RESUMEN
BACKGROUND: Atypical hemolytic uremic syndrome (aHUS), a severe thrombotic microangiopathy, is often related to complement dysregulation, but the pathomechanisms remain unknown in at least 30% of patients. Researchers have described autoantibodies to complement factor H of the IgG class in 10% of patients with aHUS but have not reported anti-factor H autoantibodies of the IgM class. METHODS: In 186 patients with thrombotic microangiopathy clinically presented as aHUS, we searched for anti-factor H autoantibodies of the IgM class and those of the IgG and IgA classes. We used immunochromatography to purify anti-factor H IgM autoantibodies and immunoenzymatic methods and a competition assay with mapping mAbs to characterize interaction with the target protein. RESULTS: We detected anti-factor H autoantibodies of the IgM class in seven of 186 (3.8%) patients with thrombotic microangiopathy presented as aHUS. No association was observed between anti-factor H IgM and homozygous deletions involving CFHR3-CFHR1. A significantly higher proportion of patients with bone marrow transplant-related thrombotic microangiopathy had anti-factor H IgM autoantibodies versus other patients with aHUS: three of 20 (15%) versus four of 166 (2.4%), respectively. The identified IgM autoantibodies recognize the SCR domain 19 of factor H molecule in all patients and interact with the factor H molecule, inhibiting its binding to C3b. CONCLUSIONS: Detectable autoantibodies to factor H of the IgM class may be present in patients with aHUS, and their frequency is six-fold higher in thrombotic microangiopathy forms associated with bone marrow transplant. The autoantibody interaction with factor H's active site may support an autoimmune mechanism in some cases previously considered to be of unknown origin.
Asunto(s)
Síndrome Hemolítico Urémico Atípico/sangre , Autoanticuerpos/sangre , Factor H de Complemento/inmunología , Inmunoglobulina M/inmunología , Adolescente , Adulto , Síndrome Hemolítico Urémico Atípico/diagnóstico , Síndrome Hemolítico Urémico Atípico/inmunología , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Hematopoietic stem cell transplant-related thrombotic microangiopathy (HSCT-TMA) is a severe complication whose pathophysiology is unknown. We describe 6 patients in which the disease was associated with complement regulatory gene abnormalities received from their respective donors. It is suggested that mutated and transplanted monocyte-derived cells are responsible for production of abnormal proteins, complement dysregulation, and, ultimately, for the disease. This observation might have important drawbacks as far as HSCT-TMA pathophysiology and treatment are concerned.
Asunto(s)
Proteínas del Sistema Complemento/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Mutación , Microangiopatías Trombóticas/diagnóstico , Microangiopatías Trombóticas/genética , Adolescente , Anemia de Diamond-Blackfan/inmunología , Anemia de Diamond-Blackfan/patología , Anemia de Diamond-Blackfan/terapia , Anemia de Células Falciformes/inmunología , Anemia de Células Falciformes/patología , Anemia de Células Falciformes/terapia , Proteínas del Sistema Complemento/inmunología , Expresión Génica , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Persona de Mediana Edad , Microangiopatías Trombóticas/etiología , Microangiopatías Trombóticas/inmunología , Donantes de Tejidos , