndrome

PubMed Central

Frye, Richard E.; Hait, Elizabeth J.

2008-01-01

This report describes an adolescent boy who has Tourette’s syndrome and developed a subtle but significant increase in vocal tics after an 8-month respite. The increase in vocal tics was associated with an acute increase in psychological stressors and resulted in recurrent air swallowing, which, in turn, caused abdominal cramping, eructation, and flatus, eventually leading to aeroenteria. Air swallowing was recognized only after a second hospital admission for recurrent ileus. Air swallowing and associated symptoms were mitigated by reinstitution of psychopharmacologic treatment and an increase in the patient’s self-awareness of the air-swallowing behavior. Clinically significant air swallowing has not been described previously in Tourette syndrome or a tic disorder. This case is important for pediatricians and pediatric gastroenterologists because either may be the first to evaluate a child or an adolescent with unexplained recurrent ileus. This report also documents the importance of the connection between the brain and the body. PMID:16651280

Gram Positive Bacterial Superantigen Outside-In Signaling Causes Toxic Shock Syndrome

PubMed Central

Brosnahan, Amanda J.; Schlievert, Patrick M.

2011-01-01

Staphylococcus aureus and Streptococcus pyogenes (group A streptococci) are gram-positive pathogens capable of producing a variety of bacterial exotoxins known as superantigens. Superantigens interact with antigen-presenting cells (APCs) and T cells to induce T cell proliferation and massive cytokine production, which leads to fever, rash, capillary leak, and subsequent hypotension, the major symptoms of toxic shock syndrome. Both S. aureus and group A streptococci colonize mucosal surfaces, including the anterior nares and vagina for S. aureus, and the oropharynx and less commonly the vagina for group A streptococci. However, due to their abilities to secrete a variety of virulence factors, the organisms can also cause illnesses from the mucosa. This review provides an updated discussion of the biochemical and structural features of one group of secreted virulence factors, the staphylococcal and group A streptococcal superantigens, and their abilities to cause toxic shock syndrome from a mucosal surface. The main focus of this review, however, is the abilities of superantigens to induce cytokines and chemokines from epithelial cells, which has been linked to a dodecapeptide region that is relatively conserved among all superantigens and is distinct from the binding sites required for interactions with APCs and T cells. This phenomenon, termed outside-in signaling, acts to recruit adaptive immune cells to the submucosa, where the superantigens can then interact with those cells to initiate the final cytokine cascades that lead to toxic shock syndrome. PMID:21535475

Gram-positive bacterial superantigen outside-in signaling causes toxic shock syndrome.

PubMed

Brosnahan, Amanda J; Schlievert, Patrick M

2011-12-01

Staphylococcus aureus and Streptococcus pyogenes (group A streptococci) are Gram-positive pathogens capable of producing a variety of bacterial exotoxins known as superantigens. Superantigens interact with antigen-presenting cells (APCs) and T cells to induce T cell proliferation and massive cytokine production, which leads to fever, rash, capillary leak and subsequent hypotension, the major symptoms of toxic shock syndrome. Both S. aureus and group A streptococci colonize mucosal surfaces, including the anterior nares and vagina for S. aureus, and the oropharynx and less commonly the vagina for group A streptococci. However, due to their abilities to secrete a variety of virulence factors, the organisms can also cause illnesses from the mucosa. This review provides an updated discussion of the biochemical and structural features of one group of secreted virulence factors, the staphylococcal and group A streptococcal superantigens, and their abilities to cause toxic shock syndrome from a mucosal surface. The main focus of this review, however, is the abilities of superantigens to induce cytokines and chemokines from epithelial cells, which has been linked to a dodecapeptide region that is relatively conserved among all superantigens and is distinct from the binding sites required for interactions with APCs and T cells. This phenomenon, termed outside-in signaling, acts to recruit adaptive immune cells to the submucosa, where the superantigens can then interact with those cells to initiate the final cytokine cascades that lead to toxic shock syndrome. © 2011 The Authors Journal compilation © 2011 FEBS.

Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency.

PubMed

Stephen, Joshi; Vilboux, Thierry; Mian, Luhe; Kuptanon, Chulaluck; Sinclair, Courtney M; Yildirimli, Deniz; Maynard, Dawn M; Bryant, Joy; Fischer, Roxanne; Vemulapalli, Meghana; Mullikin, James C; Huizing, Marjan; Gahl, William A; Malicdan, May Christine V; Gunay-Aygun, Meral

2017-04-01

Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic "molar tooth sign" on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients' fibroblasts.

Evidence of staphylococcal toxic shock syndrome caused by MRSA in a mother-newborn pair.

PubMed

Rostad, Christina A; Philipsborn, Rebecca Pass; Berkowitz, Frank E

2015-04-01

A neonate and his mother presented with fever and erythroderma. The mother met full diagnostic criteria for staphylococcal toxic shock syndrome, whereas the neonate lacked hypotension and multiorgan dysfunction. A wound culture from the neonate's circumcision site grew methicillin-resistant Staphylococcus aureus containing the tst gene. This provides evidence of the first reported case of toxic shock syndrome caused by methicillin-resistant Staphylococcus aureus in a mother-newborn pair.

Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome.

PubMed

McLarren, Keith W; Severson, Tesa M; du Souich, Christèle; Stockton, David W; Kratz, Lisa E; Cunningham, David; Hendson, Glenda; Morin, Ryan D; Wu, Diane; Paul, Jessica E; An, Jianghong; Nelson, Tanya N; Chou, Athena; DeBarber, Andrea E; Merkens, Louise S; Michaud, Jacques L; Waters, Paula J; Yin, Jingyi; McGillivray, Barbara; Demos, Michelle; Rouleau, Guy A; Grzeschik, Karl-Heinz; Smith, Raffaella; Tarpey, Patrick S; Shears, Debbie; Schwartz, Charles E; Gecz, Jozef; Stratton, Michael R; Arbour, Laura; Hurlburt, Jane; Van Allen, Margot I; Herman, Gail E; Zhao, Yongjun; Moore, Richard; Kelley, Richard I; Jones, Steven J M; Steiner, Robert D; Raymond, F Lucy; Marra, Marco A; Boerkoel, Cornelius F

2010-12-10

CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development. Copyright © 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Hyperthyroidism caused by acquired immune deficiency syndrome.

PubMed

Wang, J-J; Zhou, J-J; Yuan, X-L; Li, C-Y; Sheng, H; Su, B; Sheng, C-J; Qu, S; Li, H

2014-01-01

Acquired immune deficiency syndrome (AIDS) is an immune deficiency disease. The etiology of hyperthyroidism, which can also be immune-related, is usually divided into six classical categories, including hypophyseal, hypothalamic, thyroid, neoplastic, autoimmune and inflammatory hyperthyroidism. Hyperthyroidism is a rare complication of highly active antimicrobial therapy (HAART) for human immunodeficiency virus (HIV). Hyperthyroidism caused directly by AIDS has not been previously reported. A 29-year-old man who complained of dyspnea and asthenia for 1 month, recurrent fever for more than 20 days, and breathlessness for 1 week was admitted to our hospital. The thyroid function test showed that the level of free thyroxine (FT4) was higher than normal and that the level of thyroid-stimulating hormone (TSH) was below normal. He was diagnosed with hyperthyroidism. Additional investigations revealed a low serum albumin level and chest infection, along with diffuse lung fibrosis. Within 1 month, he experienced significant weight loss, no hand tremors, intolerance of heat, and perspiration proneness. We recommended an HIV examination; subsequently, AIDS was diagnosed based on the laboratory parameters. This is the first reported case of hyperthyroidism caused by AIDS. AIDS may cause hyperthyroidism by immunization regulation with complex, atypical, and easily ignored symptoms. Although hyperthyroidism is rare in patients with AIDS, clinicians should be aware of this potential interaction and should carefully monitor thyroid function in HIV-positive patients.

Genetics Home Reference: Alport syndrome

MedlinePlus

... particularly the organ of Corti, that transform sound waves into nerve impulses for the brain. Alterations in type IV collagen often result in abnormal inner ear function, which can lead to hearing loss. In the ...

Inflammatory cause of metabolic syndrome via brain stress and NF-κB.

PubMed

Cai, Dongsheng; Liu, Tiewen

2012-02-01

Metabolic syndrome, a network of medical disorders that greatly increase the risk for developing metabolic and cardiovascular diseases, has reached epidemic levels in many areas of today's world. Despite this alarming medicare situation, scientific understandings on the root mechanisms of metabolic syndrome are still limited, and such insufficient knowledge contributes to the relative lack of effective treatments or preventions for related diseases. Recent interdisciplinary studies from neuroendocrinology and neuroimmunology fields have revealed that overnutrition can trigger intracellular stresses to cause inflammatory changes mediated by molecules that control innate immunity. This type of nutrition-related molecular inflammation in the central nervous system, particularly in the hypothalamus, can form a common pathogenic basis for the induction of various metabolic syndrome components such as obesity, insulin resistance, and hypertension. Proinflammatory NF-κB pathway has been revealed as a key molecular system for pathologic induction of brain inflammation, which translates overnutrition and resulting intracellular stresses into central neuroendocrine and neural dysregulations of energy, glucose, and cardiovascular homeostasis, collectively leading to metabolic syndrome. This article reviews recent research advances in the neural mechanisms of metabolic syndrome and related diseases from the perspective of pathogenic induction by intracellular stresses and NF-κB pathway of the brain.

Fanconi syndrome

MedlinePlus

De Toni-Fanconi syndrome ... Fanconi syndrome can be caused by faulty genes, or it may result later in life due to kidney damage. Sometimes the cause of Fanconi syndrome is unknown. Common causes of Fanconi syndrome in ...

Mutations in SURF1 are important genetic causes of Leigh syndrome in Slovak patients.

PubMed

Danis, Daniel; Brennerova, Katarina; Skopkova, Martina; Kurdiova, Timea; Ukropec, Jozef; Stanik, Juraj; Kolnikova, Miriam; Gasperikova, Daniela

2018-04-01

Leigh syndrome is a progressive early onset neurodegenerative disease typically presenting with psychomotor regression, signs of brainstem and/or basal ganglia disease, lactic acidosis, and characteristic magnetic resonance imaging findings. At molecular level, deficiency of respiratory complexes and/or pyruvate dehydrogenase complex is usually observed. Nuclear gene SURF1 encodes an assembly factor for cytochrome c-oxidase complex of the respiratory chain and autosomal recessive mutations in SURF1 are one of the most frequent causes of cytochrome c-oxidase-related Leigh syndrome cases. Here, we aimed to elucidate the genetic basis of Leigh syndrome in three Slovak families. Three probands presenting with Leigh syndrome were selected for DNA analysis. The first proband, presenting with atypical LS onset without abnormal basal ganglia magnetic resonance imaging findings, was analyzed with whole exome sequencing. In the two remaining probands, SURF1 was screened by Sanger sequencing. Four different heterozygous mutations were identified in SURF1: c.312_321delinsAT:p.(Pro104Profs*1), c.588+1G>A, c.823_833+7del:p. (?) and c.845_846del:p.(Ser282Cysfs*9). All the mutations are predicted to have a loss-of-function effect. We identified disease-causing mutations in all three probands, which points to the important role of SURF1 gene in etiology of Leigh syndrome in Slovakia. Our data showed that patients with atypical Leigh syndrome phenotype without lesions in basal ganglia may benefit from the whole exome sequencing method. In the case of probands presenting the typical phenotype, Sanger sequencing of the SURF1 gene seems to be an effective method of DNA analysis.

Ischemic syndromes causing dizziness and vertigo.

PubMed

Choi, K-D; Lee, H; Kim, J-S

2016-01-01

Dizziness/vertigo and imbalance are the most common symptoms of vertebrobasilar ischemia. Even though dizziness/vertigo usually accompanies other neurologic symptoms and signs in cerebrovascular disorders, a diagnosis of isolated vascular vertigo is increasing markedly by virtue of recent developments in clinical neurotology and neuroimaging. It is important to differentiate isolated vertigo of a vascular cause from more benign disorders involving the inner ear, since therapeutic strategies and prognosis differ between these two conditions. Over the last decade, we have achieved a marked development in the understanding and diagnosis of vascular dizziness/vertigo. Introduction of diffusion-weighted magnetic resonance imaging (MRI) has greatly enhanced detection of infarctions in patients with vascular dizziness/vertigo, especially in the posterior-circulation territories. However, well-organized bedside neurotologic evaluation is even more sensitive than MRI in detecting acute infarction as a cause of spontaneous prolonged vertigo. Furthermore, detailed evaluation of strategic infarctions has elucidated the function of various vestibular structures of the brainstem and cerebellum. In contrast, diagnosis of isolated labyrinthine infarction still remains a challenge. This diagnostic difficulty also applies to isolated transient dizziness/vertigo of vascular origin. Regarding the common nonlacunar mechanisms in the acute vestibular syndrome from small infarctions, individual strategies may be indicated to prevent recurrences of stroke in patients with vascular vertigo. © 2016 Elsevier B.V. All rights reserved.

[Myocardial bridge as the only cause of acute coronary syndrome among the young patients].

PubMed

Miakinkova, Liudmila O; Teslenko, Yurii V; Tsyhanenko, Irina V

2018-01-01

Introduction: Myocardial bridge is an inborn anomaly of coronary artery development, when a part of it is submerged in a myocard, which is pressing the coronary artery to a systola and restrains coronary blood circulation. Generally this feature of coronary blood circulation does not cause any clinical symptoms because the 85% of coronary blood stream of the left ventricle is provided by diastolic filling. Hemodynamic changes in atherosclerosis, tahicardie, hypertrophie of myocard are leading to the manifestation of clinical symptoms of ischemia. The aim: The purpose of the investigation was to discover the features of clinical development of acute coronary syndrome caused by myocardial bridge of young patients without the features of atherosclerotical harm of coronary arteries. Materials and methods: Eight causes of acute coronary syndrome among patients of 28±8,5 years with myocardial bridge which was revealed during coronary angiography, were investigated. Standardized examination and conservative treatment of patients was held, except for three who have got interventional therapy. Results: According to our investigation, myocardial bridge of all investigated patients was located in the middle of the third front interventricular branch of the left coronary artery. Causes of acute coronary syndrome manifestation were tahicardia, spasms of coronary artery, inducted by iatrogenic factors hypertrophie of myocard, hypertrophic cardiomyopatie. Connection between the manifestation of clinical symptoms and length of tunneled segment which did not depend on the level of systolic compres was discovered. The results of conservative and interventional treatment were analyzed. Conclusions: Myocardial bridge can be the cause of myocardial ischemia among patients without signs of coronary atherosclerosis with additional hemodynamic risk facts such as tahicardia, spasms of coronary artery, hypertrophie of myocard. Clinical symptomatology of the acute coronary syndrome is more

WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4

PubMed Central

Liu, Qian; Chen, Haoqian; Ojode, Teresa; Gao, Xiangxi; Anaya-O'Brien, Sandra; Turner, Nicholas A.; Ulrick, Jean; DeCastro, Rosamma; Kelly, Corin; Cardones, Adela R.; Gold, Stuart H.; Hwang, Eugene I.; Wechsler, Daniel S.; Malech, Harry L.; Murphy, Philip M.

2012-01-01

WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G → A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4R334X, the most common truncation mutation in WHIM syndrome, CXCR4E343K mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however, CXCR4E343K had a reduced effect on blocking normal receptor down-regulation from the cell surface. Therefore, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling. PMID:22596258

Causes of the "I Can Understand English but I Can't Speak" Syndrome in Turkey

ERIC Educational Resources Information Center

Coskun, Abdullah

2016-01-01

The saying "I can understand English but I can't speak" is so commonly used by Turkish people that it would be fair to state that not being able to speak English has almost become a syndrome in society. This study delves into the causes of this syndrome. In two state high schools, 293 high school students filled out a questionnaire…

Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein–Taybi and Filippi syndromes

PubMed Central

de Vries, Tamar I; R Monroe, Glen; van Belzen, Martine J; van der Lans, Christian A; Savelberg, Sanne MC; Newman, William G; van Haaften, Gijs; Nievelstein, Rutger A; van Haelst, Mieke M

2016-01-01

Rubinstein–Taybi syndrome (RTS, OMIM 180849) and Filippi syndrome (FLPIS, OMIM 272440) are both rare syndromes, with multiple congenital anomalies and intellectual deficit (MCA/ID). We present a patient with intellectual deficit, short stature, bilateral syndactyly of hands and feet, broad thumbs, ocular abnormalities, and dysmorphic facial features. These clinical features suggest both RTS and FLPIS. Initial DNA analysis of DNA isolated from blood did not identify variants to confirm either of these syndrome diagnoses. Whole-exome sequencing identified a homozygous variant in C9orf173, which was novel at the time of analysis. Further Sanger sequencing analysis of FLPIS cases tested negative for CKAP2L variants did not, however, reveal any further variants. Subsequent analysis using DNA isolated from buccal mucosa revealed a mosaic variant in CREBBP. This report highlights the importance of excluding mosaic variants in patients with a strong but atypical clinical presentation of a MCA/ID syndrome if no disease-causing variants can be detected in DNA isolated from blood samples. As the striking syndactyly observed in the present case is typical for FLPIS, we suggest CREBBP analysis in saliva samples for FLPIS syndrome cases in which no causal CKAP2L variant is detected. PMID:26956253

Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein-Taybi and Filippi syndromes.

PubMed

de Vries, Tamar I; Monroe, Glen R; van Belzen, Martine J; van der Lans, Christian A; Savelberg, Sanne Mc; Newman, William G; van Haaften, Gijs; Nievelstein, Rutger A; van Haelst, Mieke M

2016-08-01

Rubinstein-Taybi syndrome (RTS, OMIM 180849) and Filippi syndrome (FLPIS, OMIM 272440) are both rare syndromes, with multiple congenital anomalies and intellectual deficit (MCA/ID). We present a patient with intellectual deficit, short stature, bilateral syndactyly of hands and feet, broad thumbs, ocular abnormalities, and dysmorphic facial features. These clinical features suggest both RTS and FLPIS. Initial DNA analysis of DNA isolated from blood did not identify variants to confirm either of these syndrome diagnoses. Whole-exome sequencing identified a homozygous variant in C9orf173, which was novel at the time of analysis. Further Sanger sequencing analysis of FLPIS cases tested negative for CKAP2L variants did not, however, reveal any further variants. Subsequent analysis using DNA isolated from buccal mucosa revealed a mosaic variant in CREBBP. This report highlights the importance of excluding mosaic variants in patients with a strong but atypical clinical presentation of a MCA/ID syndrome if no disease-causing variants can be detected in DNA isolated from blood samples. As the striking syndactyly observed in the present case is typical for FLPIS, we suggest CREBBP analysis in saliva samples for FLPIS syndrome cases in which no causal CKAP2L variant is detected.

Churg-Strauss Syndrome as an Unusual Cause of Dysphagia: Case Report.

PubMed

Park, Jihye; Im, Sun; Moon, Su-Jin; Park, Geun-Young; Jang, Yongjun; Kim, Yeonjin

2015-06-01

Systemic vasculitis is a rare disease, and the diagnosis is very difficult when patient shows atypical symptoms. We experienced an unusual case of dysphagia caused by Churg-Strauss syndrome with lower cranial nerve involvement. A 74-year-old man, with a past history of sinusitis, asthma, and hearing deficiency, was admitted to our department for evaluation of dysphagia. He also complained of recurrent bleeding of nasal cavities and esophagus. Brain magnetic resonance imaging did not show definite abnormality, and electrophysiologic findings were suggestive of mononeuritis multiplex. Dysphagia had not improved after conventional therapy. Biopsy of the nasal cavity showed extravascular eosinophilic infiltration. All these findings suggested a rare form of Churg-Strauss syndrome involving multiple lower cranial nerves. Dysphagia improved after steroid therapy.

An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

PubMed Central

Canna, Scott W.; de Jesus, Adriana Almeida; Gouni, Sushanth; Brooks, Stephen R.; Marrero, Bernadette; Liu, Yin; DiMattia, Michael A.; Zaal, Kristien J.M.; Montealegre Sanchez, Gina A.; Kim, Hanna; Chapelle, Dawn; Plass, Nicole; Huang, Yan; Villarino, Alejandro V.; Biancotto, Angelique; Fleisher, Thomas A.; Duncan, Joseph A.; O’Shea, John J; Benseler, Susanne; Grom, Alexei; Deng, Zuoming; Laxer, Ronald M; Goldbach-Mansky, Raphaela

2014-01-01

Inflammasomes are innate immune sensors that respond to pathogen and damage-associated signals with caspase-1 activation, IL-1β and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the Cryopyrin Associated Periodic Syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion, led to successful treatment with IL-1 blocking agents1. Herein, we report a de novo missense mutation, c.1009A>T, p.Thr337Ser, in the nucleotide-binding domain of inflammasome component NLRC4 (IPAF/CARD12) that causes early-onset recurrent fever flares and Macrophage Activation Syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1β and IL-18, the latter exceeding levels in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in transduced cells and increased production of IL-18 by both patient and NLRC4 mutant macrophages. Thus, we describe a novel monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests novel targets for therapy. PMID:25217959

Pathology of Podocytopathies Causing Nephrotic Syndrome in Children.

PubMed

Ranganathan, Sarangarajan

2016-01-01

Nephrotic syndrome (NS) in children includes a diverse group of diseases that range from genetic diseases without any immunological defects to causes that are primarily due to immunological effects. Recent advances in molecular and genomic studies have resulted in a plethora of genetic defects that have been localized to the podocyte, the basic structure that is instrumental in normal filtration process. Although the disease can manifest from birth and into adulthood, the primary focus of this review would be to describe the novel genes and pathology of primary podocyte defects that cause NS in children. This review will restrict itself to the pathology of congenital NS, minimal change disease (MCD), and its variants and focal segmental glomerulosclerosis (FSGS). The two major types of congenital NS are Finnish type characterized by dilated sausage shaped tubules morphologically and diffuse mesangial sclerosis characterized by glomerulosclerosis. MCD has usually normal appearing biopsy features on light microscopy and needs electron microscopy for diagnosis, whereas FSGS in contrast has classic segmental sclerosing lesions identified in different portions of the glomeruli and tubular atrophy. This review summarizes the pathological characteristics of these conditions and also delves into the various genetic defects that have been described as the cause of these primary podocytopathies. Other secondary causes of NS in children, such as membranoproliferative and membranous glomerulonephritis, will not be covered in this review.

[Hantavirus infection as the cause of haemorrhagic fever with renal syndrome].

PubMed

Redal-Baigorri, Belén; Chen Nielsen, Xiaohui; Martin-Iguacel, Raquel

2012-10-29

Hantavirus is an RNA virus that can cause potentially fatal pulmonary and renal diseases in humans. Infections with Hantaviruses occur through inhalation of aerosol from rodent faeces, urine or saliva. The predominant virus type in Denmark is the Puumala virus, which causes the mildest form of haemorrhagic fever with renal syndrome, the so-called nephropathia epidemica (NE) with good prognosis (mortality 0.1-0.4%). The incidence of Hantavirus-infection in Denmark is about ten cases a year. The diagnosis of Hantavirus-infection is based on serology and/or polymerase chain reaction in blood or urine.

Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.

PubMed

Gripp, Karen W; Robbins, Katherine M; Sobreira, Nara L; Witmer, P Dane; Bird, Lynne M; Avela, Kristiina; Makitie, Outi; Alves, Daniela; Hogue, Jacob S; Zackai, Elaine H; Doheny, Kimberly F; Stabley, Deborah L; Sol-Church, Katia

2015-02-01

Lateral meningocele syndrome (LMS, OMIM%130720), also known as Lehman syndrome, is a very rare skeletal disorder with facial anomalies, hypotonia and meningocele-related neurologic dysfunction. The characteristic lateral meningoceles represent the severe end of the dural ectasia spectrum and are typically most severe in the lower spine. Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance. Hyperextensibility, hernias and scoliosis reflect a connective tissue abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones and osteolysis may be present. Lateral meningocele syndrome has phenotypic overlap with Hajdu-Cheney syndrome. We performed exome resequencing in five unrelated individuals with LMS and identified heterozygous truncating NOTCH3 mutations. In an additional unrelated individual Sanger sequencing revealed a deleterious variant in the same exon 33. In total, five novel de novo NOTCH3 mutations were identified in six unrelated patients. One had a 26 bp deletion (c.6461_6486del, p.G2154fsTer78), two carried the same single base pair insertion (c.6692_93insC, p.P2231fsTer11), and three individuals had a nonsense point mutation at c.6247A > T (pK2083*), c.6663C > G (p.Y2221*) or c.6732C > A, (p.Y2244*). All mutations cluster into the last coding exon, resulting in premature termination of the protein and truncation of the negative regulatory proline-glutamate-serine-threonine rich PEST domain. Our results suggest that mutant mRNA products escape nonsense mediated decay. The truncated NOTCH3 may cause gain-of-function through decreased clearance of the active intracellular product, resembling NOTCH2 mutations in the clinically related Hajdu-Cheney syndrome and contrasting the NOTCH3 missense mutations causing CADASIL. © 2014 Wiley Periodicals, Inc.

Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency

PubMed Central

Stephen, Joshi; Vilboux, Thierry; Mian, Luhe; Kuptanon, Chulaluck; Sinclair, Courtney M.; Yildirimli, Deniz; Maynard, Dawn M.; Bryant, Joy; Fischer, Roxanne; Vemulapalli, Meghana; Mullikin, James C.; Huizing, Marjan; Gahl, William A.

2017-01-01

Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic “molar tooth sign” on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients’ fibroblasts. PMID:28220259

NSD1 Mutations Are the Major Cause of Sotos Syndrome and Occur in Some Cases of Weaver Syndrome but Are Rare in Other Overgrowth Phenotypes

PubMed Central

Douglas, Jenny; Hanks, Sandra; Temple, I. Karen; Davies, Sally; Murray, Alexandra; Upadhyaya, Meena; Tomkins, Susan; Hughes, Helen E.; Cole, Trevor R. P.; Rahman, Nazneen

2003-01-01

Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive facial appearance, height and head circumference >97th percentile, advanced bone age, and developmental delay. Weaver syndrome is characterized by the same criteria but has its own distinctive facial gestalt. Recently, a 2.2-Mb chromosome 5q35 microdeletion, encompassing NSD1, was reported as the major cause of Sotos syndrome, with intragenic NSD1 mutations identified in a minority of cases. We evaluated 75 patients with childhood overgrowth, for intragenic mutations and large deletions of NSD1. The series was phenotypically scored into four groups, prior to the molecular analyses: the phenotype in group 1 (n=37) was typical of Sotos syndrome; the phenotype in group 2 (n=13) was Sotos-like but with some atypical features; patients in group 3 (n=7) had Weaver syndrome, and patients in group 4 (n=18) had an overgrowth condition that was neither Sotos nor Weaver syndrome. We detected three deletions and 32 mutations (13 frameshift, 8 nonsense, 2 splice-site, and 9 missense) that are likely to impair NSD1 functions. The truncating mutations were spread throughout NSD1, but there was evidence of clustering of missense mutations in highly conserved functional domains between exons 13 and 23. There was a strong correlation between presence of an NSD1 alteration and clinical phenotype, in that 28 of 37 (76%) patients in group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4 had abnormalities of NSD1. Three patients with Weaver syndrome had NSD1 mutations, all between amino acids 2142 and 2184. We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes. PMID:12464997

Sheehan's Syndrome-The Most Common Cause of Panhypopituitarism at Moderate Altitude: A Sub-Himalayan Study.

PubMed

Mokta, Jatinder; Ranjan, Asha; Thakur, Surinder; Bhawani, Rajesh; Mokta, Kiran K; Sharma, Jai Bharat; Kumar, Manish

2017-12-01

Panhypopituitarism is a rare disorder with varied clinical presentation having various etiologies. Sheehan's syndrome (SS) is decreasing in frequency worldwide and is a rare cause of panhypopituitarism in developed nations. A retrospective study done between May 2011 and May 2015 in tertiary care hospital. We reviewed the records of patients with hypopituitarism. Clinical features, hormonal profile and radiological investigations noted. Total 14 patients of panhypopituitarism included with average duration of symptoms 1.93± 1.96 years. four (28.57%) were males and ten (71.43%) were females with mean age of diagnosis 37.78± 13.68 years. Sheehan's syndrome (SS) was the most common cause of panhypopituitarism in 57.14%(8 patients), followed by post surgery in 14.28% (2 patients). 80% of women had SS with a mean duration of symptoms 2.39±1.54 years. Sheehan's syndrome is not uncommon in developing countries, High degree of clinical suspicion is desired as clinical features are most often subtle.

Toxic Shock Syndrome Caused by Methicillin-Resistant Staphylococcus aureus (MRSA) After Expander-Based Breast Reconstruction.

PubMed

Suga, Hirotaka; Shiraishi, Tomohiro; Takushima, Akihiko; Harii, Kiyonori

2016-01-01

Toxic shock syndrome is a rare but life-threatening complication after plastic surgery procedures. We experienced 2 cases of toxic shock syndrome after expander-based breast reconstruction caused by methicillin-resistant Staphylococcus aureus. The first patient took a severe clinical course due to the delayed diagnosis and treatment, and the second patient recovered rapidly after the early diagnosis and treatment based on our experience of the first case. Fever, rash, and gastrointestinal symptoms (diarrhea and/or vomiting) were characteristic and important for the early diagnosis of toxic shock syndrome. Considering the increased prevalence of methicillin-resistant Staphylococcus aureus, we should suspect methicillin-resistant Staphylococcus aureus in cases of toxic shock syndrome that occur postoperatively, and the empiric administration of vancomycin should be initiated in such cases.

Non-syndromic posterior lenticonus a cause of childhood cataract: evidence for X-linked inheritance.

PubMed

Russell-Eggitt, I M

2000-12-01

When an X-linked pedigree of posterior lenticonus with cataract was identified further evidence for X-linked inheritance of this condition was sought. Forty-three cases of posterior lenticonus were identified from a database of 354 children with cataract. Two children with the X-linked syndromes of Lowe and Nance-Horan and 3 children with Fanconi syndrome have been excluded from further analysis. None of the children was deaf. None of the non-syndromic cases had microcornea. There were 38 cases of non-syndromic posterior lenticonus (approximately 11%). There were 15 children from 13 pedigrees and 23 apparently sporadic cases. Of the 106 cases on the database with unilateral cataract 15 had posterior lenticonus (approximately 14%). Eleven of 13 pedigrees were compatible with X-linked inheritance or autosomal dominant inheritance with variable expression. However, in 2 pedigrees there was father to son transmission. Posterior lenticonus is a common cause of unilateral infantile cataract, but is thought to be a rare cause of bilateral cataracts. This study suggests that posterior lenticonus is responsible for a significant proportion of childhood cataracts (approximately 14% of unilateral and approximately 9% of bilateral cases). Posterior lenticonus is generally thought to occur as a sporadic condition. This study demonstrates that there is a family history of early-onset cataract in a significant number of bilateral cases (approximately 58%).

Contiguous gene deletion of chromosome 2p16.3-p21 as a cause of Lynch syndrome.

PubMed

Salo-Mullen, Erin E; Lynn, Patricio B; Wang, Lu; Walsh, Michael; Gopalan, Anuradha; Shia, Jinru; Tran, Christina; Man, Fung Ying; McBride, Sean; Schattner, Mark; Zhang, Liying; Weiser, Martin R; Stadler, Zsofia K

2018-01-01

Lynch syndrome is an autosomal dominant condition caused by pathogenic mutations in the DNA mismatch repair (MMR) genes. Although commonly associated with clinical features such as intellectual disability and congenital anomalies, contiguous gene deletions may also result in cancer predisposition syndromes. We report on a 52-year-old male with Lynch syndrome caused by deletion of chromosome 2p16.3-p21. The patient had intellectual disability and presented with a prostatic adenocarcinoma with an incidentally identified synchronous sigmoid adenocarcinoma that exhibited deficient MMR with an absence of MSH2 and MSH6 protein expression. Family history was unrevealing. Physical exam revealed short stature, brachycephaly with a narrow forehead and short philtrum, brachydactyly of the hands, palmar transverse crease, broad and small feet with hyperpigmentation of the soles. The patient underwent total colectomy with ileorectal anastomosis for a pT3N1 sigmoid adenocarcinoma. Germline genetic testing of the MSH2, MSH6, and EPCAM genes revealed full gene deletions. SNP-array based DNA copy number analysis identified a deletion of 4.8 Mb at 2p16.3-p21. In addition to the three Lynch syndrome associated genes, the deleted chromosomal section encompassed genes including NRXN1, CRIPT, CALM2, FBXO11, LHCGR, MCFD2, TTC7A, EPAS1, PRKCE, and 15 others. Contiguous gene deletions have been described in other inherited cancer predisposition syndromes, such as Familial Adenomatous Polyposis. Our report and review of the literature suggests that contiguous gene deletion within the 2p16-p21 chromosomal region is a rare cause of Lynch syndrome, but presents with distinct phenotypic features, highlighting the need for recognition and awareness of this syndromic entity.

Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

PubMed Central

Bagni, Claudia; Tassone, Flora; Neri, Giovanni; Hagerman, Randi

2012-01-01

Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and is also linked to other neurologic and psychiatric disorders. FXS is caused by a triplet expansion that inhibits expression of the FMR1 gene; the gene product, FMRP, regulates mRNA metabolism in the brain and thus controls the expression of key molecules involved in receptor signaling and spine morphology. While there is no definitive cure for FXS, the understanding of FMRP function has paved the way for rational treatment designs that could potentially reverse many of the neurobiological changes observed in FXS. Additionally, behavioral, pharmacological, and cognitive interventions can raise the quality of life for both patients and their families. PMID:23202739

Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes.

PubMed

Schultz, Julie M; Bhatti, Rashid; Madeo, Anne C; Turriff, Amy; Muskett, Julie A; Zalewski, Christopher K; King, Kelly A; Ahmed, Zubair M; Riazuddin, Saima; Ahmad, Nazir; Hussain, Zawar; Qasim, Muhammad; Kahn, Shaheen N; Meltzer, Meira R; Liu, Xue Z; Munisamy, Murali; Ghosh, Manju; Rehm, Heidi L; Tsilou, Ekaterini T; Griffith, Andrew J; Zein, Wadih M; Brewer, Carmen C; Riazuddin, Sheikh; Friedman, Thomas B

2011-11-01

Recessive mutant alleles of MYO7A, USH1C, CDH23, and PCDH15 cause non-syndromic deafness or type 1 Usher syndrome (USH1) characterised by deafness, vestibular areflexia, and vision loss due to retinitis pigmentosa. For CDH23, encoding cadherin 23, non-syndromic DFNB12 deafness is associated primarily with missense mutations hypothesised to have residual function. In contrast, homozygous nonsense, frame shift, splice site, and some missense mutations of CDH23, all of which are presumably functional null alleles, cause USH1D. The phenotype of a CDH23 compound heterozygote for a DFNB12 allele in trans configuration to an USH1D allele is not known and cannot be predicted from current understanding of cadherin 23 function in the retina and vestibular labyrinth. To address this issue, this study sought CDH23 compound heterozygotes by sequencing this gene in USH1 probands, and families segregating USH1D or DFNB12. Five non-syndromic deaf individuals were identified with normal retinal and vestibular phenotypes that segregate compound heterozygous mutations of CDH23, where one mutation is a known or predicted USH1 allele. One DFNB12 allele in trans configuration to an USH1D allele of CDH23 preserves vision and balance in deaf individuals, indicating that the DFNB12 allele is phenotypically dominant to an USH1D allele. This finding has implications for genetic counselling and the development of therapies for retinitis pigmentosa in Usher syndrome. ACCESSION NUMBERS: The cDNA and protein Genbank accession numbers for CDH23 and cadherin 23 used in this paper are AY010111.2 and AAG27034.2, respectively.

The pacemaker-twiddler's syndrome: an infrequent cause of pacemaker failure.

PubMed

Salahuddin, Mohammad; Cader, Fathima Aaysha; Nasrin, Sahela; Chowdhury, Mashhud Zia

2016-01-20

The pacemaker-twiddler's syndrome is an uncommon cause of pacemaker malfunction. It occurs due to unintentional or deliberate manipulation of the pacemaker pulse generator within its skin pocket by the patient. This causes coiling of the lead and its dislodgement, resulting in failure of ventricular pacing. More commonly reported among elderly females with impaired cognition, the phenomenon usually occurs in the first year following pacemaker implantation. Treatment involves repositioning of the dislodged leads and suture fixation of the lead and pulse generator within its pocket. An 87 year old Bangladeshi lady who underwent a single chamber ventricular pacemaker (VVI mode: i.e. ventricle paced, ventricle sensed, inhibitory mode) implantation with the indication of complete heart block, and presented to us again 7 weeks later, with syncopal attacks. She admitted to repeatedly manipulating the pacemaker generator in her left pectoral region. Physical examination revealed a heart rate of 42 beats/minute, blood pressure 140/80 mmHg and bilateral crackles on lung auscultation. She had no cognitive deficit. An immediate electrocardiogram showed complete heart block with pacemaker spikes and failure to capture. Chest X-ray showed coiled and retracted right ventricular lead and rotated pulse generator. An emergent temporary pace maker was set at a rate of 60 beats per minute. Subsequently, she underwent successful lead repositioning with strong counselling to avoid further twiddling. Twiddler's syndrome should be considered as a cause of pacemaker failure in elderly patients presenting with bradyarrythmias following pacemaker implantation. Chest X-ray and electrocardiograms are simple and easily-available first line investigations for its diagnosis. Lead repositioning is required, however proper patient education and counselling against further manipulation is paramount to long-term management.

The heartstrings mutation in zebrafish causes heart/fin Tbx5 deficiency syndrome.

PubMed

Garrity, Deborah M; Childs, Sarah; Fishman, Mark C

2002-10-01

Holt-Oram syndrome is one of the autosomal dominant human "heart-hand" disorders, with a combination of upper limb malformations and cardiac defects. Holt-Oram syndrome is caused by mutations in the TBX5 gene, a member of a large family of T-box transcription factors that play important roles in cell-type specification and morphogenesis. In a screen for mutations affecting zebrafish cardiac function, we isolated the recessive lethal mutant heartstrings, which lacks pectoral fins and exhibits severe cardiac dysfunction, beginning with a slow heart rate and progressing to a stretched, non-functional heart. We mapped and cloned the heartstrings mutation and find it to encode the zebrafish ortholog of the TBX5 gene. The heartstrings mutation causes premature termination at amino acid 316. Homozygous mutant embryos never develop pectoral fin buds and do not express several markers of early fin differentiation. The total absence of any fin bud differentiation distinguishes heartstrings from most other mutations that affect zebrafish fin development, suggesting that Tbx5 functions very early in the pectoral fin induction pathway. Moderate reduction of Tbx5 by morpholino causes fin malformations, revealing an additional early requirement for Tbx5 in coordinating the axes of fin outgrowth. The heart of heartstrings mutant embryos appears to form and function normally through the early heart tube stage, manifesting only a slight bradycardia compared with wild-type siblings. However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. Relative to mammals, fish require lower levels of Tbx5 to produce malformed appendages and display whole-heart rather than atrial-predominant cardiac defects. However, the syndromic deficiencies of tbx5 mutation are remarkably well retained between fish and mammals.

Hypokalemia causing rhabdomyolysis in a patient with short bowel syndrome.

PubMed

Balhara, Kamna S; Highet, Bridget; Omron, Rodney

2015-04-01

Rhabdomyolysis, usually in the setting of trauma or drug use, is frequently seen in the emergency setting, and often leads to hyperkalemia at presentation. Hypokalemia, however, is a potentially underrecognized cause of rhabdomyolysis. We present a case of rhabdomyolysis likely due to hypokalemia in the setting of short bowel syndrome. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although less common, hypokalemia can be a significant cause of rhabdomyolysis via its effects on muscle. This scenario should be considered in the differential diagnosis of patients at risk for hypokalemia who present with weakness. Rapid recognition of this relationship and rapid correction of hypokalemia may prove very important in preventing the deleterious effects of rhabdomyolysis. Copyright © 2015 Elsevier Inc. All rights reserved.

Spinal intradural hydatid cyst causing arachnoiditis: A rare etiology of cauda equina syndrome

PubMed Central

Singh, Suyash; Sardhara, Jayesh; Singh, Amit Kumar; Srivastava, Arun Kumar; Bhaisora, Kamlesh Singh; Das, Kuntal Kanti; Mehrotra, Anant; Sahu, Rabi N; Jaiswal, Awadhesh Kumar; Behari, Sanjay

2016-01-01

This study aims to focus on a rare presentation of spinal hydatid cyst as cauda equine syndrome and misdiagnosed as intradural extramedullary (IDEM) benign lesion on magnetic resonance imaging. In this article, we report a case of spinal hydatid cyst masquerading as IDEM tumor, and intraoperatively, we accidently find clumped granuloma with severe arachnoiditis and hydatid cyst in lumber region, which was present as bilateral S1 radiculopathy with cauda equina syndrome. An 11-year-old boy who presented with symptoms and signs of cauda equina syndrome and planned for surgical excision. His radiological impression was IDEM possibly neurofibroma. To our surprise, we found multiple intradural cystic lesions with arachnoiditis. Dissecting in plane cyst was flushed out, and surgical cavity was irrigated with 3% saline. Postoperatively histopathology and serum tests confirmed the diagnosis of hydatid cyst. Hydatid disease is rare cause of cauda equine syndrome which can be miss diagnosed on radiological investigations. A high index of suspicion should be kept especially in a young patient from the Indian subcontinent. PMID:27891041

[Kenny-Caffey syndrome and its related syndromes].

PubMed

Isojima, Tsuyoshi; Kitanaka, Sachiko

2015-11-01

Kenny-Caffey syndrome (KCS) is a very rare dysmorphologic syndrome characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of anterior fontanelle, eye abnormalities, and hypoparathyroidism. Two types of KCS were known: the autosomal recessive form (KCS type 1), which is caused by mutations of the TBCE gene, and the autosomal dominant form (KCS type 2), which is caused by mutations of the FAM111A gene. TBCE mutation also causes hypoparathyroidism-retardation-dysmorphism syndrome, and FAM111A mutation also causes gracile bone dysplasia. These two diseases can be called as KCS-related syndromes. In this article, we review the clinical manifestations of KCS and discuss its related syndromes.

Medial abrasion syndrome: a neglected cause of knee pain in middle and old age.

PubMed

Lyu, Shaw-Ruey; Lee, Ching-Chih; Hsu, Chia-Chen

2015-04-01

Knee pain is a prevailing health problem of middle and old age. Medial plica-related medial abrasion syndrome (MAS), although a well-known cause of knee pain in younger individuals, has rarely been investigated in older individuals. This prospective study was conducted to investigate the prevalence and clinical manifestations of this syndrome as a cause of knee pain in middle and old age. The outcomes of arthroscopic treatment for this syndrome were also evaluated.A total of 232 knees of 169 patients >40 years of age (41-82, median: 63 years old) suffering from chronic knee pain were analyzed. The clinical diagnosis, predisposing factors, presenting symptoms, and physical signs were investigated. The sensitivity and specificity of each parameter of the clinical presentation for the diagnosis of MAS were evaluated after confirmation by arthroscopy. For patients with MAS, the roentgenographic and arthroscopic manifestations were investigated, and arthroscopic medial release (AMR) was performed. The outcomes were evaluated by the changes in the pain domain of the Knee Society scoring system and by patient satisfaction. The prevalence of medial plica was 95%, and osteoarthritis (OA) was the most common clinical diagnosis. Symptoms of pain and crepitus in motion and local tenderness during physical examination were the most sensitive parameters for the diagnosis. A history of a single knee injury combined with local tenderness and a palpable band found during physical examination were the most specific parameters for the diagnosis. The majority of patients suffering from this syndrome were successfully treated using AMR, yielding a satisfaction rate of 85.5% after a minimum of 3 years.MAS is a common cause of knee pain in middle and old age and can be effectively treated by AMR. Its concomitance with OA warrants further investigation.

Sjogren's Syndrome: Can It Cause Recurrent UTIs?

MedlinePlus

... home/about-sjogrens/symptoms. Accessed Nov. 11, 2015. Fox R. Clinical manifestations of Sjogren's syndrome: Exocrine gland ... www.uptodate.com/home. Accessed Nov. 11, 2015. Fox R, et al. Clinical manifestations of Sjogren's syndrome: ...

A rare cause of Cushing's syndrome: an ACTH-secreting phaeochromocytoma.

PubMed

Folkestad, Lars; Andersen, Marianne Skovsager; Nielsen, Anne Lerberg; Glintborg, Dorte

2014-10-08

Excess glucocorticoid levels cause Cushing's syndrome (CS) and may be due to pituitary, adrenal or ectopic tumours. Adrenocorticotropic hormone (ACTH) levels are useful in identifying adrenal tumours. In rare cases, ACTH-producing phaeochromocytomas are the cause of CS. We present two cases of ACTH-secreting phaeochromocytoma as the underlying cause of CS. In both cases, female patients presented with the classical clinical signs of CS and an adrenal mass. High ACTH levels raised the suspicion of an ACTH-secreting phaeochromocytoma. The diagnosis was confirmed by urinary catecholamine levels and positive fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) CT (Case 1) and fluorodeoxyglucose PET-CT (Case 2). Both patients were treated with an α-blocker prior to surgical intervention. The two cases underline the importance of thorough diagnostic workup in patients with CS. An ACTH-secreting phaeochromocytoma should be checked for in patients with an adrenal mass and elevated ACTH levels. 2014 BMJ Publishing Group Ltd.

A rare cause of Cushing's syndrome: an ACTH-secreting phaeochromocytoma

PubMed Central

Folkestad, Lars; Andersen, Marianne Skovsager; Nielsen, Anne Lerberg; Glintborg, Dorte

2014-01-01

Excess glucocorticoid levels cause Cushing's syndrome (CS) and may be due to pituitary, adrenal or ectopic tumours. Adrenocorticotropic hormone (ACTH) levels are useful in identifying adrenal tumours. In rare cases, ACTH-producing phaeochromocytomas are the cause of CS. We present two cases of ACTH-secreting phaeochromocytoma as the underlying cause of CS. In both cases, female patients presented with the classical clinical signs of CS and an adrenal mass. High ACTH levels raised the suspicion of an ACTH-secreting phaeochromocytoma. The diagnosis was confirmed by urinary catecholamine levels and positive fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) CT (Case 1) and fluorodeoxyglucose PET-CT (Case 2). Both patients were treated with an α-blocker prior to surgical intervention. The two cases underline the importance of thorough diagnostic workup in patients with CS. An ACTH-secreting phaeochromocytoma should be checked for in patients with an adrenal mass and elevated ACTH levels. PMID:25297883

Cardiovascular causes of maternal sudden death. Sudden arrhythmic death syndrome is leading cause in UK.

PubMed

Krexi, Dimitra; Sheppard, Mary N

2017-05-01

This study aims to determine the causes of sudden cardiac death during pregnancy and in the postpartum period and patients' characteristics. There are few studies in the literature. Eighty cases of sudden unexpected death due to cardiac causes in relation to pregnancy and postpartum period in a database of 4678 patients were found and examined macroscopically and microscopically. The mean age was 30±7 years with a range from 16 to 43 years. About 30% were 35 years old or older; 50% of deaths occurred during pregnancy and 50% during the postpartum period. About 59.18% were obese or overweight where body mass index data were available. The leading causes of death were sudden arrhythmic death syndrome (SADS) (53.75%) and cardiomyopathies (13.80%). Other causes include dissection of aorta or its branches (8.75%), congenital heart disease (2.50%) and valvular disease (3.75%). This study highlights sudden cardiac death in pregnancy or in the postpartum period, which is mainly due to SADS with underlying channelopathies and cardiomyopathy. We wish to raise awareness of these frequently under-recognised entities in maternal deaths and the need of cardiological screening of the family as a result of the diagnosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Cardiovascular causes of maternal sudden death. Sudden Arrhythmic Death Syndrome is leading cause in UK.

PubMed

Krexi, Dimitra; Sheppard, Mary N

2017-09-01

This study aims to determine the causes of sudden cardiac death during pregnancy and in the postpartum period and patients' characteristics. There are few studies in the literature. Eighty cases of sudden unexpected death due to cardiac causes in relation to pregnancy and postpartum period in a database of 4678 patients were found and examined macroscopically and microscopically. The mean age was 30±7years with a range from 16 to 43 years. About 30% were 35 years old or older; 50% of deaths occurred during pregnancy and 50% during the postpartum period. About 59.18% were obese or overweight where body mass index data were available. The leading causes of death were sudden arrhythmic death syndrome (SADS) (53.75%) and cardiomyopathies (13.80%). Other causes include dissection of aorta or its branches (8.75%), congenital heart disease (2.50%) and valvular disease (3.75%). This study highlights sudden cardiac death in pregnancy or in the postpartum period, which is mainly due to SADS with underlying channelopathies and cardiomyopathy. We wish to raise awareness of these frequently under-recognised entities in maternal deaths and the need of cardiological screening of the family as a result of the diagnosis. Copyright © 2017 Elsevier B.V. All rights reserved.

[Sepsis caused by Fusobacterium necrophorum (Lemierre syndrome): a rare complication of acute pharyngotonsilitis].

PubMed

Perović, Marta; Maretić, Tomislav; Begovac, Josip

2006-12-01

Lemierre syndrome is defined as an acute pharyngotonsillar infection that has spread into the lateral pharyngeal space causing thrombophlebitis of the internal jugular vein with consecutive metastatic emboli. The syndrome is most often caused by Fusobacterium (F.) necrophorum and usually involves young, previously healthy people. We present a healthy 20-year-old man who suddenly developed with high fever and sore throat followed by dyspnea, tachypnea and cough on the third day of illness. His condition worsened despite outpatient intramuscular penicillin therapy (1600 000 IU/day). He was admitted to Dr. Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, on the sixth day of his illness with clinical signs of sepsis. Chest radiograph showed bilateral multiple infiltrates. F. necrophorum was isolated from blood culture. Swelling of the neck was also observed on the fourteenth day of illness, however, thrombophlebitis of the jugular vein was not diagnosed on ultrasound examination. The patient was treated with clindamycin for five weeks and recovered completely.

Pheochromocytoma as a rare cause of hypertension in a 46 X, i(X)(q10) turner syndrome: a case report and literature review.

PubMed

Shin, Ji Yeon; Kim, Bo Hyun; Kim, Young Keum; Kim, Tae Hwa; Kim, Eun Heui; Lee, Min Jin; Kim, Jong Ho; Jeon, Yun Kyung; Kim, Sang Soo; Kim, In Joo

2018-05-10

Cardiovascular disease (CVD) presents the most serious health problems and contributes to the increased mortality in young women with Turner syndrome. Arterial hypertension in Turner syndrome patients is significantly more prevalent than that in a general age-matched control group. The aetiology of hypertension in Turner syndrome varies, even in the absence of cardiac anomalies and obvious structural renal abnormalities. Pheochromocytoma is an extremely rare cause among various etiologies for hypertension in patients with Turner syndrome. Here, we reported a pheochromocytoma as a rare cause of hypertension in Turner syndrome patient. A 21-year-old woman who has diagnosed with Turner syndrome with a karyotype of 46,X,i(X)(q10) visited for hypertension and mild headache. Transthoracic echography (TTE) showed no definite persistent ductus arteriosus shunt flow and cardiac valve abnormalities. Considering other important secondary causes like pheochromocytoma, hormonal studies were performed and the results showed increased serum norepinephrine, serum normetanephrine, and 24 h urine norepinephrine. We performed an abdominal computed tomography (CT) to confirm the location of pheochromocytoma. Abdominal CT showed a 1.9 cm right adrenal mass. I-131 meta-iodobenzylguanidine (MIBG) scintigraphy showed a right adrenal uptake. Laparoscopic adrenalectomy was performed and confirmed a pheochromocytoma. After surgery, blood pressure was within normal ranges and postoperative course was uneventful, and no recurrence developed via biochemical tests and abdominal CT until 24 months. Our case and previous literatures suggest that hypertension caused by pheochromocytoma which is a rare but important and potentially lethal cause of hypertension in Turner syndrome. This case underlines the importance of early detection of pheochromocytoma in Turner syndrome. Clinicians should keep in mind that pheochromocytoma can be a cause of hypertension in patients with Turner syndrome.

The subclavius posticus muscle: an unusual cause of thoracic outlet syndrome.

PubMed

Smayra, T; Nabhane, L; Tabet, G; Menassa-Moussa, L; Hachem, K; Haddad-Zebouni, S

2014-09-01

We present the case of a 30-year-old female, complaining of thoracic outlet compression symptoms caused by a supernumerary muscle, the subclavius posticus, accompanied by a caudally inserted middle scalenus muscle on the second rib. This rare anatomic variant was clearly shown on CT angiography and MRI images and surgical treatment was successful. As first described by Rosenmuller in 1800, subclavius posticus is a supernumerary muscle originating from the cranial surface of the sternal end of the first rib, running laterodorsally beneath the clavicle, and inserting into the superior border of the scapula. Its role in thoracic outlet syndrome has been seldom demonstrated in living patients nor described in imaging, although it is theoretically easily recognizable on modern imaging modalities. It should be taken into account during workout of patients with thoracic outlet syndrome, since it can be potentially treated.

Red man syndrome caused by vancomycin powder.

PubMed

Nagahama, Yasunori; VanBeek, Marta J; Greenlee, Jeremy D W

2018-04-01

Red man syndrome (RMS) is a well-known hypersensitivity reaction caused by intravenous administration of vancomycin, with symptoms ranging from flushing, erythematous rash, pruritus, mild to profound hypotension, and even cardiac arrest. RMS has not previously been described from local application of vancomycin powder in a surgical wound, a technique increasingly utilized for infection prophylaxis in many surgical disciplines including neurosurgery. We describe the first reported case of RMS as a result of local intra-wound application of vancomycin powder for infection prophylaxis. A 73-year-old male with a history of Parkinson's disease underwent 2-stage deep brain stimulation implantation surgeries. Vancomycin powder was applied locally in the surgical wounds for infection prophylaxis during both of the surgeries. The patient developed a well-demarcated, geometric erythematous pruritic rash following the second surgery that was clinically diagnosed as RMS and resolved without sequelae. Copyright © 2018 Elsevier Ltd. All rights reserved.

[Paralysis, organic brain syndrome, and cardiac dysrhythmias caused by chronic laxative abuse (author's transl)].

PubMed

Dahlmann, W; Volles, E; Lüderitz, B

1977-10-28

A 39-year-old woman developed generalised paralysis, reversible organic brain syndrome, and cardiac dysrhythmias after 15 years of laxative abuse. Under continuous and cautious administration of potassium the cardiac rhythm became normal within four days and two days later the paralysis and organic brain syndrome almost disappeared. The cause of the psychiatric symptoms is thought to be cerebral potassium deficiency and an abnormal sodium/potassium equilibrium. Other clinical signs and symptoms due to extreme potassium depletion are presented. The importance of Na+/K+-activated membrane ATP-ase in myocardium and CNS is discussed.

An unusual craniofacial cleft: amniotic band syndrome as a possible cause.

PubMed

Eichhorn, Mitchell G; Iacobucci, John J; Turfe, Zaahir

2015-04-01

We report the case of a no. 4 Tessier cleft in association with an unknown cleft of the mandible extending to the external auditory meatus. This has not been previously published in the literature and its underlying pathology remains undetermined. The nature of the cleft, possible classifications, and potential embryologic origins will be discussed. Amniotic band syndrome is the most likely cause of the cleft. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Minimally Invasive Treatment of Mirizzi Syndrome, a Rare Cause of Cholestasis in Childhood

PubMed Central

Yilmaz, Sezgin; Yavuz, Mustafa; Çetinkurşun, Salih

2016-01-01

Mirizzi syndrome is the compressive blockage of the cystic or choledochal duct caused by a biliary stone occupying the cystic canal or Hartmann's pouch. This occurrence is rare and, in English literature, three cases defined in children have been observed. In order to draw attention to this rare occurrence, we preferred a 14-year-old male patient with Mirizzi syndrome. In this case, ERCP was performed preoperatively and the diagnosis was carried out with the help of clear visualisation and identification of the tissue structures as well as the stent placed in bile duct; so we protected the patient from the possible iatrogenic injury occurring during surgery. PMID:27843664

Budd-Chiari Syndrome Due to Protein C Deficiency: A Rare Disorder to cause Chronic Liver Disease.

PubMed

Begum, Rukshana; Mahtab, Mamun Al; Mamun, Ayub Al; Moben, Ahmed Lutful; Hossain, Sharker Mohammad Shahadat; Das, Dulal Chandra; Malakar, Debraj; Or Rashid, Harun; Roy, Partho Protim; Rahman, Salimur

2016-01-01

The Budd-Chiari syndrome (BCS) is a rare disorder due to chronic liver disease (CLD), which is caused by the obstruction of hepatic venous outflow that can be located at any place from the small hepatic venules up to the entrance of the inferior vena cava (IVC) into the right atrium. Among the causes of BCS, the rarer one is coagulation factor deficiencies. Here, we report a case of BCS associated with deficiency of protein C resulting in thrombus in IVC. The patient was a 50-year-old male, who had been suffering from recurrent abdominal and leg swelling for a long period of 7 years. He was evaluated thoroughly, and other causes of liver cirrhosis were excluded. Begum R, Al Mahtab M, Al Mamun A, Moben AL, Hossain SMS, Das DC, Malakar D, Rashid HO, Roy PP, Rahman S. Budd-Chiari Syndrome Due to Protein C Deficiency: A Rare Disorder to cause Chronic Liver Disease. Euroasian J Hepato-Gastroenterol 2016;6(2):194-197.

Genetics and Deafness: Implications for Education and Life Care of Deaf Students

ERIC Educational Resources Information Center

Schein, Jerome D.; Miller, Maurice H.

2008-01-01

The severity of deafness can obscure the presence of other disabilities that may accompany genetic anomalies, such as occur in Alport and Usher syndromes. Recent advances in genetics have heightened attention to various disabilities and dysfunctions that may coexist with deafness. Failure to recognize these additional disabilities when they occur…

Upper gastrointestinal bleeding caused by severe esophagitis: a unique clinical syndrome.

PubMed

Guntipalli, Prathima; Chason, Rebecca; Elliott, Alan; Rockey, Don C

2014-12-01

We have recognized a unique clinical syndrome in patients with upper gastrointestinal bleeding who are found to have severe esophagitis. We aimed to more clearly describe the clinical entity of upper gastrointestinal bleeding in patients with severe esophagitis. We conducted a retrospective matched case-control study designed to investigate clinical features in patients with carefully defined upper gastrointestinal bleeding and severe esophagitis. Patient data were captured prospectively via a Gastrointestinal Bleeding Healthcare Registry, which collects data on all patients admitted with gastrointestinal bleeding. Patients with endoscopically documented esophagitis (cases) were matched with randomly selected controls that had upper gastrointestinal bleeding caused by other lesions. Epidemiologic features in patients with esophagitis were similar to those with other causes of upper gastrointestinal bleeding. However, hematemesis was more common in patients with esophagitis 86% (102/119) than in controls 55% (196/357) (p < 0.0001), while melena was less common in patients with esophagitis 38% (45/119) than in controls 68% (244/357) (p < 0.0001). Additionally, the more severe the esophagitis, the more frequent was melena. Patients with esophagitis had less abnormal vital signs, lesser decreases in hematocrit, and lesser increases in BUN. Both pre- and postRockall scores were lower in patients with esophagitis compared with controls (p = 0.01, and p < 0.0001, respectively). Length of hospital stay (p = 0.002), rebleeding rate at 42 days (p = 0.0007), and mortality were less in patients with esophagitis than controls. Finally, analysis of patients with esophagitis and cirrhosis suggested that this group of patients had more severe bleeding than those without cirrhosis. We have described a unique clinical syndrome in patients with upper gastrointestinal bleeding who have erosive esophagitis. This syndrome is manifest by typical clinical features and is associated with

Borate transporter SLC4A11 mutations cause both Harboyan syndrome and non‐syndromic corneal endothelial dystrophy

PubMed Central

Desir, Julie; Moya, Graciela; Reish, Orit; Van Regemorter, Nicole; Deconinck, Hilde; David, Karen L; Meire, Françoise M; Abramowicz, Marc J

2007-01-01

Harboyan syndrome, or corneal dystrophy and perceptive deafness (CDPD), consists of congenital corneal endothelial dystrophy and progressive perceptive deafness, and is transmitted as an autosomal recessive trait. CDPD and autosomal recessive, non‐syndromic congenital hereditary endothelial corneal dystrophy (CHED2) both map at overlapping loci at 20p13, and mutations of SLC4A11 were reported recently in CHED2. A genotype study on six families with CDPD and on one family with either CHED or CDPD, from various ethnic backgrounds (in the seventh family, hearing loss could not be assessed because of the proband's young age), is reported here. Novel SLC4A11 mutations were found in all patients. Why some mutations cause hearing loss in addition to corneal dystrophy is presently unclear. These findings extend the implication of the SLC4A11 borate transporter beyond corneal dystrophy to perceptive deafness. PMID:17220209

YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.

PubMed

Gabriele, Michele; Vulto-van Silfhout, Anneke T; Germain, Pierre-Luc; Vitriolo, Alessandro; Kumar, Raman; Douglas, Evelyn; Haan, Eric; Kosaki, Kenjiro; Takenouchi, Toshiki; Rauch, Anita; Steindl, Katharina; Frengen, Eirik; Misceo, Doriana; Pedurupillay, Christeen Ramane J; Stromme, Petter; Rosenfeld, Jill A; Shao, Yunru; Craigen, William J; Schaaf, Christian P; Rodriguez-Buritica, David; Farach, Laura; Friedman, Jennifer; Thulin, Perla; McLean, Scott D; Nugent, Kimberly M; Morton, Jenny; Nicholl, Jillian; Andrieux, Joris; Stray-Pedersen, Asbjørg; Chambon, Pascal; Patrier, Sophie; Lynch, Sally A; Kjaergaard, Susanne; Tørring, Pernille M; Brasch-Andersen, Charlotte; Ronan, Anne; van Haeringen, Arie; Anderson, Peter J; Powis, Zöe; Brunner, Han G; Pfundt, Rolph; Schuurs-Hoeijmakers, Janneke H M; van Bon, Bregje W M; Lelieveld, Stefan; Gilissen, Christian; Nillesen, Willy M; Vissers, Lisenka E L M; Gecz, Jozef; Koolen, David A; Testa, Giuseppe; de Vries, Bert B A

2017-06-01

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Kabuki syndrome is not caused by a microdeletion in the DiGeorge/velocardiofacial chromosomal region within 22q11.2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, M.; Zackai, E.H.; Kaplan, P.

1996-10-16

Kabuki syndrome (KS) or Niikawa-Kuroki syndrome is a sporadic disorder characterized by postnatal growth retardation, developmental delay, mild to moderate retardation, and a characteristic facial appearance. Cardiovascular defects, clefts of the lip, palate, or both, and musculoskeletal abnormalities occur in about 50% of patients with KS. The cause of this multiple congenital anomaly syndrome is unknown, and investigators have speculated that KS is a contiguous gene-deletion syndrome. Based on the presence of congenital heart defects in patients with KS, it was suggested that this disorder might share a common cause with the 22q11 deletion syndromes. A preliminary study of 2more » patients with KS failed to detect a deletion within 22q11. We report the results of fluorescence in situ hybridization with cosmid probes for loci D22S75 (N25) and D22S259 (1132) within the DiGeorge chromosomal region (DGCR) on metaphase spreads from an additional 5 patients, 2 non-Japanese and 3 Japanese, with KS. None of the 5 had deletions at either locus. It is unlikely that KS is caused by a deletion within 22q11. 16 refs.« less

Genome Sequence of the Hemolytic-Uremic Syndrome-Causing Strain Escherichia coli NCCP15647

PubMed Central

Jeong, Haeyoung; Zhao, Fumei; Igori, Davaajargal; Oh, Kyung-Hwan; Kim, Seon-Young; Kang, Sung Gyun; Kim, Byung Kwon; Kwon, Soon-Kyeong; Lee, Choong Hoon; Song, Ju Yeon; Yu, Dong Su; Park, Mi-Sun

2012-01-01

Enterohemorrhagic Escherichia coli (EHEC) causes a disease involving diarrhea, hemorrhagic colitis, and hemolytic-uremic syndrome (HUS). Here we present the draft genome sequence of NCCP15647, an EHEC isolate from an HUS patient. Its genome exhibits features of EHEC, such as genes for verotoxins, a type III secretion system, and prophages. PMID:22740672

A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome.

PubMed

Clendenning, M; Senter, L; Hampel, H; Robinson, K Lagerstedt; Sun, S; Buchanan, D; Walsh, M D; Nilbert, M; Green, J; Potter, J; Lindblom, A; de la Chapelle, A

2008-06-01

When compared to the other mismatch repair genes involved in Lynch syndrome, the identification of mutations within PMS2 has been limited (<2% of all identified mutations), yet the immunohistochemical analysis of tumour samples indicates that approximately 5% of Lynch syndrome cases are caused by PMS2. This disparity is primarily due to complications in the study of this gene caused by interference from pseudogene sequences. Using a recently developed method for detecting PMS2 specific mutations, we have screened 99 patients who are likely candidates for PMS2 mutations based on immunohistochemical analysis. We have identified a frequently occurring frame-shift mutation (c.736_741del6ins11) in 12 ostensibly unrelated Lynch syndrome patients (20% of patients we have identified with a deleterious mutation in PMS2, n = 61). These individuals all display the rare allele (population frequency <0.05) at a single nucleotide polymorphism (SNP) in exon 11, and have been shown to possess a short common haplotype, allowing us to calculate that the mutation arose around 1625 years ago (65 generations; 95% confidence interval 22 to 120). Ancestral analysis indicates that this mutation is enriched in individuals with British and Swedish ancestry. We estimate that there are >10 000 carriers of this mutation in the USA alone. The identification of both the mutation and the common haplotype in one Swedish control sample (n = 225), along with evidence that Lynch syndrome associated cancers are rarer than expected in the probands' families, would suggest that this is a prevalent mutation with reduced penetrance.

