RESUMO
INTRODUCTION: Atypical haemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) associated with complement dysregulation; aHUS may be associated with other 'triggers' or 'clinical conditions'. This study aimed to characterize this patient population using data from the Global aHUS Registry, the largest collection of real-world data on patients with aHUS. METHODS: Patients enrolled in the Global aHUS Registry between April 2012 and June 2021 and with recorded aHUS-associated triggers or clinical conditions prior/up to aHUS onset were analysed. aHUS was diagnosed by the treating physician. Data were classified by age at onset of aHUS (< or ≥18 years) and additionally by the presence/absence of identified pathogenic complement genetic variant(s) and/or anti-complement factor H (CFH) antibodies. Genetically/immunologically untested patients were excluded. RESULTS: 1947 patients were enrolled in the Global aHUS Registry by June 2021, and 349 (17.9%) met inclusion criteria. 307/349 patients (88.0%) had a single associated trigger or clinical condition and were included in the primary analysis. Malignancy was most common (58/307, 18.9%), followed by pregnancy and acute infections (both 53/307, 17.3%). Patients with an associated trigger or clinical condition were generally more likely to be adults at aHUS onset. CONCLUSION: Our analysis suggests that aHUS-associated triggers or clinical conditions may be organized into clinically relevant categories, and their presence does not exclude the concurrent presence of pathogenic complement genetic variants and/or anti-CFH antibodies. Considering a diagnosis of aHUS with associated triggers or clinical conditions in patients presenting with TMA may allow faster and more appropriate treatment.
Assuntos
Síndrome Hemolítico-Urêmica Atípica , Sistema de Registros , Humanos , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/epidemiologia , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/imunologia , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Adolescente , Gravidez , Fator H do Complemento/genética , Fator H do Complemento/imunologia , Criança , Neoplasias/epidemiologia , Idade de Início , Pré-Escolar , Fatores de Risco , IdosoRESUMO
OBJECTIVE: Malnutrition and obesity are complex burdensome challenges in pediatric chronic kidney disease (CKD) management that can adversely affect growth, disease progression, wellbeing, and response to treatment. Total energy expenditure (TEE) and energy requirements in children are essential for growth outcomes but are poorly defined, leaving clinical practice varied and insecure. The aims of this study were to explore a practical approach to guide prescribed nutritional interventions, using measurements of TEE, physical activity energy expenditure (PAEE), and their relationship to kidney function. DESIGN AND METHODS: In a cross-sectional prospective age-matched and sex-matched controlled study, 18 children with CKD (6-17 years, mean stage 3) and 20 healthy, age-matched, and gender-matched controls were studied. TEE and PAEE were measured using basal metabolic rate (BMR), activity diaries and doubly labeled water (healthy subjects). Results were related to estimated glomerular filtration rate (eGFR). The main outcome measure was TEE measured by different methods (factorial, doubly labeled water, and a novel device). RESULTS: Total energy expenditure and PAEE with or without adjustments for age, gender, weight, and height did not differ between the groups and was not related to eGFR. TEE ranged from 1927 ± 91 to 2330 ± 73 kcal/d; 95 ± 5 to 109 ± 5% estimated average requirement (EAR), physical activity level (PAL) 1.52 ± 0.01 to 1.71 ± 0.17, and PAEE 24 to 34% EAR. Comparisons between DLW and alternative methods in healthy children did not differ significantly, except for 2 (factorial methods and a fixed PAL; and the novel device). CONCLUSION: In clinical practice, structured approaches using supportive evidence (weight, height, BMI sds), predictive BMR or TEE values and simple questions on activity, are sufficient for most children with CKD as a starting energy prescription.
Assuntos
Metabolismo Energético , Insuficiência Renal Crônica , Humanos , Criança , Adolescente , Estudos Transversais , Estudos Prospectivos , Metabolismo Energético/fisiologia , Metabolismo Basal/fisiologia , Água , Insuficiência Renal Crônica/terapiaRESUMO
Renal Fanconi syndrome (RFS) is a generalised disorder of the proximal convoluted tubule. Many genes have been associated with RFS including those that cause systemic disorders such as cystinosis, as well as isolated RFS. We discuss the case of a 10-year-old female who presented with leg pain and raised creatinine on a screening blood test. Her mother has RFS and required a kidney transplant in her thirties. Further investigations confirmed RFS in the daughter. Exome sequencing was performed on the affected mother, child, and unaffected father. We identified a novel variant in GATM; c.965G>C p.(Arg322Pro) segregating dominantly in the mother and daughter. We validated our finding with molecular dynamics simulations and demonstrated a dynamic signature that differentiates our variant and two previously identified pathogenic variants in GATM from wildtype. Genetic testing has uncovered a novel pathogenic variant that predicts progression to end stage kidney failure and has important implications for family planning and cascade testing. We recommend that GATM is screened for in children presenting with RFS, in addition to adults, particularly with kidney failure, who may have had previous negative gene testing.
Assuntos
Síndrome de Fanconi , Falência Renal Crônica , Criança , Adulto , Feminino , Humanos , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/genética , Síndrome de Fanconi/complicações , Falência Renal Crônica/genética , Falência Renal Crônica/complicações , Testes Genéticos , CausalidadeRESUMO
This report describes the rationale and design of a study assessing tolvaptan in children with autosomal dominant polycystic kidney disease (ADPKD). Phase A is a 1-year, randomized, double-blind, placebo-controlled, multicenter trial. Phase B is a 2-year, open-label extension. The target population is at least 60 children aged 12-17 years, diagnosed by family history and/or genetic criteria and the presence of ≥ 10 renal cysts, each ≥ 0.5 cm on magnetic resonance imaging. Subjects will be allocated into 4 groups: females 15-17 years; females 12-14 years; males 15-17 years; and males 12-14 years. Up to 40 subjects aged 4-11 years may also enroll, provided they meet the entry criteria. Weight-adjusted tolvaptan doses, titrated once to achieve a tolerated maintenance dose, and matching placebo will be administered twice-daily. Assessments include spot urine osmolality and specific gravity (co-primary endpoints), height-adjusted total kidney volume, estimated glomerular filtration rate, pharmacodynamic parameters (urine volume, fluid intake and fluid balance, serum sodium, serum creatinine, free water clearance), pharmacokinetic parameters, safety (aquaretic adverse events, changes from baseline in creatinine, vital signs, laboratory values including liver function tests), and generic pediatric quality of life assessments.Conclusion: This will be the first clinical study to evaluate tolvaptan in pediatric ADPKD. What is Known: ⢠Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder causing the development of cysts that impede kidney function over time and eventually induce renal failure ⢠There are few data on the effects of tolvaptan, the only treatment approved for adults to slow disease progression, in pediatric ADPKD patients with early-stage disease What is New: ⢠A phase 3, placebo-controlled study is evaluating tolvaptan over 3 years in children and adolescents with ADPKD ⢠This study is designed to account for challenges of tolvaptan dosing and outcome assessment specific to the pediatric population.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/administração & dosagem , Rim Policístico Autossômico Dominante/tratamento farmacológico , Tolvaptan/administração & dosagem , Adolescente , Criança , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Método Duplo-Cego , Feminino , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
We report five individuals with loss-of-function of the X-linked AMMECR1: a girl with a balanced X-autosome translocation and inactivation of the normal X-chromosome; two boys with maternally inherited and de novo nonsense variants; and two half-brothers with maternally inherited microdeletion variants. They present with short stature, cardiac and skeletal abnormalities, and hearing loss. Variants of unknown significance in AMMECR1 in four male patients from two families with partially overlapping phenotypes were previously reported. AMMECR1 is coexpressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alterations. Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients' features. The increased transcript and encoded protein levels of AMMECR1L, an AMMECR1 paralog, in the t(X;9) patient's cells indicate a possible partial compensatory mechanism. AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid-binding RAGNYA folds. Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart, and kidney alterations with or without elliptocytosis.
Assuntos
Osso e Ossos/fisiologia , Coração/fisiologia , Proteínas/genética , Animais , Western Blotting , Osso e Ossos/metabolismo , Ciclo Celular/genética , Ciclo Celular/fisiologia , Linhagem Celular , Exoma/genética , Feminino , Células HeLa , Humanos , Masculino , Sequenciamento Completo do Genoma , Peixe-ZebraRESUMO
Thrombotic microangiopathy is a potentially lethal complication of haematopoietic stem cell (bone marrow) transplantation. The pathophysiology is incompletely understood, although endothelial damage appears to be central. Platelet activation, neutrophil extracellular traps and complement activation appear to play key roles. Diagnosis may be difficult and universally accepted diagnostic criteria are not available. Treatment remains controversial. In some cases, withdrawal of calcineurin inhibitors is adequate. Rituximab and defibrotide also appear to have been used successfully. In severe cases, complement inhibitors such as eculizumab may play a valuable role. Further research is required to define the pathophysiology and determine both robust diagnostic criteria and the optimal treatment.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Rim/patologia , Microvasos/patologia , Microangiopatias Trombóticas/diagnóstico , Proteína ADAMTS13/sangue , Proteína ADAMTS13/metabolismo , Biópsia , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/efeitos adversos , Ativação do Complemento/efeitos dos fármacos , Ativação do Complemento/imunologia , Inativadores do Complemento/uso terapêutico , Células Endoteliais/imunologia , Células Endoteliais/patologia , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Incidência , Rim/irrigação sanguínea , Rim/citologia , Rim/imunologia , Microvasos/citologia , Microvasos/imunologia , Troca Plasmática , Fatores de Risco , Rituximab/uso terapêutico , Microangiopatias Trombóticas/epidemiologia , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/terapia , Resultado do TratamentoRESUMO
BACKGROUND: Deletions in the Xq22.3-Xq23 region, inclusive of COL4A5, have been associated with a contiguous gene deletion syndrome characterised by Alport syndrome with intellectual disability (Mental retardation), Midface hypoplasia and Elliptocytosis (AMME). The extrarenal biological and clinical significance of neighbouring genes to the Alport locus has been largely speculative. We sought to discover a genetic cause for two half-brothers presenting with nephrocalcinosis, early speech and language delay and midface hypoplasia with submucous cleft palate and bifid uvula. METHODS: Whole exome sequencing was undertaken on maternal half-siblings. In-house genomic analysis included extraction of all shared variants on the X chromosome in keeping with X-linked inheritance. Patient-specific mutants were transfected into three cell lines and microscopically visualised to assess the nuclear expression pattern of the mutant protein. RESULTS: In the affected half-brothers, we identified a hemizygous novel non-synonymous variant of unknown significance in AMMECR1 (c.G530A; p.G177D), a gene residing in the AMME disease locus. Transfected cell lines with the p.G177D mutation showed aberrant nuclear localisation patterns when compared with the wild type. Blood films revealed the presence of elliptocytes in the older brother. CONCLUSIONS: Our study shows that a single missense mutation in AMMECR1 causes a phenotype of midface hypoplasia, mild intellectual disability and the presence of elliptocytes, previously reported as part of a contiguous gene deletion syndrome. Functional analysis confirms mutant-specific protein dysfunction. We conclude that AMMECR1 is a critical gene in the pathogenesis of AMME, causing midface hypoplasia and elliptocytosis and contributing to early speech and language delay, infantile hypotonia and hearing loss, and may play a role in dysmorphism, nephrocalcinosis and submucous cleft palate.
Assuntos
Deficiências do Desenvolvimento/genética , Eliptocitose Hereditária/genética , Nefrite Hereditária/genética , Proteínas/genética , Sequência de Bases , Deficiências do Desenvolvimento/fisiopatologia , Eliptocitose Hereditária/fisiopatologia , Exoma/genética , Predisposição Genética para Doença , Genótipo , Humanos , Nefrite Hereditária/fisiopatologia , Linhagem , Fenótipo , Mutação PuntualRESUMO
Factor H autoantibodies can impair complement regulation, resulting in atypical hemolytic uremic syndrome, predominantly in childhood. There are no trials investigating treatment, and clinical practice is only informed by retrospective cohort analysis. Here we examined 175 children presenting with atypical hemolytic uremic syndrome in the United Kingdom and Ireland for factor H autoantibodies that included 17 children with titers above the international standard. Of the 17, seven had a concomitant rare genetic variant in a gene encoding a complement pathway component or regulator. Two children received supportive treatment; both developed established renal failure. Plasma exchange was associated with a poor rate of renal recovery in seven of 11 treated. Six patients treated with eculizumab recovered renal function. Contrary to global practice, immunosuppressive therapy to prevent relapse in plasma exchange-treated patients was not adopted due to concerns over treatment-associated complications. Without immunosuppression, the relapse rate was high (five of seven). However, reintroduction of treatment resulted in recovery of renal function. All patients treated with eculizumab achieved sustained remission. Five patients received renal transplants without specific factor H autoantibody-targeted treatment with recurrence in one who also had a functionally significant CFI mutation. Thus, our current practice is to initiate eculizumab therapy for treatment of factor H autoantibody-mediated atypical hemolytic uremic syndrome rather than plasma exchange with or without immunosuppression. Based on this retrospective analysis we see no suggestion of inferior treatment, albeit the strength of our conclusions is limited by the small sample size.
Assuntos
Síndrome Hemolítico-Urêmica Atípica/imunologia , Autoanticorpos/sangue , Falência Renal Crônica/imunologia , Transplante de Rim , Adolescente , Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/sangue , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/terapia , Criança , Pré-Escolar , Fator H do Complemento/imunologia , Proteínas do Sistema Complemento/análise , Proteínas do Sistema Complemento/genética , Feminino , Humanos , Terapia de Imunossupressão/efeitos adversos , Terapia de Imunossupressão/métodos , Lactente , Irlanda , Falência Renal Crônica/sangue , Falência Renal Crônica/genética , Falência Renal Crônica/terapia , Masculino , Troca Plasmática , Recidiva , Diálise Renal , Estudos Retrospectivos , Reino UnidoRESUMO
Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9-30% in selected series. Using whole exome sequencing we sought to stratify a national population of children with SRNS into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1, NPHS2, and WT1 but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL, COL4A3, and DGKE associated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence-based algorithm for clinical management.
Assuntos
Genômica/métodos , Mutação , Síndrome Nefrótica/congênito , Medicina de Precisão , Adolescente , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Exoma , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Hereditariedade , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Estimativa de Kaplan-Meier , Rim/patologia , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/genética , Falência Renal Crônica/terapia , Masculino , Proteínas de Membrana/genética , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/genética , Síndrome Nefrótica/terapia , Linhagem , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Sistema de Registros , Fatores de Risco , Reino Unido , Proteínas WT1/genética , Adulto JovemRESUMO
BACKGROUND: Severe neonatal autosomal-dominant polycystic kidney disease (ADPKD) is rare and easily confused with recessive PKD. Managing such infants is difficult and often unsuccessful. CASE DIAGNOSIS/TREATMENT: A female infant with massive renal enlargement, respiratory compromise and hyponatraemia was treated with the arginine vasopressin receptor 2 antagonist tolvaptan. This resolved hyponatraemia, and there was no further increase in renal size. CONCLUSION: Tolvaptan may be a useful treatment for severe neonatal PKD.
Assuntos
Benzazepinas/uso terapêutico , Rim Policístico Autossômico Dominante/tratamento farmacológico , Edema/tratamento farmacológico , Edema/etiologia , Feminino , Taxa de Filtração Glomerular , Humanos , Recém-Nascido , Testes de Função Renal , Nutrição Parenteral , Rim Policístico Autossômico Dominante/congênito , Rim Policístico Autossômico Dominante/genética , Gravidez , Receptores de Vasopressinas/genética , Canais de Cátion TRPP/genética , Tolvaptan , Resultado do Tratamento , Adulto JovemRESUMO
Biochemical analysis and whole-exome sequencing identified mutations in the Golgi-localized UDP-galactose transporter SLC35A2 that define an undiagnosed X-linked congenital disorder of glycosylation (CDG) in three unrelated families. Each mutation reduced UDP-galactose transport, leading to galactose-deficient glycoproteins. Two affected males were somatic mosaics, suggesting that a wild-type SLC35A2 allele may be required for survival. In infancy, the commonly used biomarker transferrin showed abnormal glycosylation, but its appearance became normal later in childhood, without any corresponding clinical improvement. This may indicate selection against cells carrying the mutant allele. To detect other individuals with such mutations, we suggest transferrin testing in infancy. Here, we report somatic mosaicism in CDG, and our work stresses the importance of combining both genetic and biochemical diagnoses.