Kindler syndrome causing severe cicatricial ectropion.

PubMed

Lelli, Gary J

2010-01-01

A 32-year-old female with Kindler syndrome presented with a 5-year history of lower eyelid malposition, corneal exposure, and recurrent erosions. Severe anterior lamellar cicatricial changes were noted bilaterally, with bilateral lower eyelid ectropion and retraction. Tarsal eversion was noted on the left lower eyelid. The patient had repeatedly failed conservative treatments for keratopathy and was treated surgically, with resolution of corneal disease and improved lower eyelid position. A review of Kindler syndrome is provided, geared toward the oculoplastic surgeon who may participate in the care of these patients.

What Causes Prader-Willi Syndrome?

MedlinePlus

... Browse AZTopics Browse A-Z Adrenal Gland Disorders Autism Spectrum Disorder (ASD) Down Syndrome Endometriosis Learning Disabilities Menstruation and ... NICHD Research Information Find a Study More Information Autism Spectrum Disorder (ASD) About NICHD Research Information Find a Study ...

Confirmation that RIPK4 mutations cause not only Bartsocas-Papas syndrome but also CHAND syndrome.

PubMed

Busa, Tiffany; Jeraiby, Mohammed; Clémenson, Alix; Manouvrier, Sylvie; Granados, Viviana; Philip, Nicole; Touraine, Renaud

2017-11-01

CHAND syndrome is an autosomal recessive disorder characterized by curly hair, ankyloblepharon, and nail dysplasia. Only few patients were reported to date. A homozygous RIPK4 mutation was recently identified by homozygosity mapping and whole exome sequencing in three patients from an expanded consanguineous kindred with a clinical diagnosis of CHAND syndrome. RIPK4 was previously known to be implicated in Bartsocas-Papas syndrome, the autosomal recessive form of popliteal pterygium syndrome. We report here two cases of RIPK4 homozygous mutations in a fetus with severe Bartsocas-Papas syndrome and a patient with CHAND syndrome. The patient with CHAND syndrome harbored the same mutation as the one identified in the family previously reported. We thus confirm the implication of RIPK4 gene in CHAND syndrome in addition to Bartsocas-Papas syndrome and discuss genotype/phenotype correlations. © 2017 Wiley Periodicals, Inc.

Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies.

PubMed

Belaya, Katsiaryna; Rodríguez Cruz, Pedro M; Liu, Wei Wei; Maxwell, Susan; McGowan, Simon; Farrugia, Maria E; Petty, Richard; Walls, Timothy J; Sedghi, Maryam; Basiri, Keivan; Yue, Wyatt W; Sarkozy, Anna; Bertoli, Marta; Pitt, Matthew; Kennett, Robin; Schaefer, Andrew; Bushby, Kate; Parton, Matt; Lochmüller, Hanns; Palace, Jacqueline; Muntoni, Francesco; Beeson, David

2015-09-01

Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected

Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies

PubMed Central

Belaya, Katsiaryna; Rodríguez Cruz, Pedro M.; Liu, Wei Wei; Maxwell, Susan; McGowan, Simon; Farrugia, Maria E.; Petty, Richard; Walls, Timothy J.; Sedghi, Maryam; Basiri, Keivan; Yue, Wyatt W.; Sarkozy, Anna; Bertoli, Marta; Pitt, Matthew; Kennett, Robin; Schaefer, Andrew; Bushby, Kate; Parton, Matt; Lochmüller, Hanns; Palace, Jacqueline; Muntoni, Francesco

2015-01-01

Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected

Schmidt's syndrome: a rare cause of puberty menorrhagia.

PubMed

Sharma, J B; Tiwari, S; Gulati, N; Sharma, S

1990-12-01

Schmidt's syndrome, also known as polyglandular deficiency syndrome, is the presence of Addison's disease and hypothyrodism in a single patient. It is usually associated with other autoimmune disorders like vitiligo, diabetes mellitus, myasthenia gravis. A rare case of an 18-year-old girl having Schmidt's syndrome and vitiligo who presented with puberty menorrhagia is reported. A brief review of the literature is also given.

[Hypogonadism caused by Gorlin-Goltz syndrome].

PubMed

Marín Romero, Olivia; Hernández Marín, Imelda; Ayala Ruiz, Aquiles R

2006-09-01

The Gorlin-Goltz syndrome is a dominant autosomic disorder characterized by cancerigenic predisposition and multiple development defects, apparently without reproductive compromise. The complex is characterized by four primary symptoms, which include nevoid basal cell epitheliomas malignantly prone, keratocystic jaw, skeletal abnormalities and intracranial calcifications. Apparently, reproductive problems reported had been rarely associated with this syndrome. We present the case of a patient with clinic stigmatae of Gorlin-Goltz syndrome, who had a characteristic progress as seen in the literature; he was the fifth product of a 43 year-old female (father was 48 years old); who at birth disclosed right eye microftalmy, bilateral cryptorchidism surgically treated at age of six. At puberty, an odontogenic cyst of the jaw was noted and enucleated. He also showed facial nevi in neck, thorax and abdomen. When he was admitted being 14 years old in our clinic, he had recurrent bilateral cryptorchidism, sexual immatturity and infertility. It is important to take into consideration Gorlin-Goltz stigmatae in cases of hypogonadism in order to recognize a further genetic influence.

Invasive liver abscess syndrome caused by Klebsiella pneumoniae with definite K2 serotyping in Japan: a case report.

PubMed

Seo, Ryota; Kudo, Daisuke; Gu, Yoshiaki; Yano, Hisakazu; Aoyagi, Tetsuji; Omura, Taku; Irino, Shigemi; Kaku, Mitsuo; Kushimoto, Shigeki

2016-12-01

Klebsiella pneumonia is a well-known human pathogen, and recently, a distinct invasive syndrome caused by K. pneumoniae serotypes K1 and K2 has been recognized in Southeast Asia. This syndrome is characterized by primary liver abscess and extrahepatic complications resulting from bacteremic dissemination. We report the first adult case of primary liver abscess caused by the definite K2 serotyped pathogen, with endogenous endophthalmitis in Japan. A 64-year-old woman was admitted to a nearby hospital for a high fever and diarrhea. She had visual loss of her right eye, renal dysfunction, and thrombocytopenia within 24 h from admission. She was transferred to our institution. On admission, she had no alteration of mental status and normal vital signs; however, she had almost complete ablepsia of the right eye. Laboratory data showed severe inflammation, liver dysfunction, thrombocytopenia, an increased serum creatinine level, and coagulopathy. Computed tomography showed a low density area in the right lobe of the liver. Invasive liver abscess syndrome probably caused by K. pneumonia was highly suspected and immediately administered broad-spectrum antibiotics for severe sepsis. Concurrently, endogenous endophthalmitis was diagnosed, and we performed vitrectomy on the day of admission. The blood culture showed K. pneumoniae infection. Percutaneous drainage of the liver abscess was also performed. Although she was discharged in a good general condition on day 22, she had complete ablepsia of the right eye. The K2A gene was detected by polymerase chain reaction (PCR), which is consistent with the K2 serotype. PCR was also positive for the virulence-associated gene rmpA. Final diagnosis was invasive liver abscess syndrome caused by K2 serotype K. pneumonia. Although the primary liver abscess caused by K. pneumoniae with a hypermucoviscous phenotype is infrequently reported outside Southeast Asia, physicians should recognize this syndrome, and appropriate diagnosis and

[Invasive infection caused Streptococcus group A and streptococcal toxic shock syndrome].

PubMed

Danilova, T A

2001-01-01

Modern data on the etiology and pathogenesis of invasive streptococcal infection and the syndrome of streptococcal toxic shock are presented. In the course of the last 10-15 years essential changes in the system of interaction of group A streptococci and the macroorganism have been noted. The growth of morbidity in severe invasive forms of streptococcal infection with different clinical manifestations, including the syndrome of toxic shock, is observed. Most often this disease develops in elderly people, making up a group of risk, but sometimes affects healthy young people. Different pathogenicity factors of streptococci, capable of inducing the development of infection, are analyzed. Special attention is given to superantigens: pyrogenic toxins and M-protein. The suggestion that the development of the disease is seemingly linked with the state of specific protective immunity is substantiated. In spite of achievements in the field of the microbiology and immunology of group A streptococci, the causes of the appearance and development of invasive streptococcal infection have not yet been determined.

What causes dryness in Sjögren's syndrome patients and how can it be targeted?

PubMed

Pflugfelder, Stephen C

2014-04-01

Concepts regarding what causes dryness in Sjögren's syndrome have evolved over the past decade. Inflammation in the lacrimal functional unit contributes to development of dry eye by causing dysfunction and even death of tear secreting epithelium in the lacrimal gland and conjunctiva that alters tear composition and stability. Disease-relevant inflammatory mediators have been identified and therapies targeting these mediators are beginning to emerge.

Antiphospholipid Syndrome with Antiβ2glicoprotein-1 Antibodies as the Cause of Recurrent Tibial Vein Thrombosis in SAPHO syndrome.

PubMed

Przepiera-Będzak, Hanna; Brzosko, Marek

2016-12-01

thrombosis in this syndrome, but the patient with multiple venous thrombosis presented in his case report was negative for aCL antibodies; however, he was not tested for anti-β2G-1 antibodies. There was a paper demonstrating increased level of aCL antibodies in 5 of 12 patients with SAPHO syndrome (11). In our observations of 17 patients with SAPHO syndrome, only 1 had increased level of aCL antibodies without symptoms of thrombosis (12). That patient was negative for aCL antibodies, aPT antibodies, aPS antibodies, and antiphosphatidylserine antibodies, but she was positive twice for anti-β2G-1 antibodies. The presence of anti-β2G-1antibodies may be caused by an infectious agent, but in our case bacteria culture of the discharge from pustules was negative. One year after the first episode of deep vein thrombosis, our patient met the criteria of antiphospholipid syndrome. We conclude that antiphospholipid syndrome, especially the presence of anti-β2G-1 antibodies, could be the cause of increased risk of vein thrombosis in SAPHO syndrome.

Identification of HIBCH gene mutations causing autosomal recessive Leigh syndrome: a gene involved in valine metabolism.

PubMed

Soler-Alfonso, Claudia; Enns, Gregory M; Koenig, Mary Kay; Saavedra, Heather; Bonfante-Mejia, Eliana; Northrup, Hope

2015-03-01

Leigh syndrome is a progressive neurodegenerative disorder with usual onset of symptoms during the first year of life. The disorder has been associated with mutations in over 30 genes. This difficulty with genetic heterogeneity makes whole exome sequencing a more cost-effective approach for investigation of etiology. We describe an individual with typical Leigh syndrome who was found to have compound heterozygous mutations in the gene HIBCH (3-hydroxyisobutyryl coenzyme A hydrolase), an enzyme involved in the catabolism of valine. She exhibited significant clinical improvement after a valine-restricted diet. A subset of patients with uncharacterized Leigh syndrome present with specific biochemical abnormalities. This report highpoints the challenges and restrictions of routine metabolic testing and features the recognition of inborn errors of metabolism as potential treatable causes of Leigh syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.

The Common Inversion of the Williams–Beuren Syndrome Region at 7q11.23 Does Not Cause Clinical Symptoms

PubMed Central

Tam, Elaine; Young, Edwin J.; Morris, Colleen A.; Marshall, Christian R.; Loo, Wayne; Scherer, Stephen W.; Mervis, Carolyn B.; Osborne, Lucy R.

2010-01-01

Williams–Beuren syndrome (WBS) is caused by a ~1.5 million base pair deletion at 7q11.23. A common inversion of the region, WBSinv-1, exists as a polymorphism but was also found in individuals with WBS-like features but no deletion, suggesting it could cause clinical symptoms. We performed a full clinical, developmental and genetic assessment of two previously reported individuals with clinical symptoms and WBSinv-1 but no 7q11.23 deletion. We also examined expression of genes at 7q11.23 in individuals in the general population who have WBSinv-1. We show that individuals with clinical symptoms and WBSinv-1 do not show significant clinical or psychological overlap with individuals with WBS. In addition, a 1.3 Mb duplication of part of the velocardiofacial syndrome region on chromosome 22q11.2 was found in one participant with WBSinv-1 and clinical symptoms. We also demonstrate that individuals with WBSinv-1 show normal expression of genes from the WBS region. These results suggest that WBSinv-1 does not cause clinical symptoms and we advise caution when diagnosing individuals with atypical presentation of rare syndromes. Whole genome analysis may reveal previously unidentified copy number variants that could contribute to syndromic features. PMID:18553513

Case Report: A Rare Cause of Complicated Urinary Tract Infection in a Woman with Herlyn-Werner-Wunderlich Syndrome.

PubMed

Tsai, Jun-Li; Tsai, Shang-Feng

2016-11-01

Urinary tract infection is a common disease in the general population. However, in patients with frequent urinary tract infection, it is important to determine any treatable cause to avoid recurrence. Herlyn-Werner-Wunderlich syndrome or OHVIRA syndrome is a very rare congenital anomaly with uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis. The earliest presentation of this syndrome is hematocolpos that develops during menstruation and results in dysmenorrhea and a pelvic mass shortly after menarche. Herein, we report a patient with Herlyn-Werner-Wunderlich syndrome manifested with unusual symptoms, delayed onset and without surgery. The unique point of this patient is the partial obstruction of cervico-vaginal junction. Early diagnosis and timely treatment of OHVIRA syndrome can prevent long-term complications, such as recurrent urinary tract infection and infertility. A high index of suspicion is required, even though OHVIRA syndrome is extremely rare and may have an atypical presentation.

Compound heterozygous PNPLA6 mutations cause Boucher-Neuhäuser syndrome with late-onset ataxia.

PubMed

Deik, A; Johannes, B; Rucker, J C; Sánchez, E; Brodie, S E; Deegan, E; Landy, K; Kajiwara, Y; Scelsa, S; Saunders-Pullman, R; Paisán-Ruiz, C

2014-12-01

PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.

Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome.

PubMed

Sousa, Sérgio B; Jenkins, Dagan; Chanudet, Estelle; Tasseva, Guergana; Ishida, Miho; Anderson, Glenn; Docker, James; Ryten, Mina; Sa, Joaquim; Saraiva, Jorge M; Barnicoat, Angela; Scott, Richard; Calder, Alistair; Wattanasirichaigoon, Duangrurdee; Chrzanowska, Krystyna; Simandlová, Martina; Van Maldergem, Lionel; Stanier, Philip; Beales, Philip L; Vance, Jean E; Moore, Gudrun E

2014-01-01

Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase 1 (PSS1). PSS1 is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS1. We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism.

Association of metabolic syndrome and its components with all-cause and cardiovascular mortality in the elderly: A meta-analysis of prospective cohort studies.

PubMed

Ju, Sang-Yhun; Lee, June-Young; Kim, Do-Hoon

2017-11-01

There is increasing evidence regarding the relationship between metabolic syndrome and mortality. However, previous research examining metabolic syndrome and mortality in older populations has produced mixed results. In addition, there is a clear need to identify and manage individual components of metabolic syndrome to decrease cardiovascular disease (CVD) mortality. In this meta-analysis, we searched the MEDLINE databases using PubMed, Cochrane Library, and EMBASE databases. Based on 20 prospective cohort studies, metabolic syndrome was associated with a higher risk of all-cause mortality [relative risk (RR), 1.23; 95% confidence interval (CI), 1.15-1.32; I = 55.9%] and CVD mortality (RR, 1.24; 95% CI, 1.11-1.39; I = 58.1%). The risk estimates of all-cause mortality for single components of metabolic syndrome were significant for higher values of waist circumference or body mass index (RR, 0.94; 95% CI, 0.88-1.00), higher values of blood glucose (RR, 1.19; 95% CI, 1.05-1.34), and lower values of high-density lipoprotein (HDL) cholesterol (RR, 1.11; 95% CI, 1.02-1.21). In the elderly population, metabolic syndrome was associated with an increased risk of all-cause and CVD mortality. Among the individual components of metabolic syndrome, increased blood glucose and HDL cholesterol levels were significantly associated with increased mortality. However, older obese or overweight individuals may have a decreased mortality risk. Thus, the findings of the current meta-analysis raise questions about the utility of the definition of metabolic syndrome in predicting all-cause mortality and CVD mortality in the elderly population.

[From gene to disease; genetic causes of hearing loss and visual impairment sometimes accompanied by vestibular problems (Usher syndrome)].

PubMed

Pennings, R J E; Kremer, H; Deutman, A F; Kimberling, W J; Cremers, C W R J

2002-12-07

Usher syndrome is an autosomal recessively inherited disease, characterised by sensorineural hearing loss, tapetoretinal degeneration and in some cases vestibular problems. Based on the clinical heterogeneity, the disease can be classified into three clinical types (I, II and III), which have their own genetic subtypes (Usher 1A-Usher IG, Usher 2A-Usher 2C and Usher 3). The majority of the Usher type I cases are caused by mutations in the MYO7A gene (Usher 1B) while mutations in the USH2A gene (Usher 2A) are the cause of most cases of type II. Usher syndrome type III, caused by mutations in the USH3 gene, is frequently seen only in Finland.

Ascending aortic aneurysm causing hoarse voice: a variant of Ortner's syndrome

PubMed Central

Eccles, Sinan Robert; Banks, John; Kumar, Pankaj

2012-01-01

A 68-year-old man with a persistent hoarse voice was found to have a left vocal cord paralysis. Clinical examination revealed signs consistent with aortic regurgitation. Subsequent investigation revealed an ascending aortic aneurysm. He underwent aortic root and ascending aorta replacement and his hoarseness improved. Ortner's syndrome refers to hoarseness due to recurrent laryngeal nerve palsy secondary to a cardiovascular abnormality. Recurrent laryngeal nerve palsy due to aneurysmal dilation of the ascending aorta is extremely rare, with aneurysms of the aortic arch being a more common cause. PMID:23060380

Neuroendocrine carcinoma of the ampulla of Vater causing ectopic adrenocorticotropic hormone-dependent Cushing's syndrome.

PubMed

Kato, Akihisa; Hayashi, Kazuki; Naitoh, Itaru; Seno, Kyoji; Okada, Yukiko; Ban, Tesshin; Kondo, Hiromu; Nishi, Yuji; Umemura, Shuichiro; Hori, Yasuki; Natsume, Makoto; Joh, Takashi

2016-07-01

Ectopic adrenocorticotropic hormone (ACTH) is rarely secreted by neuroendocrine tumors. Although neuroendocrine tumors may occur at any site in the gastrointestinal system, they very rarely occur in the ampulla of Vater and have a poor prognosis. The present study described the first Cushing's syndrome as a result of ectopic ACTH arising from the ampulla of Vater neuroendocrine carcinoma. A 69-year-old female was admitted with clinical features of Cushing's syndrome, confirmed biochemically by hypokalemia, and elevated levels of ACTH and cortisol. In further investigations, a tumor of the ampulla of Vater and liver metastases were detected. Pathological analysis of the biopsy confirmed a neuroendocrine carcinoma, which was immunohistochemically positive for chromogranin A, synaptophysin, cluster of differentiation 56 and ACTH. Therefore, the present study diagnosed a functional and metastatic neuroendocrine carcinoma of the ampulla of Vater with ectopic ACTH production causing Cushing's syndrome. The patient succumbed to mortality 4 months later, despite administration of combined chemotherapy with irinotecan and cisplatin.

Hepatitis E as a cause of acute jaundice syndrome in northern Uganda, 2010-2012.

PubMed

Gerbi, Gemechu B; Williams, Roxanne; Bakamutumaho, Barnabas; Liu, Stephen; Downing, Robert; Drobeniuc, Jan; Kamili, Saleem; Xu, Fujie; Holmberg, Scott D; Teshale, Eyasu H

2015-02-01

Hepatitis E virus (HEV) is a common cause of acute viral hepatitis in developing countries; however, its contribution to acute jaundice syndrome is not well-described. A large outbreak of hepatitis E occurred in northern Uganda from 2007 to 2009. In response to this outbreak, acute jaundice syndrome surveillance was established in 10 district healthcare facilities to determine the proportion of cases attributable to hepatitis E. Of 347 acute jaundice syndrome cases reported, the majority (42%) had hepatitis E followed by hepatitis B (14%), malaria (10%), hepatitis C (5%), and other/unknown (29%). Of hepatitis E cases, 72% occurred in Kaboong district, and 68% of these cases occurred between May and August of 2011. Residence in Kaabong district was independently associated with hepatitis E (adjusted odds ratio = 13; 95% confidence interval = 7-24). The findings from this surveillance show that an outbreak and sporadic transmission of hepatitis E occur in northern Uganda. © The American Society of Tropical Medicine and Hygiene.

[Long QT syndrome. History, genetics, clinical symptoms, causes and therapy].

PubMed

Krönauer, T; Friederich, P

2015-08-01

The long QT syndrome is caused by a change in cardiac repolarization due to functional ion channel defects. A differentiation is made between a congenital (cLQTS) and an acquired (aLQTS) form of the disease. The disease results in the name-giving prolongation of the QT interval in the electrocardiogram and represents a predisposition for cardiac arrhythmia and sudden cardiac death. This article summarizes the current knowledge on the history, pathophysiology, clinical symptoms and therapy of cLQTS and aLQTS. This knowledge of pathophysiological features of the symptoms allows the underlying anesthesiological approach for individualized perioperative concepts for patients suffering from LQTS to be derived.

Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome.

PubMed

Parvari, Ruti; Hershkovitz, Eli; Grossman, Nili; Gorodischer, Rafael; Loeys, Bart; Zecic, Alexandra; Mortier, Geert; Gregory, Simon; Sharony, Reuven; Kambouris, Marios; Sakati, Nadia; Meyer, Brian F; Al Aqeel, Aida I; Al Humaidan, Abdul Karim; Al Zanhrani, Fatma; Al Swaid, Abdulrahman; Al Othman, Johara; Diaz, George A; Weiner, Rory; Khan, K Tahseen S; Gordon, Ronald; Gelb, Bruce D

2002-11-01

The syndrome of congenital hypoparathyroidism, mental retardation, facial dysmorphism and extreme growth failure (HRD or Sanjad-Sakati syndrome; OMIM 241410) is an autosomal recessive disorder reported almost exclusively in Middle Eastern populations. A similar syndrome with the additional features of osteosclerosis and recurrent bacterial infections has been classified as autosomal recessive Kenny-Caffey syndrome (AR-KCS; OMIM 244460). Both traits have previously been mapped to chromosome 1q43-44 (refs 5,6) and, despite the observed clinical variability, share an ancestral haplotype, suggesting a common founder mutation. We describe refinement of the critical region to an interval of roughly 230 kb and identification of deletion and truncation mutations of TBCE in affected individuals. The gene TBCE encodes one of several chaperone proteins required for the proper folding of alpha-tubulin subunits and the formation of alpha-beta-tubulin heterodimers. Analysis of diseased fibroblasts and lymphoblastoid cells showed lower microtubule density at the microtubule-organizing center (MTOC) and perturbed microtubule polarity in diseased cells. Immunofluorescence and ultrastructural studies showed disturbances in subcellular organelles that require microtubules for membrane trafficking, such as the Golgi and late endosomal compartments. These findings demonstrate that HRD and AR-KCS are chaperone diseases caused by a genetic defect in the tubulin assembly pathway, and establish a potential connection between tubulin physiology and the development of the parathyroid.

Extreme sensitivity to ultraviolet light in the fungal pathogen causing white-nose syndrome of bats

Treesearch

Jonathan M. Palmer; Kevin P. Drees; Jeffrey T. Foster; Daniel L. Lindner

2018-01-01

Bat white-nose syndrome (WNS), caused by the fungal pathogen Pseudogymnoascus destructans, has decimated North American hibernating bats since its emergence in 2006. Here, we utilize comparative genomics to examine the evolutionary history of this pathogen in comparison to six closely related nonpathogenic species....

Catatonia in Down syndrome; a treatable cause of regression

PubMed Central

Ghaziuddin, Neera; Nassiri, Armin; Miles, Judith H

2015-01-01

Objective: The main aim of this case series report is to alert physicians to the occurrence of catatonia in Down syndrome (DS). A second aim is to stimulate the study of regression in DS and of catatonia. A subset of individuals with DS is noted to experience unexplained regression in behavior, mood, activities of daily living, motor activities, and intellectual functioning during adolescence or young adulthood. Depression, early onset Alzheimer’s, or just “the Down syndrome” are often blamed after general medical causes have been ruled out. Clinicians are generally unaware that catatonia, which can cause these symptoms, may occur in DS. Study design: Four DS adolescents who experienced regression are reported. Laboratory tests intended to rule out causes of motor and cognitive regression were within normal limits. Based on the presence of multiple motor disturbances (slowing and/or increased motor activity, grimacing, posturing), the individuals were diagnosed with unspecified catatonia and treated with anti-catatonic treatments (benzodiazepines and electroconvulsive therapy [ECT]). Results: All four cases were treated with a benzodiazepine combined with ECT and recovered their baseline functioning. Conclusion: We suspect catatonia is a common cause of unexplained deterioration in adolescents and young adults with DS. Moreover, pediatricians and others who care for individuals with DS are generally unfamiliar with the catatonia diagnosis outside schizophrenia, resulting in misdiagnosis and years of morbidity. Alerting physicians to catatonia in DS is essential to prompt diagnosis, appropriate treatment, and identification of the frequency and course of this disorder. PMID:25897230

Leigh syndrome caused by a novel m.4296G>A mutation in mitochondrial tRNA isoleucine.

PubMed

Cox, Rachel; Platt, Julia; Chen, Li Chieh; Tang, Sha; Wong, Lee-Jun; Enns, Gregory M

2012-03-01

Leigh syndrome is a severe neurodegenerative disease with heterogeneous genetic etiology. We report a novel m.4296G>A variant in the mitochondrial tRNA isoleucine gene in a child with Leigh syndrome, mitochondrial proliferation, lactic acidosis, and abnormal respiratory chain enzymology. The variant is present at >75% heteroplasmy in blood and cultured fibroblasts from the proband, <5% in asymptomatic maternal relatives, and is absent in 3000 controls. It is located in the highly conserved anticodon region of tRNA(Ile) where three other pathogenic changes have been described. We conclude that there is strong evidence to classify m.4296G>A as a pathogenic mutation causing Leigh syndrome. Copyright © 2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

Cerebral fat embolism syndrome causing brain death after long-bone fractures and acetazolamide therapy.

PubMed

Walshe, Criona M; Cooper, James D; Kossmann, Thomas; Hayes, Ivan; Iles, Linda

2007-06-01

A 19-year-old woman with multiple fractures and mild brain injury developed severe cerebral fat embolism syndrome after "damage control" orthopaedic surgery. Acetazolamide therapy to manage ocular trauma, in association with hyperchloraemia, caused a profound metabolic acidosis with appropriate compensatory hypocapnia. During ventilator weaning, unexpected brainstem coning followed increased sedation and brief normalisation of arterial carbon dioxide concentration. Autopsy found severe cerebral fat embolism and brain oedema. In patients with multiple trauma, cerebral fat embolism syndrome is difficult to diagnose, and may be more common after delayed fixation of long-bone fractures. Acetazolamide should be used with caution, as sudden restoration of normocapnia during compensated metabolic acidosis in patients with raised intracranial pressure may precipitate coning.

Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA).

PubMed

Horváth, R; Abicht, A; Holinski-Feder, E; Laner, A; Gempel, K; Prokisch, H; Lochmüller, H; Klopstock, T; Jaksch, M

2006-01-01

Detailed clinical, neuroradiological, histological, biochemical, and genetic investigations were undertaken in a child suffering from Leigh syndrome. The clinical symptoms started at age five months and led to a severe progressive neurodegenerative disorder causing epilepsy, psychomotor retardation, and tetraspasticity. Biochemical measurement of skeletal muscle showed a severe decrease in mitochondrial complex II. Sequencing of SDHA revealed compound heterozygosity for a nonsense mutation in exon 4 (W119X) and a missense mutation in exon 3 (A83V), both absent in normal controls. In six additional patients--five with Leigh or Leigh-like syndrome and one with neuropathy and ataxia associated with isolated deficiency of complex II--mutations in SDHA were not detected, indicating genetic heterogeneity.

Audiometry

MedlinePlus

... any cause. Common causes of hearing loss include: Acoustic trauma Chronic ear infections Diseases of the inner ... hearing. The following conditions may affect test results: Acoustic neuroma Acoustic trauma Age-related hearing loss Alport ...

Toxic Shock Syndrome

MedlinePlus

... toxic shock syndrome results from toxins produced by Staphylococcus aureus (staph) bacteria, but the condition may also be ... a skin or wound infection. Causes Most commonly, Staphylococcus aureus (staph) bacteria cause toxic shock syndrome. The syndrome ...

Subacute peripheral and optic neuropathy syndrome with no evidence of a toxic or nutritional cause.

PubMed

Allen, D; Riordan-Eva, P; Paterson, R W; Hadden, R D M

2013-08-01

The syndrome of subacute simultaneous peripheral neuropathy and bilateral optic neuropathy is known to occur in tropical countries, probably due to malnutrition or toxicity, but not often seen in developed countries. We report seven patients in London who were not malnourished or alcoholic, and in whom no clear cause was found. We retrospectively reviewed the case notes and arranged some further investigations. All patients developed peripheral and bilateral optic neuropathy within 6 months. Patients were aged 30-52, and all of Jamaican birth and race but lived in the UK. Most had subacute, painful ataxic sensory axonal neuropathy or neuronopathy, some with myelopathy. Nerve conduction studies revealed minor demyelinating features in two cases. The optic neuropathy was symmetrical, subacute and monophasic, usually with marked reduction in visual acuity. CSF protein concentration was usually elevated but other laboratory investigations were normal. Patients showed only modest improvement at follow-up. These patients share a common clinical and electrophysiological phenotype, age, ethnicity and elevated CSF protein, but otherwise normal laboratory investigations. The syndrome is a cause of significant morbidity in young people. The cause remains uncertain despite thorough investigation. Copyright © 2013 Elsevier B.V. All rights reserved.

Staphylococcal scalded skin syndrome in a premature newborn caused by methicillin-resistant Staphylococcus aureus: case report.

PubMed

Hörner, Andreas; Hörner, Rosmari; Salla, Adenilde; Nunes, Melise Silveira; Garzon, Litiérri Razia; Rampelotto, Roberta Filipini; Martini, Rosiéli; Santos, Silvana Oliveira dos; Gindri, Lívia; Rodrigues, Mônica de Abreu; Giacomolli, Cláudia

2015-01-01

Staphylococcal scalded skin syndrome is an exfoliative skin disease. Reports of this syndrome in newborns caused by methicillin-resistant Staphylococcus aureus are rare but, when present, rapid diagnosis and treatment is required in order to decrease morbidity and mortality. A premature newly born girl weighing 1,520 g, born with a gestational age of 29 weeks and 4 days, developed staphylococcal scalded skin syndrome on the fifth day of life. Cultures on blood samples collected on the first and fourth days were negative, but Pseudomonas aeruginosa and Enterococcus sp. (vancomycin-sensitive) developed in blood cultures performed on the day of death (seventh day), and Pseudomonas aeruginosa and Serratia marcescens were identified in cultures on nasopharyngeal, buttock and abdominal secretions. In addition to these two Gram-negative bacilli, methicillin-resistant Staphylococcus aureus was isolated in a culture on the umbilical stump (seventh day). The diagnosis of staphylococcal scalded skin syndrome was based on clinical criteria.

Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation

PubMed Central

Nelson-Williams, Carol; Stiegler, Amy L; Loring, Erin; Choi, Murim; Overton, John; Meffre, Eric; Khokha, Mustafa K; Huttner, Anita J; West, Brian; Podoltsev, Nikolai A; Boggon, Titus J; Kazmierczak, Barbara I; Lifton, Richard P

2014-01-01

Upon detection of pathogen-associated molecular patterns, innate immune receptors initiate inflammatory responses. These receptors include cytoplasmic NOD-like receptors (NLRs), whose stimulation recruits and proteolytically activates caspase-1 within the inflammasome, a multi-protein complex. Caspase-1 mediates the production of interleukin-1 family cytokines (IL1FCs), leading to fever, and inflammatory cell death (pyroptosis)1,2. Mutations that constitutively activate these pathways underlie several autoinflammatory diseases with diverse clinical features3. We describe a family with a previously unreported syndrome featuring neonatal-onset enterocolitis, periodic fever, and fatal/near-fatal episodes of autoinflammation caused by a de novo gain-of-function mutation (p.V341A) in the HD1 domain of NLRC4 that co-segregates with disease. Mutant NLRC4 causes constitutive Interleukin-1 family cytokine production and macrophage cell death. Infected patient macrophages are polarized toward pyroptosis and exhibit abnormal staining for inflammasome components. These findings describe and reveal the cause of a life-threatening but treatable autoinflammatory disease that underscores the divergent roles of the NLRC4 inflammasome. PMID:25217960

Coracoid syndrome: a neglected cause of anterior shoulder pain.

PubMed

Gigante, Antonio; Bottegoni, Carlo; Barbadoro, Pamela

2016-01-01

the present prospective open-label study was designed to gain further insights into a condition thought to constitute a neglected but not uncommon syndrome characterized by anterior shoulder pain and tenderness to palpation over the apex of the coracoid process, not related to rotator cuff or pectoralis minor tendinopathy, long head of the biceps tendon disorders, or instability. The aim was to clarify its prevalence, clinical characteristics, differential diagnosis and response to corticosteroid injections. patients with primary anterior shoulder pain precisely reproduced by deep pressure on the apex of the coracoid process were recruited. Patients with clinical or instrumental signs of other shoulder disorders were excluded. Patients were given an injection of triamcinolone acetonide 40 mg/ml 1 ml at the coracoid trigger point. They were evaluated after 15, 30 and 60 days and at 2 years using Equal Visual Analog Scale (EQ-VAS) and the Italian version of the Simple Shoulder Test (SST). between January 1 and December 31 2010, we treated 15 patients aged 26-66 years. The majority were women (86.67%). At 15 days, 6 (40%) patients reported complete resolution of their symptoms, while 9 (60%) complained of residual symptoms and received another injection. At 30 days, 14 (93.33%) patients were pain-free and very satisfied. At 2 years, the 14 patients who had been asymptomatic at 30 days reported that they had experienced no further pain or impaired shoulder function. The analysis of variance for repeated measures showed a significant effect of time on EQ-VAS and SST scores. the present study documents the existence, and characteristics, of a "coracoid syndrome" characterized by anterior shoulder pain and tenderness to palpation over the apex of the coracoid process and showed that the pain is usually amenable to steroid treatment. This syndrome should be clearly distinguished from anterior shoulder pain due to other causes, in order to avoid inappropriate conservative

A Novel Mutation in ERCC8 Gene Causing Cockayne Syndrome

PubMed Central

Taghdiri, Maryam; Dastsooz, Hassan; Fardaei, Majid; Mohammadi, Sanaz; Farazi Fard, Mohammad Ali; Faghihi, Mohammad Ali

2017-01-01

Cockayne syndrome (CS) is a rare autosomal recessive multisystem disorder characterized by impaired neurological and sensory functions, cachectic dwarfism, microcephaly, and photosensitivity. This syndrome shows a variable age of onset and rate of progression, and its phenotypic spectrum include a wide range of severity. Due to the progressive nature of this disorder, diagnosis can be more important when additional signs and symptoms appear gradually and become steadily worse over time. Therefore, mutation analysis of genes involved in CS pathogenesis can be helpful to confirm the suspected clinical diagnosis. Here, we report a novel mutation in ERCC8 gene in a 16-year-old boy who suffers from poor weight gain, short stature, microcephaly, intellectual disability, and photosensitivity. The patient was born to consanguineous family with no previous documented disease in his parents. To identify disease-causing mutation in the patient, whole exome sequencing utilizing next-generation sequencing on an Illumina HiSeq 2000 platform was performed. Results revealed a novel homozygote mutation in ERCC8 gene (NM_000082: exon 11, c.1122G>C) in our patient. Another gene (ERCC6), which is also involved in CS did not have any disease-causing mutations in the proband. The new identified mutation was then confirmed by Sanger sequencing in the proband, his parents, and extended family members, confirming co-segregation with the disease. In addition, different bioinformatics programs which included MutationTaster, I-Mutant v2.0, NNSplice, Combined Annotation Dependent Depletion, The PhastCons, Genomic Evolutationary Rate Profiling conservation score, and T-Coffee Multiple Sequence Alignment predicted the pathogenicity of the mutation. Our study identified a rare novel mutation in ERCC8 gene and help to provide accurate genetic counseling and prenatal diagnosis to minimize new affected individuals in this family. PMID:28848724

A Novel Mutation in ERCC8 Gene Causing Cockayne Syndrome.

PubMed

Taghdiri, Maryam; Dastsooz, Hassan; Fardaei, Majid; Mohammadi, Sanaz; Farazi Fard, Mohammad Ali; Faghihi, Mohammad Ali

2017-01-01

Cockayne syndrome (CS) is a rare autosomal recessive multisystem disorder characterized by impaired neurological and sensory functions, cachectic dwarfism, microcephaly, and photosensitivity. This syndrome shows a variable age of onset and rate of progression, and its phenotypic spectrum include a wide range of severity. Due to the progressive nature of this disorder, diagnosis can be more important when additional signs and symptoms appear gradually and become steadily worse over time. Therefore, mutation analysis of genes involved in CS pathogenesis can be helpful to confirm the suspected clinical diagnosis. Here, we report a novel mutation in ERCC8 gene in a 16-year-old boy who suffers from poor weight gain, short stature, microcephaly, intellectual disability, and photosensitivity. The patient was born to consanguineous family with no previous documented disease in his parents. To identify disease-causing mutation in the patient, whole exome sequencing utilizing next-generation sequencing on an Illumina HiSeq 2000 platform was performed. Results revealed a novel homozygote mutation in ERCC8 gene (NM_000082: exon 11, c.1122G>C) in our patient. Another gene ( ERCC6 ), which is also involved in CS did not have any disease-causing mutations in the proband. The new identified mutation was then confirmed by Sanger sequencing in the proband, his parents, and extended family members, confirming co-segregation with the disease. In addition, different bioinformatics programs which included MutationTaster, I-Mutant v2.0, NNSplice, Combined Annotation Dependent Depletion, The PhastCons, Genomic Evolutationary Rate Profiling conservation score, and T-Coffee Multiple Sequence Alignment predicted the pathogenicity of the mutation. Our study identified a rare novel mutation in ERCC8 gene and help to provide accurate genetic counseling and prenatal diagnosis to minimize new affected individuals in this family.

GPR98 mutations cause Usher syndrome type 2 in males.

PubMed

Ebermann, I; Wiesen, M H J; Zrenner, E; Lopez, I; Pigeon, R; Kohl, S; Löwenheim, H; Koenekoop, R K; Bolz, H J

2009-04-01

Mutations in the large GPR98 gene underlie Usher syndrome type 2C (USH2C), and all patients described to date have been female. It was speculated that GPR98 mutations cause a more severe, and eventually lethal, phenotype in males. We describe for the first time two male patients with USH2 with novel GPR98 mutations. Clinical characterization of a male patient and his affected sister revealed a typical USH2 phenotype in both. GPR98 may have been excluded from systematic investigation in previous studies, and the proportion of patients with USH2C probably underestimated. GPR98 should be considered in patients with USH2 of both sexes.

HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease

PubMed Central

Chen, Zhiyong; Migeon, Tiffany; Verpont, Marie-Christine; Zaidan, Mohamad; Sado, Yoshikazu; Kerjaschki, Dontscho; Ronco, Pierre

2016-01-01

Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the α1 chain of collagen IV, a major component of basement membranes. Patients present with cerebral small vessel disease, retinal tortuosity, muscle cramps, and kidney disease consisting of multiple renal cysts, chronic kidney failure, and sometimes hematuria. Mutations producing HANAC syndrome localize within the integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To investigate the pathophysiology of HANAC syndrome, we generated mice harboring the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1 G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation without reduction of nephron number, causing albuminuria and hematuria in newborns. The glomerular defects resolved within the first month, but glomerular cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman’s capsule was associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells that abnormally expressed CD44, α-SMA, ILK, and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles. Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and urinary concentration defects. These results reveal a developmental role for the α1α1α2 collagen IV molecule in the embryonic glomerular basement membrane, affecting podocyte differentiation. The observed association between molecular alteration of the collagenous network in Bowman’s capsule of the mature kidney and activation of parietal epithelial cells, matrix remodeling, and inflammation may account for glomerular cyst development and CKD in patients with COL4A1-related disorders. PMID:26260163

HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease.

PubMed

Chen, Zhiyong; Migeon, Tiffany; Verpont, Marie-Christine; Zaidan, Mohamad; Sado, Yoshikazu; Kerjaschki, Dontscho; Ronco, Pierre; Plaisier, Emmanuelle

2016-04-01

Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the α1 chain of collagen IV, a major component of basement membranes. Patients present with cerebral small vessel disease, retinal tortuosity, muscle cramps, and kidney disease consisting of multiple renal cysts, chronic kidney failure, and sometimes hematuria. Mutations producing HANAC syndrome localize within the integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To investigate the pathophysiology of HANAC syndrome, we generated mice harboring the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1 G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation without reduction of nephron number, causing albuminuria and hematuria in newborns. The glomerular defects resolved within the first month, but glomerular cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman's capsule was associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells that abnormally expressed CD44,α-SMA, ILK, and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles. Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and urinary concentration defects. These results reveal a developmental role for the α1α1α2 collagen IV molecule in the embryonic glomerular basement membrane, affecting podocyte differentiation. The observed association between molecular alteration of the collagenous network in Bowman's capsule of the mature kidney and activation of parietal epithelial cells, matrix remodeling, and inflammation may account for glomerular cyst development and CKD in patients with COL4A1-related disorders. Copyright © 2016 by the American Society of Nephrology.

Stent Implantation for Superior Vena Cava Syndrome of Malignant Cause.

PubMed

Büstgens, Felix A; Loose, Reinhard; Ficker, Joachim H; Wucherer, Michael; Uder, Michael; Adamus, Ralf

2017-05-01

Purpose  The purpose of this paper is the retrospective analysis of endovascular therapy for the treatment of superior vena cava syndrome (SVCS) of malignant cause. This study focuses on the effectiveness of the therapy regarding the duration of remission, symptom control and practicability. Materials and Methods  From January 2003 to November 2012, therapeutic implantation of one or more stents was performed in 141 patients suffering from SVCS. The medical history was retrospectively researched using digitalized patient files. If those were incomplete, secondary research was conducted using the cancer registry of the General Hospital Nuremberg, the cancer registry of the tumor center at Friedrich-Alexander-University Erlangen-Nuremberg (FAU) or information given by physicians in private practice. This data was collected using Microsoft Office Excel ® and statistically analyzed using IBM SPSS Statistics 22 ® . Results  168 stents were implanted in 141 patients (median age: 64.6 years; range: 36 - 84), 86 being male and 55 being female. In 121 patients, SVCS was caused by lung cancer (85.8 %), in 9 patients by mediastinal metastasis of an extrathoracic carcinoma (6.4 %), in 3 patients by mesothelioma of the pleura (2.1 %) and in 1 patient by Hodgkin's disease (0.7 %). There was no histological diagnosis in 7 cases (4.9 %). The primary intervention was successful in 138 patients (97.9 %). Immediate thrombosis in the stent occurred in the remaining 3 cases. Recurrence of SVCS was observed in 22 patients (15.6 %), including 5 early and 17 late occlusions. Stent dislocation or breakage was not observed. As expected, the survival after implantation was poor. The median survival was 101 days, and the median occlusion-free survival was 80 days. Conclusion  The symptomatic therapy of SVCS with endovascular stents is effective and safe. Despite effective symptom control and a low rate of recurrence, the patients' prognosis is poor. Key

Cushing syndrome

MedlinePlus

Hypercortisolism; Cortisol excess; Glucocorticoid excess - Cushing syndrome ... The most common cause of Cushing syndrome is taking too much ... Cushing syndrome . Prednisone, dexamethasone, and prednisolone ...