Assuntos
Defeitos Congênitos da Glicosilação/etiologia , Proteínas de Transporte de Monossacarídeos/genética , Mosaicismo , Mutação/genética , Uridina Difosfato Galactose/metabolismo , Transporte Biológico , Estudos de Casos e Controles , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/metabolismo , Defeitos Congênitos da Glicosilação/patologia , Exoma/genética , Feminino , Glicosilação , Humanos , Masculino , Espectrometria de Massas por Ionização por Electrospray , Transferrina/análise , Transferrina/metabolismoRESUMO
BACKGROUND: Paediatric renal biopsy standards introduced in the UK in 2010 were intended to reduce variation and improve practice. A concurrent national drive was aimed at building robust paediatric nephrology networks to ensure services cater for the needs of the family and minimise time away from home. We aimed to identify current national practice since these changes on behalf of the British Association for Paediatric Nephrology. METHODS: All UK paediatric nephrology centres were invited to complete a survey of their biopsy practice, including advance preparation. From 1 January to 30 June 2012, a national prospective audit of renal biopsies was undertaken at participating centres comparing practice with the British Association for Paediatric Nephrology (BAPN) standards and audit results from 2005. RESULTS: Survey results from 11 centres demonstrated increased use of pre-procedure information leaflets (63.6 % vs 45.5 %, P = 0.39) and play preparation (90.9 % vs 9.1 %, P = 0.0001). Audit of 331 biopsies showed a move towards day-case procedures (49.5 % vs 32.9 %, P = 0.17) and reduced major complications (4.5 % vs 10.4 %, P = 0.002). Biopsies with 18-gauge needles had significantly higher mean pass rates (3.2 vs 2.3, P = 0.0008) and major complications (15.3 % vs 3.3 %, P = 0.0015) compared with 16-gauge needles. CONCLUSIONS: Percutaneous renal biopsy remains a safe procedure in children, thus improving family-centered service provision in the UK.
Assuntos
Biópsia/tendências , Atenção à Saúde/tendências , Nefropatias/diagnóstico , Rim/patologia , Nefrologia/tendências , Pediatria/tendências , Padrões de Prática Médica/tendências , Medicina Estatal/tendências , Adolescente , Biópsia/efeitos adversos , Biópsia/normas , Criança , Pré-Escolar , Atenção à Saúde/normas , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Lactente , Recém-Nascido , Nefropatias/patologia , Masculino , Auditoria Médica , Nefrologia/normas , Assistência Centrada no Paciente/tendências , Pediatria/normas , Padrões de Prática Médica/normas , Valor Preditivo dos Testes , Estudos Prospectivos , Indicadores de Qualidade em Assistência à Saúde/tendências , Medicina Estatal/normas , Reino Unido , Adulto JovemRESUMO
BACKGROUND: Meeting energy requirements of children with chronic kidney disease (CKD) is paramount to optimising growth and clinical outcome, but little information on this subject has been published. In this study, we examined basal metabolic rate (BMR; a component of energy expenditure) with the aim to determine whether it is related to kidney function independently of weight, height and lean body mass (LBM). METHODS: Twenty children with CKD and 20 healthy age- and gender-matched control children were studied on one occasion. BMR was measured by indirect open circuit calorimetry and predicted by the Schofield equation. Estimated glomerular filtration rate (eGFR) was related to BMR and adjusted for weight, height, age and LBM measured by skinfold thickness. RESULTS: The adjusted BMR of children with CKD did not differ significantly from that of healthy subjects (1296 ± 318 vs.1325 ± 178 kcal/day; p = 0.720). Percentage of predicted BMR also did not differ between the two groups (102 ± 12% vs. 99 ± 14%; p = 0.570). Within the CKD group, eGFR (mean 33.7 ± 20.5 mL/min/m(2)) was significantly related to BMR (ß 0.3, r = 0.517, p = 0.019) independently of nutritional status and LBM. CONCLUSIONS: It seems reasonable to use estimated average requirement as the basis of energy prescriptions for children with CKD (mean CKD stage 3 disease). However, those who were sicker had significantly lower metabolic rates.