[Epigenome: what we learned from Rett syndrome, a neurological disease caused by mutation of a methyl-CpG binding protein].

PubMed

Kubota, Takeo

2013-01-01

Epigenome is defined as DNA and histone modification-dependent gene regulation system. Abnormalities in this system are known to cause various neuro-developmental diseases. We recently reported that neurological symptoms of Rett syndrome, which is an autistic disorder caused by mutations in methyl-CpG binding protein 2 (MeCP2), was associated with failure of epigenomic gene regulation in neuronal cells, and that clinical differences in the identical twins with Rett syndrome in the differences in DNA methylation in neuronal genes, but not caused by DNA sequence differences. Since central nervus system requires precise gene regulation, neurological diseases including Alzheimer and Parkinson diseases may be caused by acquired DNA modification (epigenomic) changes that results in aberrant gene regulation as well as DNA sequence changes congenitally occurred (mutation).

Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations

PubMed Central

Ockeloen, Charlotte W; Willemsen, Marjolein H; de Munnik, Sonja; van Bon, Bregje WM; de Leeuw, Nicole; Verrips, Aad; Kant, Sarina G; Jones, Elizabeth A; Brunner, Han G; van Loon, Rosa LE; Smeets, Eric EJ; van Haelst, Mieke M; van Haaften, Gijs; Nordgren, Ann; Malmgren, Helena; Grigelioniene, Giedre; Vermeer, Sascha; Louro, Pedro; Ramos, Lina; Maal, Thomas JJ; van Heumen, Celeste C; Yntema, Helger G; Carels, Carine EL; Kleefstra, Tjitske

2015-01-01

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases. PMID:25424714

Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations.

PubMed

Ockeloen, Charlotte W; Willemsen, Marjolein H; de Munnik, Sonja; van Bon, Bregje W M; de Leeuw, Nicole; Verrips, Aad; Kant, Sarina G; Jones, Elizabeth A; Brunner, Han G; van Loon, Rosa L E; Smeets, Eric E J; van Haelst, Mieke M; van Haaften, Gijs; Nordgren, Ann; Malmgren, Helena; Grigelioniene, Giedre; Vermeer, Sascha; Louro, Pedro; Ramos, Lina; Maal, Thomas J J; van Heumen, Celeste C; Yntema, Helger G; Carels, Carine E L; Kleefstra, Tjitske

2015-09-01

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.

[Neurological syndromes linked with the intake of plants and fungi containing a toxic component (I). Neurotoxic syndromes caused by the ingestion of plants, seeds and fruits].

PubMed

Carod-Artal, F J

A wide range of plants, seeds and fruits used for nutritional and medicinal purposes can give rise to neurotoxic symptoms. We review the neurological pathology associated with the acute or chronic consumption of plants, seeds and fruits in human beings and in animals. Of the plants that can trigger acute neurotoxic syndromes in humans, some of the most notable include Mandragora officinalis, Datura stramonium, Conium maculatum (hemlock), Coriaria myrtifolia (redoul), Ricinus communis, Gloriosa superba, Catharanthus roseus, Karwinskia humboldtiana and Podophyllum pelatum. We also survey different neurological syndromes linked with the ingestion of vegetable foodstuffs that are rich in cyanogenic glycosides, Jamaican vomiting sickness caused by Blighia sapida, Parkinson dementia ALS of Guam island and exposition to Cycas circinalis, Guadeloupean parkinsonism and exposition to Annonaceae, konzo caused by ingestion of wild manioc and neurolathyrism from ingestion of Lathyrus sativus, the last two being models of motor neurone disease. Locoism is a chronic disease that develops in livestock feeding on plants belonging to Astragalus and Oxytropis sp., Sida carpinifolia and Ipomea carnea, which are rich in swainsonine, a toxin that inhibits the enzyme alpha mannosidase and induces a cerebellar syndrome. The ingestion of neurotoxic seeds, fruits and plants included in the diet and acute poisoning by certain plants can give rise to different neurological syndromes, some of which are irreversible.

Triple X Syndrome: Symptoms and Causes

MedlinePlus

... be more pronounced — possibly including developmental delays and learning disabilities. Treatment for triple X syndrome depends on which ... motor skills, such as sitting up and walking Learning disabilities, such as difficulty with reading (dyslexia), understanding or ...

Macroscopic hematuria caused by congenital portosystemic shunt and concomitant nutcracker syndrome.

PubMed

Lee, Sang Hyub; Lee, Dong-Gi

2015-06-01

Nutcracker syndrome (NCS) is an uncommon vascular abnormality that causes a variety of symptoms that range from asymptomatic microscopic hematuria to severe pelvic congestion. Congenital portosystemic shunt (CPSS) is an extremely rare anomaly that causes serious complications. Many cases of NCS and CPSS that have presented separately have been reported, but no cases of concomitant NCS and CPSS have been reported. We present a case of intermittent macroscopic hematuria in a patient with both NCS and CPSS. We diagnosed NCS on pressure gradient between the left renal vein (LRV) and the inferior vena cava. The presence of CPSS, which emerged from the LRV and connected to the extrahepatic portal vein, was confirmed on computed tomography. The interaction between NCS and CPSS resulted in mild intermittent macroscopic hematuria only, rather than the more common symptoms that occur when NCS or CPSS present separately. © 2015 Japan Pediatric Society.

Burning Mouth Syndrome and "Burning Mouth Syndrome".

PubMed

Rifkind, Jacob Bernard

2016-03-01

Burning mouth syndrome is distressing to both the patient and practitioner unable to determine the cause of the patient's symptoms. Burning mouth syndrome is a diagnosis of exclusion, which is used only after nutritional deficiencies, mucosal disease, fungal infections, hormonal disturbances and contact stomatitis have been ruled out. This article will explore the many causes and treatment of patients who present with a chief complaint of "my mouth burns," including symptomatic treatment for those with burning mouth syndrome.

A Very Rare Cause of Anal Atresia: Currarino Syndrome

PubMed Central

Buyukbese Sarsu, Sevgi; Parmaksiz, Mehmet Ergun; Cabalar, Esra; Karapur, Ali; Kaya, Cihat

2016-01-01

Currarino syndrome (triad) is an extremely rare condition characterized by presacral mass, anorectal malformation, and sacral bone deformation. The complete form of this syndrome displays all three irregularities. Herein, we report a male case who was admitted to our hospital with symptoms of urinary system infection and persistent constipation 2 years after colostomy operation performed with the indication of rectovestibular fistula and anal atresia, diagnosed as Currarino syndrome based on imaging modalities. In a patient who was admitted because of the presence of anal atresia, in order to preclude potential complications, probable concomitancy of this syndrome should not be forgotten. Early diagnosis is important for the prevention of meningitis, urinary tract infections, and malignant change. PMID:27081429

Usher Syndrome

MedlinePlus

Usher syndrome is an inherited disease that causes serious hearing loss and retinitis pigmentosa, an eye disorder that causes ... and vision. There are three types of Usher syndrome: People with type I are deaf from birth ...

Noonan Syndrome: An Underestimated Cause of Severe to Profound Sensorineural Hearing Impairment. Which Clues to Suspect the Diagnosis?

PubMed

Ziegler, Alban; Loundon, Natalie; Jonard, Laurence; Cavé, Hélène; Baujat, Geneviève; Gherbi, Souad; Couloigner, Vincent; Marlin, Sandrine

2017-09-01

To highlight Noonan syndrome as a clinically recognizable cause of severe to profound sensorineural hearing impairment. New clinical cases and review. Patients evaluated for etiological diagnosis by a medical geneticist in a reference center for hearing impairment. Five patients presenting with confirmed Noonan syndrome and profound sensorineural hearing impairment. Diagnostic and review of the literature. Five patients presented with profound sensorineural hearing impairment and molecularly confirmed Noonan syndrome. Sensorineural hearing impairment has been progressive for three patients. Cardiac echography identified pulmonary stenosis in two patients and was normal for the three other patients. Short stature was found in two patients. Mild intellectual disability was found in one patient. Inconspicuous clinical features as facial dysmorphism, cryptorchidism, or easy bruising were of peculiar interest to reach the diagnosis of Noonan syndrome. Profound sensorineural hearing impairment can be the main feature of Noonan syndrome. Associated features are highly variable; thus, detailed medical history and careful physical examination are mandatory to consider the diagnosis in case of a sensorineural hearing impairment.

Elsberg syndrome: A rarely recognized cause of cauda equina syndrome and lower thoracic myelitis.

PubMed

Savoldi, Filippo; Kaufmann, Timothy J; Flanagan, Eoin P; Toledano, Michel; Weinshenker, Brian G

2017-07-01

Elsberg syndrome (ES) is an established but often unrecognized cause of acute lumbosacral radiculitis with myelitis related to recent herpes virus infection. We defined ES, determined its frequency in patients with cauda equina syndrome (CES) with myelitis, and evaluated its clinical, radiologic, and microbiologic features and outcomes. We searched the Mayo Clinic medical records for ES and subsequently for combinations of index terms to identify patients with suspected CES and myelitis. Our search yielded 30 patients, 2 diagnosed with ES and an additional 28 with clinical or radiologic evidence of CES retrospectively suspected of having ES. We classified patients in 5 groups according to diagnostic certainty. MRI and EMG confirmed that 2 had only myelitis, 5 only radiculitis, and 16 both. Two had preceding sacral herpes infection and 1 oral herpes simplex. Spinal cord lesions were commonly multiple, discontinuous, not expansile, and centrally or ventrally positioned. Lesions generally spared the distal conus. Nerve root enhancement was occasionally prominent and was smooth rather than nodular. Lymphocytic CSF pleocytosis was common. Thirteen patients (43%) had viral isolation studies, which were commonly delayed; the delay may have accounted for the low rate of viral detection. Acyclovir was administered to 6 patients. Most patients recovered with sequelae; 1 patient experienced encephalomyelitis and died. ES is a definable condition likely responsible for 10% of patients with combined CES and myelitis. Radiologic findings are not entirely specific but may help in differentiating ES from some competing diagnostic considerations. We propose criteria to facilitate diagnosis.

When the face says it all: dysmorphology in identifying syndromic causes of epilepsy.

PubMed

Dixit, Abhijit; Suri, Mohnish

2016-04-01

Identifying the underlying cause of epilepsy often helps in choosing the appropriate management, suggests the long-term prognosis and clarifies the risk of the same condition in relatives. Epilepsy has many causes and a small but significant proportion of affected people have an identifiable genetic cause. Here, we discuss the role of genetic testing in adults with epilepsy, focusing on dysmorphic features noticeable on physical examination that might provide a strong clue to a specific genetic syndrome. We give illustrative examples of recognisable facial 'gestalt'. An astute clinician can recognise such clues and significantly shorten the process of making the underlying diagnosis in their patient. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Hepatitis E as a Cause of Acute Jaundice Syndrome in Northern Uganda, 2010–2012

PubMed Central

Gerbi, Gemechu B.; Williams, Roxanne; Bakamutumaho, Barnabas; Liu, Stephen; Downing, Robert; Drobeniuc, Jan; Kamili, Saleem; Xu, Fujie; Holmberg, Scott D.; Teshale, Eyasu H.

2015-01-01

Hepatitis E virus (HEV) is a common cause of acute viral hepatitis in developing countries; however, its contribution to acute jaundice syndrome is not well-described. A large outbreak of hepatitis E occurred in northern Uganda from 2007 to 2009. In response to this outbreak, acute jaundice syndrome surveillance was established in 10 district healthcare facilities to determine the proportion of cases attributable to hepatitis E. Of 347 acute jaundice syndrome cases reported, the majority (42%) had hepatitis E followed by hepatitis B (14%), malaria (10%), hepatitis C (5%), and other/unknown (29%). Of hepatitis E cases, 72% occurred in Kaboong district, and 68% of these cases occurred between May and August of 2011. Residence in Kaabong district was independently associated with hepatitis E (adjusted odds ratio = 13; 95% confidence interval = 7–24). The findings from this surveillance show that an outbreak and sporadic transmission of hepatitis E occur in northern Uganda. PMID:25448237

Malabsorption Syndromes

MedlinePlus

... foods you eat. If you have a malabsorption syndrome, your small intestine cannot absorb nutrients from foods. Causes of malabsorption syndromes include Celiac disease Lactose intolerance Short bowel syndrome. ...

Malformation syndromes caused by disorders of cholesterol synthesis

PubMed Central

Porter, Forbes D.; Herman, Gail E.

2011-01-01

Cholesterol homeostasis is critical for normal growth and development. In addition to being a major membrane lipid, cholesterol has multiple biological functions. These roles include being a precursor molecule for the synthesis of steroid hormones, neuroactive steroids, oxysterols, and bile acids. Cholesterol is also essential for the proper maturation and signaling of hedgehog proteins, and thus cholesterol is critical for embryonic development. After birth, most tissues can obtain cholesterol from either endogenous synthesis or exogenous dietary sources, but prior to birth, the human fetal tissues are dependent on endogenous synthesis. Due to the blood-brain barrier, brain tissue cannot utilize dietary or peripherally produced cholesterol. Generally, inborn errors of cholesterol synthesis lead to both a deficiency of cholesterol and increased levels of potentially bioactive or toxic precursor sterols. Over the past couple of decades, a number of human malformation syndromes have been shown to be due to inborn errors of cholesterol synthesis. Herein, we will review clinical and basic science aspects of Smith-Lemli-Opitz syndrome, desmosterolosis, lathosterolosis, HEM dysplasia, X-linked dominant chondrodysplasia punctata, Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects Syndrome, sterol-C-4 methyloxidase-like deficiency, and Antley-Bixler syndrome. PMID:20929975

Classic Bartter syndrome: a rare cause of failure to thrive in a child.

PubMed

Vieira, Helena; Mendes, Leonor; Mendes, Patricia; da Silva, José Esteves

2012-06-28

Bartter syndrome is a group of rare autosomal-recessive disorders caused by a defect in distal tubule transport of sodium and chloride. Blood gases and plasma electrolytes raise suspicion of this diagnosis and the definitive diagnosis is made by genetic study. Early treatment improves prognosis. The authors present the case of an 11-month-old child with early failure to thrive and severe regurgitation. Blood gases revealed hypochloraemic metabolic alkalosis, hyponatraemia and hypokalaemia. Blood pressure was normal and polyuria was documented. She began therapy with potassium chloride supplementation and indomethacin. There was clinical improvement and plasma potassium and bicarbonate normalised. The molecular study confirmed it was the classic form of Bartter syndrome. Despite being rare in clinical practice, which may lead to unnecessary medical investigation and diagnosis delay, in a child with failure to thrive, hypochloraemic metabolic alkalosis and hypokalaemia, this diagnosis must be considered.

Classic Bartter syndrome: a rare cause of failure to thrive in a child

PubMed Central

Vieira, Helena; Mendes, Leonor; Mendes, Patricia; da Silva, José Esteves

2012-01-01

Bartter syndrome is a group of rare autosomal-recessive disorders caused by a defect in distal tubule transport of sodium and chloride. Blood gases and plasma electrolytes raise suspicion of this diagnosis and the definitive diagnosis is made by genetic study. Early treatment improves prognosis. The authors present the case of an 11-month-old child with early failure to thrive and severe regurgitation. Blood gases revealed hypochloraemic metabolic alkalosis, hyponatraemia and hypokalaemia. Blood pressure was normal and polyuria was documented. She began therapy with potassium chloride supplementation and indomethacin. There was clinical improvement and plasma potassium and bicarbonate normalised. The molecular study confirmed it was the classic form of Bartter syndrome. Despite being rare in clinical practice, which may lead to unnecessary medical investigation and diagnosis delay, in a child with failure to thrive, hypochloraemic metabolic alkalosis and hypokalaemia, this diagnosis must be considered. PMID:22744244

The medial tibial stress syndrome. A cause of shin splints.

PubMed

Mubarak, S J; Gould, R N; Lee, Y F; Schmidt, D A; Hargens, A R

1982-01-01

The medial tibial stress syndrome is a symptom complex seen in athletes who complain of exercise-induced pain along the distal posterior-medial aspect of the tibia. Intramuscular pressures within the posterior compartments of the leg were measured in 12 patients with this disorder. These pressures were not elevated and therefore this syndrome is a not a compartment syndrome. Available information suggests that the medial tibial stress syndrome most likely represents a periostitis at this location of the leg.

D-lactic acidosis: an unusual cause of encephalopathy in a patient with short bowel syndrome.

PubMed

Dahlqvist, G; Guillen-Anaya, M A; Vincent, M F; Thissen, J P; Hainaut, P

2013-01-01

A 24-year-old woman with a short bowel syndrome following post-ischemic small bowel resection, developed several episodes of lethargy, echolalia and ataxia. D-lactic acidosis was identified as the cause of neurological disturbances. This infrequent disorder can be precipitated by intake of a large amount of sugars, in patients with short bowel syndrome. It should be suspected in the presence of metabolic acidosis with increased anion gap and a normal level of L-lactic acid. The diagnosis relies on the specific dosage of D-lactic stereoisomer. Proper management involves rehydration, diet adaptation and oral administration of poorly absorbed antibiotics in order to modify the colonic flora responsible for D-lactic production.

Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome

PubMed Central

O'Grady, Gina L.; Verschuuren, Corien; Yuen, Michaela; Webster, Richard; Menezes, Manoj; Fock, Johanna M.; Pride, Natalie; Best, Heather A.; Benavides Damm, Tatiana; Turner, Christian; Lek, Monkol; Engel, Andrew G.; North, Kathryn N.; Clarke, Nigel F.; MacArthur, Daniel G.; Kamsteeg, Erik-Jan

2016-01-01

Objective: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3. Methods: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter (VAChT), through whole-exome sequencing. Results: The patients demonstrated features seen in presynaptic congenital myasthenic syndrome, including ptosis, ophthalmoplegia, fatigable weakness, apneic crises, and deterioration of symptoms in cold water for patient 1. Both patients demonstrated moderate clinical improvement on pyridostigmine. Patient 1 had a broader phenotype, including learning difficulties and left ventricular dysfunction. Electrophysiologic studies were typical for a presynaptic defect. Both patients showed profound electrodecrement on low-frequency repetitive stimulation followed by a prolonged period of postactivation exhaustion. In patient 1, this was unmasked only after isometric contraction, a recognized feature of presynaptic disease, emphasizing the importance of activation procedures. Conclusions: VAChT is responsible for uptake of acetylcholine into presynaptic vesicles. The clinical and electrographic characteristics of the patients described are consistent with previously reported mouse models of VAChT deficiency. These findings make it very likely that defects in VAChT due to variants in SLC18A3 are a cause of congenital myasthenic syndrome in humans. PMID:27590285

Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome.

PubMed

Ekvall, Sara; Sjörs, Kerstin; Jonzon, Anders; Vihinen, Mauno; Annerén, Göran; Bondeson, Marie-Louise

2014-03-01

Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present. © 2013 Wiley Periodicals, Inc.

Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43% of 35 Families With Midaortic Syndrome.

PubMed

Warejko, Jillian K; Schueler, Markus; Vivante, Asaf; Tan, Weizhen; Daga, Ankana; Lawson, Jennifer A; Braun, Daniela A; Shril, Shirlee; Amann, Kassaundra; Somers, Michael J G; Rodig, Nancy M; Baum, Michelle A; Daouk, Ghaleb; Traum, Avram Z; Kim, Heung Bae; Vakili, Khashayar; Porras, Diego; Lock, James; Rivkin, Michael J; Chaudry, Gulraiz; Smoot, Leslie B; Singh, Michael N; Smith, Edward R; Mane, Shrikant M; Lifton, Richard P; Stein, Deborah R; Ferguson, Michael A; Hildebrandt, Friedhelm

2018-04-01

Midaortic syndrome (MAS) is a rare cause of severe childhood hypertension characterized by narrowing of the abdominal aorta in children and is associated with extensive vascular disease. It may occur as part of a genetic syndrome, such as neurofibromatosis, or as consequence of a pathological inflammatory disease. However, most cases are considered idiopathic. We hypothesized that in a high percentage of these patients, a monogenic cause of disease may be detected by evaluating whole exome sequencing data for mutations in 1 of 38 candidate genes previously described to cause vasculopathy. We studied a cohort of 36 individuals from 35 different families with MAS by exome sequencing. In 15 of 35 families (42.9%), we detected likely causal dominant mutations. In 15 of 35 (42.9%) families with MAS, whole exome sequencing revealed a mutation in one of the genes previously associated with vascular disease ( NF1 , JAG1 , ELN , GATA6 , and RNF213 ). Ten of the 15 mutations have not previously been reported. This is the first report of ELN , RNF213 , or GATA6 mutations in individuals with MAS. Mutations were detected in NF1 (6/15 families), JAG1 (4/15 families), ELN (3/15 families), and one family each for GATA6 and RNF213 Eight individuals had syndromic disease and 7 individuals had isolated MAS. Whole exome sequencing can provide conclusive molecular genetic diagnosis in a high fraction of individuals with syndromic or isolated MAS. Establishing an etiologic diagnosis may reveal genotype/phenotype correlations for MAS in the future and should, therefore, be performed routinely in MAS. © 2018 American Heart Association, Inc.

Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome.

PubMed

Simon, Mariella; Richard, Elodie M; Wang, Xinjian; Shahzad, Mohsin; Huang, Vincent H; Qaiser, Tanveer A; Potluri, Prasanth; Mahl, Sarah E; Davila, Antonio; Nazli, Sabiha; Hancock, Saege; Yu, Margret; Gargus, Jay; Chang, Richard; Al-Sheqaih, Nada; Newman, William G; Abdenur, Jose; Starr, Arnold; Hegde, Rashmi; Dorn, Thomas; Busch, Anke; Park, Eddie; Wu, Jie; Schwenzer, Hagen; Flierl, Adrian; Florentz, Catherine; Sissler, Marie; Khan, Shaheen N; Li, Ronghua; Guan, Min-Xin; Friedman, Thomas B; Wu, Doris K; Procaccio, Vincent; Riazuddin, Sheikh; Wallace, Douglas C; Ahmed, Zubair M; Huang, Taosheng; Riazuddin, Saima

2015-03-01

Here we demonstrate association of variants in the mitochondrial asparaginyl-tRNA synthetase NARS2 with human hearing loss and Leigh syndrome. A homozygous missense mutation ([c.637G>T; p.Val213Phe]) is the underlying cause of nonsyndromic hearing loss (DFNB94) and compound heterozygous mutations ([c.969T>A; p.Tyr323*] + [c.1142A>G; p.Asn381Ser]) result in mitochondrial respiratory chain deficiency and Leigh syndrome, which is a neurodegenerative disease characterized by symmetric, bilateral lesions in the basal ganglia, thalamus, and brain stem. The severity of the genetic lesions and their effects on NARS2 protein structure cosegregate with the phenotype. A hypothetical truncated NARS2 protein, secondary to the Leigh syndrome mutation p.Tyr323* is not detectable and p.Asn381Ser further decreases NARS2 protein levels in patient fibroblasts. p.Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNAAsn in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome.

Mutations in STAMBP, encoding a deubiquitinating enzyme, cause Microcephaly-Capillary Malformation syndrome

PubMed Central

McDonell, Laura M.; Mirzaa, Ghayda M.; Alcantara, Diana; Schwartzentruber, Jeremy; Carter, Melissa T.; Lee, Leo J.; Clericuzio, Carol L.; Graham, John M.; Morris-Rosendahl, Deborah J.; Polster, Tilman; Acsadi, Gyula; Townshend, Sharron; Williams, Simon; Halbert, Anne; Isidor, Bertrand; Smyser, Christopher D.; Paciorkowski, Alex R.; Willing, Marcia; Woulfe, John; Das, Soma; Beaulieu, Chandree L.; Marcadier, Janet; Geraghty, Michael T.; Frey, Brendan J.; Majewski, Jacek; Bulman, Dennis E.; Dobyns, William B.; O’Driscoll, Mark; Boycott, Kym M.

2014-01-01

Microcephaly-capillary malformation (MIC-CAP) syndrome exhibits severe microcephaly with progressive cortical atrophy, intractable epilepsy, profound developmental delay and multiple small capillary malformations on the skin. We employed whole-exome sequencing of five patients with MIC-CAP syndrome and identified novel recessive mutations in STAMBP, a gene encoding the deubiquitinating (DUB) isopeptidase STAMBP (STAM-binding protein)/AMSH (Associated Molecule with the SH3 domain of STAM), that plays a key role in cell surface receptor-mediated endocytosis and sorting. Patient cell lines showed reduced STAMBP expression associated with accumulation of ubiquitin-conjugated protein aggregates, elevated apoptosis and insensitive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways. The latter cellular phenotype is significant considering the established connection between these pathways and their association with vascular and capillary malformations. Furthermore, our findings of a congenital human disorder caused by a defective DUB protein that functions in endocytosis, implicates ubiquitin-conjugate aggregation and elevated apoptosis as factors potentially influencing the progressive neuronal loss underlying MIC-CAP. PMID:23542699

Lennox-Gastaut syndrome of unknown cause: phenotypic characteristics of patients in the Epilepsy Phenome/Genome Project.

PubMed

Widdess-Walsh, Peter; Dlugos, Dennis; Fahlstrom, Robyn; Joshi, Sucheta; Shellhaas, Renée; Boro, Alex; Sullivan, Joseph; Geller, Eric

2013-11-01

Lennox-Gastaut syndrome (LGS) is a devastating childhood-onset epilepsy syndrome. The cause is unknown in 25% of cases. Little has been described about the specific clinical or electroencephalography (EEG) features of LGS of unknown or genetic cause (LGS(u)). The Epilepsy Phenome/Genome Project (EPGP) aims to characterize LGS(u) by phenotypic analysis of patients with LGS(u) and their parents. One hundred thirty-five patients with LGS with no known etiology and their parents were enrolled from 19 EPGP centers in the United States and Australia. Clinical data from medical records, standardized questionnaires, imaging, and EEG were collected with use of online informatics systems developed for EPGP. LGS(u) in the EPGP cohort had a broad range of onset of epilepsy from 1 to 13 years, was male predominant (p < 0.0002), and was associated with normal development prior to seizure onset in 59.2% of patients. Despite the diagnosis, almost half of the adult patients with LGS(u) completed secondary school. Parents were cognitively normal. All subjects had EEG recordings with generalized epileptiform abnormalities with a spike wave frequency range of 1-5 Hz (median 2 Hz), whereas 8.1% of subjects had EEG studies with a normal posterior dominant rhythm. Almost 12% of patients evolved from West syndrome. LGS(u) has distinctive characteristics including a broad age range of onset, male predominance, and often normal development prior to the onset of seizures. Cognitive achievements such as completion of secondary school were possible in half of adult patients. Our phenotypic description of LGS(u) coupled with future genetic studies will advance our understanding of this epilepsy syndrome. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Novel partial duplication of EYA1 causes branchiootic syndrome in a large Brazilian family.

PubMed

Dantas, Vitor G L; Freitas, Erika L; Della-Rosa, Valter A; Lezirovitz, Karina; de Moraes, Ana Maria S M; Ramos, Silvia B; Oiticica, Jeanne; Alves, Leandro U; Pearson, Peter L; Rosenberg, Carla; Mingroni-Netto, Regina C

2015-01-01

To identify novel genetic causes of syndromic hearing loss in Brazil. To map a candidate chromosomal region through linkage studies in an extensive Brazilian family and identify novel pathogenic variants using sequencing and array-CGH. Brazilian pedigree with individuals affected by BO syndrome characterized by deafness and malformations of outer, middle and inner ear, auricular and cervical fistulae, but no renal abnormalities. Whole genome microarray-SNP scanning on samples of 11 affected individuals detected a multipoint Lod score of 2.6 in the EYA1 gene region (chromosome 8). Sequencing of EYA1 in affected patients did not reveal pathogenic mutations. However, oligonucleotide-array-CGH detected a duplication of 71.8Kb involving exons 4 to 10 of EYA1 (heterozygous state). Real-time-PCR confirmed the duplication in fourteen of fifteen affected individuals and absence in 13 unaffected individuals. The exception involved a consanguineous parentage and was assumed to involve a different genetic mechanism. Our findings implicate this EYA1 partial duplication segregating with BO phenotype in a Brazilian pedigree and is the first description of a large duplication leading to the BOR/BO syndrome.

A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle.

PubMed

Agerholm, Jørgen S; McEvoy, Fintan J; Heegaard, Steffen; Charlier, Carole; Jagannathan, Vidhya; Drögemüller, Cord

2017-08-02

Surveillance for bovine genetic diseases in Denmark identified a hitherto unreported congenital syndrome occurring among progeny of a Holstein sire used for artificial breeding. A genetic aetiology due to a dominant inheritance with incomplete penetrance or a mosaic germline mutation was suspected as all recorded cases were progeny of the same sire. Detailed investigations were performed to characterize the syndrome and to reveal its cause. Seven malformed calves were submitted examination. All cases shared a common morphology with the most striking lesions being severe facial dysplasia and complete prolapse of the eyes. Consequently the syndrome was named facial dysplasia syndrome (FDS). Furthermore, extensive brain malformations, including microencephaly, hydrocephalus, lobation of the cerebral hemispheres and compression of the brain were present. Subsequent data analysis of progeny of the sire revealed that around 0.5% of his offspring suffered from FDS. High density single nucleotide polymorphism (SNP) genotyping data of the seven cases and their parents were used to map the defect in the bovine genome. Significant genetic linkage was obtained for three regions, including chromosome 26 where whole genome sequencing of a case-parent trio revealed two de novo variants perfectly associated with the disease: an intronic SNP in the DMBT1 gene and a single non-synonymous variant in the FGFR2 gene. This FGFR2 missense variant (c.927G>T) affects a gene encoding a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and across species. It is predicted to change an evolutionary conserved tryptophan into a cysteine residue (p.Trp309Cys). Both variant alleles were proven to result from de novo mutation events in the germline of the sire. FDS is a novel genetic disorder of Holstein cattle. Mutations in the human FGFR2 gene are associated with various dominant inherited craniofacial dysostosis syndromes. Given

Founder Fukutin mutation causes Walker-Warburg syndrome in four Ashkenazi Jewish families†

PubMed Central

Chang, Wendy; Winder, Thomas L.; LeDuc, Charles A.; Simpson, Lynn L.; Millar, William S.; Dungan, Jeffrey; Ginsberg, Norman; Plaga, Stacey; Moore, Steven A.; Chung, Wendy K.

2009-01-01

Objective Walker-Warburg syndrome (WWS) is a genetically heterogeneous congenital muscular dystrophy caused by abnormal glycosylation of α-dystroglycan (α-DG) that is associated with brain malformations and eye anomalies. The Fukutin (FKTN) gene, which causes autosomal recessively inherited WWS is most often associated with Fukuyama congenital muscular dystrophy in Japan. We describe the clinical features of four nonconsanguinous Ashkenazi Jewish families with WWS and identify the underlying genetic basis for WWS. Method We screened for mutations in POMGnT1, POMT1, POMT2, and FKTN, genes causing WWS, by dideoxy sequence analysis. Results We identified an identical homozygous c.1167insA mutation in the FKTN gene on a common haplotype in all four families and identified 2/299 (0.7%) carriers for the c.1167insA mutation among normal American Ashkenazi Jewish adults. Conclusion These data suggest that the c.1167insA FKTN mutation described by us is a founder mutation that can be used to target diagnostic testing and carrier screening in the Ashkenazi Jewish population. PMID:19266496

Founder Fukutin mutation causes Walker-Warburg syndrome in four Ashkenazi Jewish families.

PubMed

Chang, Wendy; Winder, Thomas L; LeDuc, Charles A; Simpson, Lynn L; Millar, William S; Dungan, Jeffrey; Ginsberg, Norman; Plaga, Stacey; Moore, Steven A; Chung, Wendy K

2009-06-01

Walker-Warburg syndrome (WWS) is a genetically heterogeneous congenital muscular dystrophy caused by abnormal glycosylation of alpha-dystroglycan (alpha-DG) that is associated with brain malformations and eye anomalies. The Fukutin (FKTN) gene, which causes autosomal recessively inherited WWS is most often associated with Fukuyama congenital muscular dystrophy in Japan. We describe the clinical features of four nonconsanguinous Ashkenazi Jewish families with WWS and identify the underlying genetic basis for WWS. We screened for mutations in POMGnT1, POMT1, POMT2, and FKTN, genes causing WWS, by dideoxy sequence analysis. We identified an identical homozygous c.1167insA mutation in the FKTN gene on a common haplotype in all four families and identified 2/299 (0.7%) carriers for the c.1167insA mutation among normal American Ashkenazi Jewish adults. These data suggest that the c.1167insA FKTN mutation described by us is a founder mutation that can be used to target diagnostic testing and carrier screening in the Ashkenazi Jewish population. Copyright (c) 2009 John Wiley & Sons, Ltd.

Trends in socioeconomic inequalities in risk of sudden infant death syndrome, other causes of infant mortality, and stillbirth in Scotland: population based study.

PubMed

Wood, Angela M; Pasupathy, Dharmintra; Pell, Jill P; Fleming, Michael; Smith, Gordon C S

2012-03-16

To compare changes in inequalities in sudden infant death syndrome with other causes of infant mortality and stillbirth in Scotland, 1985-2008. Retrospective cohort study. Scotland 1985-2008, analysed by four epochs of six years. Singleton births of infants with birth weight >500 g born at 28-43 weeks' gestation. Sudden infant death syndrome, other causes of postneonatal infant death, neonatal death, and stillbirth. Odds ratios expressed as the association across the range of seven categories of Carstairs deprivation score. The association between deprivation and the risk of all cause stillbirth and infant death varied between the four epochs (P=0.04). This was wholly explained by variation in the risk of sudden infant death syndrome (P<0.001 for interaction). Among women living in areas of low deprivation, there was a sharp decline in the rate of sudden infant death syndrome from 1990 to 1993. Among women living in areas of high deprivation, there was a slower decline in sudden infant death syndrome rates between 1992 and 2004. Consequently, the odds ratio for the association between socioeconomic deprivation and sudden infant death syndrome increased from 2.04 (95% confidence interval 1.53 to 2.72) in 1985-90, to 7.52 (4.62 to 12.25) in 1991-6, and 9.50 (5.46 to 16.53) in 1997-2002 but fell to 1.78 (0.87 to 3.65) in 2002-8. The interaction remained significant after adjustment for maternal characteristics. The rate of sudden infant death syndrome declined throughout Scotland in the early 1990s. The decline had a later onset and was slower among women living in areas of high deprivation, probably because of slower uptake of recommended changes in infant sleeping position. The effect was to create a strong independent association between deprivation and sudden infant death syndrome where one did not exist before.

Obesity Hypoventilation Syndrome

MedlinePlus

... Home / < Back To Health Topics / Obesity Hypoventilation Syndrome Obesity Hypoventilation Syndrome Also known as Pickwickian Syndrome What ... your neck is larger than normal. Complications of Obesity Hypoventilation Syndrome When left untreated, OHS can cause ...

Loeys-Dietz Syndrome

MedlinePlus

... to the signs and symptoms of Loeys-Dietz syndrome. Marfan syndrome is different from Loeys-Dietz syndrome in that the gene mutation which causes Marfan syndrome is in fibrillin-1 (FBN-1), a protein ...

Horner Syndrome

MedlinePlus

... at birth Tumor of the hormonal and nervous systems (neuroblastoma) Unknown causes In some cases the cause of Horner syndrome cannot be identified. This is known as idiopathic Horner syndrome. By Mayo Clinic Staff . Mayo Clinic Footer Legal Conditions and Terms Any use of this site ...

Marfan Syndrome

MedlinePlus

Marfan syndrome is a disorder that affects connective tissue. Connective tissues are proteins that support skin, bones, blood vessels, ... A problem with the fibrillin gene causes Marfan syndrome. Marfan syndrome can be mild to severe, and ...

Mitochondrial disorder caused Charles Darwin's cyclic vomiting syndrome.

PubMed

Finsterer, Josef; Hayman, John

2014-01-08

Charles Darwin (CD), "father of modern biology," suffered from multisystem illness from early adulthood. The most disabling manifestation was cyclic vomiting syndrome (CVS). This study aims at finding the possible cause of CVS in CD. A literature search using the PubMed database was carried out, and CD's complaints, as reported in his personal writings and those of his relatives, friends, colleagues, biographers, were compared with various manifestations of mitochondrial disorders (MIDs), known to cause CVS, described in the literature. Organ tissues involved in CD's disease were brain, nerves, muscles, vestibular apparatus, heart, gut, and skin. Cerebral manifestations included episodic headache, visual disturbance, episodic memory loss, periodic paralysis, hysterical crying, panic attacks, and episodes of depression. Manifestations of polyneuropathy included numbness, paresthesias, increased sweating, temperature sensitivity, and arterial hypotension. Muscular manifestations included periods of exhaustion, easy fatigability, myalgia, and muscle twitching. Cardiac manifestations included episodes of palpitations and chest pain. Gastrointestinal manifestations were CVS, dental problems, abnormal seasickness, eructation, belching, and flatulence. Dermatological manifestations included painful lips, dermatitis, eczema, and facial edema. Treatments with beneficial effects to his complaints were rest, relaxation, heat, and hydrotherapy. CVS in CD was most likely due to a multisystem, nonsyndromic MID. This diagnosis is based upon the multisystem nature of his disease, the fact that CVS is most frequently the manifestation of a MID, the family history, the variable phenotypic expression between affected family members, the fact that symptoms were triggered by stress, and that only few symptoms could not be explained by a MID.

Mutations in the evolutionarily highly conserved KEOPS complex genes cause nephrotic syndrome with microcephaly

PubMed Central

Braun, Daniela A.; Rao, Jia; Mollet, Geraldine; Schapiro, David; Daugeron, Marie-Claire; Tan, Weizhen; Gribouval, Olivier; Boyer, Olivia; Revy, Patrick; Jobst-Schwan, Tilman; Schmidt, Johanna Magdalena; Lawson, Jennifer A.; Schanze, Denny; Ashraf, Shazia; Boddaert, Nathalie; Collinet, Bruno; Martin, Gaëlle; Liger, Dominique; Lovric, Svjetlana; Furlano, Monica; Guerrera, I. Chiara; Sanchez-Ferras, Oraly; Menten, Björn; Vergult, Sarah; De Rocker, Nina; Airik, Merlin; Hermle, Tobias; Shril, Shirlee; Widmeier, Eugen; Gee, Heon Yung; Choi, Won-Il; Sadowski, Carolin E.; Pabst, Werner L.; Warejko, Jillian; Daga, Ankana; LeBerre, Tamara Basta; Matejas, Verena; Behnam, Babak; Beeson, Brendan; Begtrup, Amber; Bruce, Malcolm; Ch'ng, Gaik-Siew; Lin, Shuan-Pei; Chang, Jui-Hsing; Chen, Chao-Huei; Cho, Megan T.; Gipson, Patrick E.; Hsu, Chyong-Hsin; Kari, Jameela A.; Ke, Yu-Yuan; Kiraly-Borri, Cathy; Lai, Wai-ming; Lemyre, Emmanuelle; Littlejohn, Rebecca Okasha; Masri, Amira; Moghtaderi, Mastaneh; Nakamura, Kazuyuki; Praet, Marleen; Prasad, Chitra; Prytula, Agnieszka; Roeder, Elizabeth; Rump, Patrick; Schnur, Rhonda E.; Shiihara, Takashi; Sinha, Manish; Soliman, Neveen A; Soulami, Kenza; Sweetser, David A.; Tsai, Wen-Hui; Tsai, Jeng-Daw; Vester, Udo; Viskochil, David H.; Vatanavicharn, Nithiwat; Waxler, Jessica L.; Wolf, Matthias T.F.; Wong, Sik-Nin; Poduri, Annapurna; Truglio, Gessica; Mane, Shrikant; Lifton, Richard P.; Bouchard, Maxime; Kannu, Peter; Chitayat, David; Magen, Daniella; Calleweart, Bert; van Tilbeurgh, Herman; Zenker, Martin; Antignac, Corinne; Hildebrandt, Friedhelm

2018-01-01

Galloway-Mowat syndrome (GAMOS) is a severe autosomal-recessive disease characterized by the combination of early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies. To date, mutations of WDR73 are the only known monogenic cause of GAMOS and in most affected individuals the molecular diagnosis remains elusive. We here identify recessive mutations of OSGEP, TP53RK, TPRKB, or LAGE3, encoding the 4 subunits of the KEOPS complex in 33 individuals of 30 families with GAMOS. CRISPR/Cas9 knockout in zebrafish and mice recapitulates the human phenotype of microcephaly and results in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibits cell proliferation, which human mutations fail to rescue, and knockdown of either gene activates DNA damage response signaling and induces apoptosis. OSGEP and TP53RK molecularly interact and co-localize with the actin-regulating ARP2/3 complex. Furthermore, knockdown of OSGEP and TP53RK induces defects of the actin cytoskeleton and reduces migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identify 4 novel monogenic causes of GAMOS, describe the first link between KEOPS function and human disease, and delineate potential pathogenic mechanisms. PMID:28805828

Impact of anaemia on mortality and its causes in elderly patients with acute coronary syndromes.

PubMed

Ariza-Solé, Albert; Formiga, Francesc; Salazar-Mendiguchía, Joel; Garay, Alberto; Lorente, Victòria; Sánchez-Salado, José C; Sánchez-Elvira, Guillermo; Gómez-Lara, Josep; Gómez-Hospital, Joan A; Cequier, Angel

2015-06-01

Prognostic impact of anaemia in the elderly with acute coronary syndromes has not been specifically analysed, and little information exists about causes of mortality in this setting. We prospectively included consecutive patients with acute coronary syndromes. Anaemia was defined as haemoglobin < 130 g/L in men, and < 120 g/L in women. Primary outcome was mid-term mortality and its causes. Analyses were performed by Cox regression method. We included 2128 patients, of whom 394 (18.6%) were aged 75 years or older. Anaemia was more common in the elderly (40.4% vs 19.5%, p <0.001). Mean follow-up was 386 days. Anaemia independently predicted overall mortality (HR 1.47, 95% CI 1.05-2.06), cardiac mortality (HR 1.76, 95% CI 1.06-2.94) and non-cardiac mortality (HR 1.59, 95% CI 1.03-2.45) in the overall cohort. In young patients the association between anaemia and mortality was significant only for non-cardiac causes. The association between anaemia and mortality was not significant in the elderly (HR 1.08, 95% CI 0.71-1.63, p 0.736). The impact of anaemia on cause specific of mortality seem to be different according to age subgroup. The association between anaemia and mortality was not observed in elderly patients from our series. Copyright © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Stickler syndrome caused by COL2A1 mutations: genotype–phenotype correlation in a series of 100 patients

PubMed Central

Hoornaert, Kristien P; Vereecke, Inge; Dewinter, Chantal; Rosenberg, Thomas; Beemer, Frits A; Leroy, Jules G; Bendix, Laila; Björck, Erik; Bonduelle, Maryse; Boute, Odile; Cormier-Daire, Valerie; De Die-Smulders, Christine; Dieux-Coeslier, Anne; Dollfus, Hélène; Elting, Mariet; Green, Andrew; Guerci, Veronica I; Hennekam, Raoul C M; Hilhorts-Hofstee, Yvonne; Holder, Muriel; Hoyng, Carel; Jones, Kristi J; Josifova, Dragana; Kaitila, Ilkka; Kjaergaard, Suzanne; Kroes, Yolande H; Lagerstedt, Kristina; Lees, Melissa; LeMerrer, Martine; Magnani, Cinzia; Marcelis, Carlo; Martorell, Loreto; Mathieu, Michèle; McEntagart, Meriel; Mendicino, Angela; Morton, Jenny; Orazio, Gabrielli; Paquis, Véronique; Reish, Orit; Simola, Kalle O J; Smithson, Sarah F; Temple, Karen I; Van Aken, Elisabeth; Van Bever, Yolande; van den Ende, Jenneke; Van Hagen, Johanna M; Zelante, Leopoldo; Zordania, Riina; De Paepe, Anne; Leroy, Bart P; De Buyzere, Marc; Coucke, Paul J; Mortier, Geert R

2010-01-01

Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P<0.01). Overall, 20 of 23 sporadic patients with a COL2A1 mutation had either a cleft palate or retinal detachment with vitreous anomalies. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history were shown to be good indicators for a COL2A1 defect. In conclusion, we confirm that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as >90% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome. PMID:20179744

Concurrent Van der Woude syndrome and Turner syndrome: A case report.