Assuntos
Metabolismo Basal/fisiologia , Insuficiência Renal Crônica/metabolismo , Calorimetria Indireta , Criança , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) is a rare disorder usually caused by dysregulation of the alternative complement pathway. Uncontrolled complement activation results in systemic complement-mediated thrombotic microangiopathy (TMA) and subsequent multi-organ damage. The two most common extrarenal complications comprise neurological and cardiovascular involvement. Eculizumab, a humanised anti-C5 monoclonal antibody, has recently been introduced as a therapy for this condition. CASE-DIAGNOSIS/TREATMENT: A 19-month-old child suffering from aHUS with severe neurological involvement, dilated cardiomyopathy and renal impairment requiring dialysis received eculizumab as first-line treatment, initiated within 12 h of admission, resulting in significant improvements in her neurological state and normalisation of cardiac and renal function. These positive outcomes have been sustained with fortnightly eculizumab therapy (at the time of writing, on-going for 1 year). No further complications of TMA have occurred. CONCLUSION: Severe cardiac involvement in a child with aHUS is an important indication for prompt, first-line treatment with eculizumab, resulting in rapid normalisation of cardiac function.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/complicações , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Cardiomiopatia Dilatada/etiologia , Feminino , Humanos , Lactente , Diálise Renal , Insuficiência Renal/etiologia , Convulsões/etiologiaRESUMO
A girl aged 6 presented with haematuria and her sister (aged 5) presented with haematuria and proteinuria. Family history showed multiple individuals suffering from end stage renal failure from the paternal side of the pedigree. Following kidney biopsy in the father and paternal grandmother, the pathological diagnosis was of focal segmental glomerulosclerosis (FSGS). Exome sequencing was undertaken in the proband's sister and grandmother. Genetic variants shared by both affected individuals were interrogated to identify the genetic cause of disease. Candidate variants were then sequenced in all the family members to determine segregation with the disease. A mutation of COL4A5 known to cause Alport syndrome segregated with disease from the paternal side of the pedigree and a variant in NPHS1 was present in both paediatric cases and inherited from their mother. This study highlights the advantages of exome sequencing over single gene testing; disease presentation can be heterogeneous with several genes representing plausible candidates; candidate gene(s) may be unavailable as a diagnostic test; consecutive, single gene testing typically concludes once a single causal mutation is identified. In this family, we were able to confirm a diagnosis of Alport syndrome, which will facilitate testing in other family members.
Assuntos
Exoma , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/genética , Adulto , Biópsia , Criança , Pré-Escolar , Colágeno Tipo IV/genética , Diagnóstico Diferencial , Feminino , Humanos , Rim/patologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/genética , Linhagem , Análise de Sequência de DNARESUMO
BACKGROUND: Dominant polycystic kidney disease is common and usually presents clinically in adulthood. Recessive polycystic kidney disease is much less common and frequently presents antenatally or in the neonatal period with severe renal involvement. These are usually thought of as clinically distinct entities but diagnostic confusion is not infrequent. CASE-DIAGNOSIS/TREATMENT: We describe an infant with antenatally diagnosed massive renal enlargement and oligohydramnios with no resolvable cysts on ultrasound scanning. He underwent bilateral nephrectomy because of respiratory compromise and poor renal function but died subsequently of overwhelming sepsis. Genetic analysis revealed that he had bilineal inheritance of abnormalities of PKD1 and no demonstrable abnormalities of PKD2 or PKHD1. CONCLUSIONS: Biallelic inheritance of abnormalities of PKD1 may causextremely severe disease resembling autosomal recessive polycystic kidney disease (ARPKD) which can result indiagnostic confusion. Accurate diagnosis is essential forgenetic counseling [corrected].
Assuntos
Rim Policístico Autossômico Recessivo/patologia , Canais de Cátion TRPP/deficiência , Canais de Cátion TRPP/genética , Acidose Respiratória/etiologia , Adulto , Apneia/etiologia , Cesárea , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Testes de Função Renal , Masculino , Mutação/genética , Nefrectomia , Hibridização de Ácido Nucleico , Pré-Eclâmpsia , Gravidez , Diagnóstico Pré-Natal , Troca Gasosa Pulmonar , Sepse/etiologiaRESUMO
BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) is caused by dysregulated complement activation. A humanised anti-C5 monoclonal antibody has recently become available for treatment of this condition CASE-DIAGNOSIS/TREATMENT: We present the first description of an infant with an activating mutation of complement factor B successfully treated with eculizumab. On standard doses she had evidence of ongoing C5 cleavage despite a good clinical response. CONCLUSIONS: Eculizumab is effective therapy for aHUS associated with factor B mutations, but recommended doses may not be adequate for all patients.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Fator B do Complemento/genética , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Mutação , Síndrome Hemolítico-Urêmica Atípica , Biomarcadores/sangue , Biópsia , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Feminino , Predisposição Genética para Doença , Síndrome Hemolítico-Urêmica/diagnóstico , Síndrome Hemolítico-Urêmica/genética , Síndrome Hemolítico-Urêmica/imunologia , Humanos , Lactente , L-Lactato Desidrogenase/sangue , Fenótipo , Resultado do TratamentoRESUMO
Dent disease type 1 is suspected in the presence of a complete phenotype of low molecular weight (LMW) proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, nephrolithiasis, haematuria, hypophosphatemia or chronic kidney disease (CKD). We present two brothers who presented with CKD alone. In the absence of typical clinical features, further assessment of LMW proteinuria and hypercalciuria was not undertaken. Whole-genome sequencing revealed hemizygous loss of function mutations in chloride voltage-gated channel 5 (CLCN5) consistent with Dent disease. Dent disease should, therefore, be considered in patients with an incomplete phenotype, including unexplained CKD alone.
RESUMO
With the increased availability of genomic sequencing technologies, the molecular bases for kidney diseases such as nephronophthisis and mitochondrially inherited and autosomal-dominant tubulointerstitial kidney diseases (ADTKD) has become increasingly apparent. These tubulointerstitial kidney diseases (TKD) are monogenic diseases of the tubulointerstitium and result in interstitial fibrosis and tubular atrophy (IF/TA). However, monogenic inheritance alone does not adequately explain the highly variable onset of kidney failure and extra-renal manifestations. Phenotypes vary considerably between individuals harbouring the same pathogenic variant in the same putative monogenic gene, even within families sharing common environmental factors. While the extreme end of the disease spectrum may have dramatic syndromic manifestations typically diagnosed in childhood, many patients present a more subtle phenotype with little to differentiate them from many other common forms of non-proteinuric chronic kidney disease (CKD). This review summarises the expanding repertoire of genes underpinning TKD and their known phenotypic manifestations. Furthermore, we collate the growing evidence for a role of modifier genes and discuss the extent to which these data bridge the historical gap between apparently rare monogenic TKD and polygenic non-proteinuric CKD (excluding polycystic kidney disease).
Assuntos
Doenças Renais Policísticas , Insuficiência Renal Crônica , Humanos , Rim , Mapeamento Cromossômico , Genes ModificadoresRESUMO
Autosomal recessive whole gene deletions of nephrocystin-1 (NPHP1) result in abnormal structure and function of the primary cilia. These deletions can result in a tubulointerstitial kidney disease known as nephronophthisis and retinal (Senior-Løken syndrome) and neurological (Joubert syndrome) diseases. Nephronophthisis is a common cause of end-stage kidney disease (ESKD) in children and up to 1% of adult onset ESKD. Single nucleotide variants (SNVs) and small insertions and deletions (Indels) have been less well characterised. We used a gene pathogenicity scoring system (GenePy) and a genotype-to-phenotype approach on individuals recruited to the UK Genomics England (GEL) 100,000 Genomes Project (100kGP) (n = 78,050). This approach identified all participants with NPHP1-related diseases reported by NHS Genomics Medical Centres and an additional eight participants. Extreme NPHP1 gene scores, often underpinned by clear recessive inheritance, were observed in patients from diverse recruitment categories, including cancer, suggesting the possibility of a more widespread disease than previously appreciated. In total, ten participants had homozygous CNV deletions with eight homozygous or compound heterozygous with SNVs. Our data also reveals strong in-silico evidence that approximately 44% of NPHP1 related disease may be due to SNVs with AlphaFold structural modelling evidence for a significant impact on protein structure. This study suggests historical under-reporting of SNVS in NPHP1 related diseases compared with CNVs.