PubMed

Los, Evan; Baines, Hayley; Guttmann-Bauman, Ines

2017-01-01

Most cases of Van der Woude syndrome are caused by a mutation to interferon regulatory factor 6 on chromosome 1. Turner syndrome is caused by complete or partial absence of the second sex chromosome in girls. We describe a unique case of the two syndromes occurring concurrently though apparently independently in a girl with Van der Woude syndrome diagnosed at birth and Turner syndrome at 14 years 9 months. Short stature was initially misattributed to Van der Woude syndrome and pituitary insufficiency associated with clefts before correctly diagnosing Turner syndrome. We discuss the prevalence of delayed diagnosis of Turner syndrome, the rarity of reports of concurrent autosomal chromosome mutation and sex chromosome deletion, as well as the need to consider the diagnosis of Turner syndrome in all girls with short stature regardless of prior medical history.

A novel STXBP1 mutation causes typical Rett syndrome in a Japanese girl.

PubMed

Yuge, Kotaro; Iwama, Kazuhiro; Yonee, Chihiro; Matsufuji, Mayumi; Sano, Nozomi; Saikusa, Tomoko; Yae, Yukako; Yamashita, Yushiro; Mizuguchi, Takeshi; Matsumoto, Naomichi; Matsuishi, Toyojiro

2018-06-01

Rett syndrome (RTT) is a neurodevelopmental disorder mostly caused by mutations in Methyl-CpG-binding protein 2 (MECP2); however, mutations in various other genes may lead to RTT-like phenotypes. Here, we report the first case of a Japanese girl with RTT caused by a novel syntaxin-binding protein 1 (STXBP1) frameshift mutation (c.60delG, p.Lys21Argfs*16). She showed epilepsy at one year of age, regression of acquired psychomotor abilities thereafter, and exhibited stereotypic hand and limb movements at 3 years of age. Her epilepsy onset was earlier than is typical for RTT patients. However, she fully met the 2010 diagnostic criteria of typical RTT. STXBP1 mutations cause early infantile epileptic encephalopathy (EIEE), various intractable epilepsies, and neurodevelopmental disorders. However, the case described here presented a unique clinical presentation of typical RTT without EIEE and a novel STXBP1 mutation. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome).

PubMed

Buchanan, Daniel D; Rosty, Christophe; Clendenning, Mark; Spurdle, Amanda B; Win, Aung Ko

2014-01-01

Carriers of a germline mutation in one of the DNA mismatch repair (MMR) genes have a high risk of developing numerous different cancers, predominantly colorectal cancer and endometrial cancer (known as Lynch syndrome). MMR gene mutation carriers develop tumors with MMR deficiency identified by tumor microsatellite instability or immunohistochemical loss of MMR protein expression. Tumor MMR deficiency is used to identify individuals most likely to carry an MMR gene mutation. However, MMR deficiency can also result from somatic inactivation, most commonly methylation of the MLH1 gene promoter. As tumor MMR testing of all incident colorectal and endometrial cancers (universal screening) is becoming increasingly adopted, a growing clinical problem is emerging for individuals who have tumors that show MMR deficiency who are subsequently found not to carry an MMR gene mutation after genetic testing using the current diagnostic approaches (Sanger sequencing and multiplex ligation-dependent probe amplification) and who also show no evidence of MLH1 methylation. The inability to determine the underlying cause of tumor MMR deficiency in these "Lynch-like" or "suspected Lynch syndrome" cases has significant implications on the clinical management of these individuals and their relatives. When the data from published studies are combined, 59% (95% confidence interval [CI]: 55% to 64%) of colorectal cancers and 52% (95% CI: 41% to 62%) of endometrial cancers with MMR deficiency were identified as suspected Lynch syndrome. Recent studies estimated that colorectal cancer risk for relatives of suspected Lynch syndrome cases is lower than for relatives of those with MMR gene mutations, but higher than for relatives of those with tumor MMR deficiency resulting from methylation of the MLH1 gene promoter. The cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely due to either unidentified germline MMR gene mutations, somatic cell mosaicism, or biallelic somatic

Whole Exome Sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome

PubMed Central

Martinez, Fernando; Lee, Jeong Ho; Lee, Ji Eun; Blanco, Sandra; Nickerson, Elizabeth; Gabriel, Stacey; Frye, Michaela; Al-Gazali, Lihadh; Gleeson, Joseph G.

2016-01-01

Dubowitz Syndrome is an autosomal recessive disorder characterized by the constellation of mild microcephaly, growth and mental retardation, eczema and peculiar facies, but causes are still unknown. We studied a multiplex consanguineous family with many features of Dubowitz syndrome using whole exome sequencing and identified a splice mutation in NSUN2, encoding a conserved RNA methyltransferase. NSUN2 has been implicated in Myc-induced cell proliferation and mitotic spindle stability, which might help explain the varied clinical presentations that can include chromosomal instability and immunological defects. Patient cells displayed loss of NSUN2-specific methylation at two residues of the aspartate tRNA. Our findings establish NSUN2 as the first causal gene with relationship to the Dubowitz syndrome spectrum phenotype. PMID:22577224

Neonatal Bartter syndrome and unilateral ectopic renal cyst as new renal causes of hydrops fetalis: two case reports and review of the literature.

PubMed

Çetinkaya, Merih; Durmaz, Oguzhan; Büyükkale, Gökhan; Ozbek, Sibel; Acar, Deniz; Kilicaslan, Isin; Kavuncuoglu, Sultan

2013-07-01

Non-immune hydrops fetalis (NIHF) is a challenging entity as it represents the end stage of several different disorders. Renal and genitourinary causes of NIHF are rare and include congenital renal malformations, tumors and ureter-urethra disorders. Herein, two NIHF cases with different renal causes were presented. The first case that had antenatal NIHF was diagnosed neonatal Bartter syndrome. The second case of NIHF with antenatal large cyst in the surrenal gland area required surgery and ectopic renal cyst was diagnosed. To our best of knowledge, these are the first reports of NIHF associated with neonatal Bartter syndrome and ectopic renal cyst in neonates. Although it may be coincidental, these cases suggest that both neonatal Bartter syndrome and unilateral ectopic renal cyst may cause NIHF development in neonates by several different mechanisms. Therefore, these two rare entities should be suspected in cases of NIHF with similar findings.

Central Pain Syndrome

MedlinePlus

... cord. This syndrome can be caused by stroke, multiple sclerosis, tumors, epilepsy, brain or spinal cord trauma, or ... cord. This syndrome can be caused by stroke, multiple sclerosis, tumors, epilepsy, brain or spinal cord trauma, or ...

Ectopic Cushing' syndrome caused by a neuroendocrine carcinoma of the mesentery.

PubMed

Fasshauer, Mathias; Lincke, Thomas; Witzigmann, Helmut; Kluge, Regine; Tannapfel, Andrea; Moche, Michael; Buchfelder, Michael; Petersenn, Stephan; Kratzsch, Juergen; Paschke, Ralf; Koch, Christian A

2006-04-27

ACTH overproduction within the pituitary gland or ectopically leads to hypercortisolism. Here, we report the first case of Cushing' syndrome caused by an ectopic ACTH-secreting neuroendocrine carcinoma of the mesentery. Moreover, diagnostic procedures and pitfalls associated with ectopic ACTH-secreting tumors are demonstrated and discussed. A 41 year-old man presented with clinical features and biochemical tests suggestive of ectopic Cushing's syndrome. First, subtotal thyroidectomy was performed without remission of hypercortisolism, because an octreotide scan showed increased activity in the left thyroid gland and an ultrasound revealed nodules in both thyroid lobes one of which was autonomous. In addition, the patient had a 3 mm hypoenhancing lesion of the neurohypophysis and a 1 cm large adrenal tumor. Surgical removal of the pituitary lesion within the posterior lobe did not improve hypercortisolism and we continued to treat the patient with metyrapone to block cortisol production. At 18-months follow-up from initial presentation, we detected an ACTH-producing neuroendocrine carcinoma of the mesentery by using a combination of octreotide scan, computed tomography scan, and positron emission tomography. Intraoperatively, use of a gamma probe after administration of radiolabeled (111)In-pentetreotide helped identify the mesenteric neuroendocrine tumor. After removal of this carcinoma, the patient improved clinically. Laboratory testing confirmed remission of hypercortisolism. An octreotide scan 7 months after surgery showed normal results. This case underscores the diagnostic challenge in identifying an ectopic ACTH-producing tumor and the pluripotency of cells, in this case of mesenteric cells that can start producing and secreting ACTH. It thereby helps elucidate the pathogenesis of neuroendocrine tumors. This case also suggests that patients with ectopic Cushing's syndrome and an octreotide scan positive in atypical locations may benefit from explorative

Ectopic Cushing' syndrome caused by a neuroendocrine carcinoma of the mesentery

PubMed Central

Fasshauer, Mathias; Lincke, Thomas; Witzigmann, Helmut; Kluge, Regine; Tannapfel, Andrea; Moche, Michael; Buchfelder, Michael; Petersenn, Stephan; Kratzsch, Juergen; Paschke, Ralf; Koch, Christian A

2006-01-01

Background ACTH overproduction within the pituitary gland or ectopically leads to hypercortisolism. Here, we report the first case of Cushing' syndrome caused by an ectopic ACTH-secreting neuroendocrine carcinoma of the mesentery. Moreover, diagnostic procedures and pitfalls associated with ectopic ACTH-secreting tumors are demonstrated and discussed. Case presentation A 41 year-old man presented with clinical features and biochemical tests suggestive of ectopic Cushing's syndrome. First, subtotal thyroidectomy was performed without remission of hypercortisolism, because an octreotide scan showed increased activity in the left thyroid gland and an ultrasound revealed nodules in both thyroid lobes one of which was autonomous. In addition, the patient had a 3 mm hypoenhancing lesion of the neurohypophysis and a 1 cm large adrenal tumor. Surgical removal of the pituitary lesion within the posterior lobe did not improve hypercortisolism and we continued to treat the patient with metyrapone to block cortisol production. At 18-months follow-up from initial presentation, we detected an ACTH-producing neuroendocrine carcinoma of the mesentery by using a combination of octreotide scan, computed tomography scan, and positron emission tomography. Intraoperatively, use of a gamma probe after administration of radiolabeled 111In-pentetreotide helped identify the mesenteric neuroendocrine tumor. After removal of this carcinoma, the patient improved clinically. Laboratory testing confirmed remission of hypercortisolism. An octreotide scan 7 months after surgery showed normal results. Conclusion This case underscores the diagnostic challenge in identifying an ectopic ACTH-producing tumor and the pluripotency of cells, in this case of mesenteric cells that can start producing and secreting ACTH. It thereby helps elucidate the pathogenesis of neuroendocrine tumors. This case also suggests that patients with ectopic Cushing's syndrome and an octreotide scan positive in atypical

Gastric inhibitory polypeptide-dependent cortisol hypersecretion--a new cause of Cushing's syndrome.

PubMed

Lacroix, A; Bolté, E; Tremblay, J; Dupré, J; Poitras, P; Fournier, H; Garon, J; Garrel, D; Bayard, F; Taillefer, R

1992-10-01

Corticotropin-independent nodular adrenal hyperplasia is a rare cause of Cushing's syndrome, and the factors responsible for the adrenal hyperplasia are not known. We studied a 48-year-old woman with Cushing's syndrome, nodular adrenal hyperplasia, and undetectable plasma corticotropin concentrations in whom food stimulated cortisol secretion. Cortisol secretion had an inverse diurnal rhythm in this patient, with low-to-normal fasting plasma cortisol concentrations and elevated postprandial cortisol concentrations that could not be suppressed with dexamethasone. The cortisol concentrations increased in response to oral glucose (4-fold increase) and a lipid-rich meal (4.8-fold increase) or a protein-rich meal (2.6-fold increase), but not intravenous glucose. The infusion of somatostatin blunted the plasma cortisol response to oral glucose. Intravenous infusion of gastric inhibitory polypeptide (GIP) for one hour increased the plasma cortisol concentration in the patient but not in four normal subjects. Fasting plasma GIP concentrations in the patient were similar to those in the normal subjects; feeding the patient test meals induced increases in plasma GIP concentrations that paralleled those in plasma cortisol concentrations. Cell suspensions of adrenal tissue from the patient produced more cortisol when stimulated by GIP than when stimulated by corticotropin. In contrast, adrenal cells from normal adults and fetuses or patients with cortisol-producting or aldosterone-producing adenomas responded to corticotropin but not to GIP. Nodular adrenal hyperplasia and Cushing's syndrome may be food-dependent as a result of abnormal responsiveness of adrenal cells to physiologic secretion of GIP. "Illicit" (ectopic) expression of GIP receptors on adrenal cells presumably underlies this disorder.

Acute Compartment Syndrome Which Causes Rhabdomyolysis by Carbon Monoxide Poisoning and Sciatic Nerve Injury Associated with It: A Case Report.

PubMed

Ji, Jung-Woo

2017-09-01

Rhabdomyolysis is most frequently caused by soft tissue injury with trauma to the extremities. Non-traumatic rhabdomyolysis may be caused by alcohol or drug abuse, infection, collagen disease, or intensive exercise, but incidence is low. In particular, rhabdomyolysis resulting from carbon monoxide poisoning is especially rare. If caught before death, carbon monoxide poisoning has been shown to cause severe muscle necrosis and severe muscle damage leading to acute renal failure. In cases of carbon-monoxide-induced rhabdomyolsis leading to acute compartment syndrome in the buttocks and sciatic nerve injury are rare. We have experience treating patients with acute compartment syndrome due to rhabdomyolysis following carbon monoxide poisoning. We report the characteristic features of muscle necrosis observed during a decompression operation and magnetic resonance imaging findings with a one-year follow-up in addition to a review of the literature.

Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro–costo–mandibular syndrome

PubMed Central

Lynch, Danielle C.; Revil, Timothée; Schwartzentruber, Jeremy; Bhoj, Elizabeth J.; Innes, A. Micheil; Lamont, Ryan E.; Lemire, Edmond G.; Chodirker, Bernard N.; Taylor, Juliet P.; Zackai, Elaine H.; McLeod, D. Ross; Kirk, Edwin P.; Hoover-Fong, Julie; Fleming, Leah; Savarirayan, Ravi; Boycott, Kym; MacKenzie, Alex; Brudno, Michael; Bulman, Dennis; Dyment, David; Majewski, Jacek; Jerome-Majewska, Loydie A.; Parboosingh, Jillian S.; Bernier, Francois P.

2014-01-01

Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro–costo–mandibular syndrome. This exon contains a premature termination codon that triggers nonsense-mediated mRNA decay when included in the transcript. These mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. We provide evidence for the functional importance of this conserved intragenic element in the regulation of alternative splicing and development, and suggest that the evolution of such a regulatory mechanism has contributed to the complexity of mammalian development. PMID:25047197

Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome.

PubMed

Lynch, Danielle C; Revil, Timothée; Schwartzentruber, Jeremy; Bhoj, Elizabeth J; Innes, A Micheil; Lamont, Ryan E; Lemire, Edmond G; Chodirker, Bernard N; Taylor, Juliet P; Zackai, Elaine H; McLeod, D Ross; Kirk, Edwin P; Hoover-Fong, Julie; Fleming, Leah; Savarirayan, Ravi; Majewski, Jacek; Jerome-Majewska, Loydie A; Parboosingh, Jillian S; Bernier, Francois P

2014-07-22

Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro-costo-mandibular syndrome. This exon contains a premature termination codon that triggers nonsense-mediated mRNA decay when included in the transcript. These mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. We provide evidence for the functional importance of this conserved intragenic element in the regulation of alternative splicing and development, and suggest that the evolution of such a regulatory mechanism has contributed to the complexity of mammalian development.

Eye Development Genes and Known Syndromes

PubMed Central

Slavotinek, Anne M.

2011-01-01

Anophthalmia and microphthalmia (A/M) are significant eye defects because they can have profound effects on visual acuity. A/M is associated with non-ocular abnormalities in an estimated 33–95% of cases and around 25% of patients have an underlying genetic syndrome that is diagnosable. Syndrome recognition is important for targeted molecular genetic testing, prognosis and for counseling regarding recurrence risks. This review provides clinical and molecular information for several of the commonest syndromes associated with A/M: Anophthalmia-Esophageal-Genital syndrome, caused by SOX2 mutations, Anophthalmia and pituitary abnormalities caused by OTX2 mutations, Matthew-Wood syndrome caused by STRA6 mutations, Oculocardiafaciodental syndrome and Lenz microphthalmia caused by BCOR mutations, Microphthalmia Linear Skin pigmentation syndrome caused by HCCS mutations, Anophthalmia, pituitary abnormalities, polysyndactyly caused by BMP4 mutations and Waardenburg anophthalmia caused by mutations in SMOC1. In addition, we briefly discuss the ocular and extraocular phenotypes associated with several other important eye developmental genes, including GDF6, VSX2, RAX, SHH, SIX6 and PAX6. PMID:22005280

Guillain-Barre Syndrome

MedlinePlus

Guillain-Barre syndrome is a rare disorder that causes your immune system to attack your peripheral nervous system (PNS). The PNS ... your brain. No one knows what causes the syndrome. Sometimes it is triggered by an infection, surgery, ...

Origins of the E. coli Strain Causing an Outbreak of Hemolytic–Uremic Syndrome in Germany

PubMed Central

Rasko, David A.; Webster, Dale R.; Sahl, Jason W.; Bashir, Ali; Boisen, Nadia; Scheutz, Flemming; Paxinos, Ellen E.; Sebra, Robert; Chin, Chen-Shan; Iliopoulos, Dimitris; Klammer, Aaron; Peluso, Paul; Lee, Lawrence; Kislyuk, Andrey O.; Bullard, James; Kasarskis, Andrew; Wang, Susanna; Eid, John; Rank, David; Redman, Julia C.; Steyert, Susan R.; Frimodt-Møller, Jakob; Struve, Carsten; Petersen, Andreas M.; Krogfelt, Karen A.; Nataro, James P.; Schadt, Eric E.; Waldor, Matthew K.

2011-01-01

BACKGROUND A large outbreak of diarrhea and the hemolytic–uremic syndrome caused by an unusual serotype of Shiga-toxin–producing Escherichia coli (O104:H4) began in Germany in May 2011. As of July 22, a large number of cases of diarrhea caused by Shiga-toxin–producing E. coli have been reported — 3167 without the hemolytic–uremic syndrome (16 deaths) and 908 with the hemolytic–uremic syndrome (34 deaths) — indicating that this strain is notably more virulent than most of the Shiga-toxin–producing E. coli strains. Preliminary genetic characterization of the outbreak strain suggested that, unlike most of these strains, it should be classified within the enteroaggregative pathotype of E. coli. METHODS We used third-generation, single-molecule, real-time DNA sequencing to determine the complete genome sequence of the German outbreak strain, as well as the genome sequences of seven diarrhea-associated enteroaggregative E. coli serotype O104:H4 strains from Africa and four enteroaggregative E. coli reference strains belonging to other serotypes. Genomewide comparisons were performed with the use of these enteroaggregative E. coli genomes, as well as those of 40 previously sequenced E. coli isolates. RESULTS The enteroaggregative E. coli O104:H4 strains are closely related and form a distinct clade among E. coli and enteroaggregative E. coli strains. However, the genome of the German outbreak strain can be distinguished from those of other O104:H4 strains because it contains a prophage encoding Shiga toxin 2 and a distinct set of additional virulence and antibiotic-resistance factors. CONCLUSIONS Our findings suggest that horizontal genetic exchange allowed for the emergence of the highly virulent Shiga-toxin–producing enteroaggregative E. coli O104:H4 strain that caused the German outbreak. More broadly, these findings highlight the way in which the plasticity of bacterial genomes facilitates the emergence of new pathogens. PMID:21793740

Manganese intoxication: the cause of an inexplicable epileptic syndrome in a 3 year old child.

PubMed

Herrero Hernandez, Elena; Discalzi, Gianluigi; Dassi, Patrizia; Jarre, Laura; Pira, Enrico

2003-08-01

Excess manganese (Mn) can cause several neurotoxic effects, however only a few studies have reported epileptic syndromes related to manganese intoxication. We describe an epileptic syndrome due to manganese intoxication in a 3 year old male child. His blood manganese was elevated, but no other abnormal values or toxic substances were found in blood or urine. The electroencephalogram (EEG) showed a picture of progressive encephalopathy, while brain magnetic resonance was normal. The patient's conditions rapidly worsened to epileptic status despite the use of antiepileptic drugs. Chelating treatment with CaNa(2)EDTA was initiated to remove excess manganese and promptly succeeded in reverting epileptic symptoms. Concurrently, manganese blood levels and electroencephalogram progressively normalized. Thereafter it has been possible to discontinue antiepileptic treatment, and the patient remains in excellent conditions without any treatment.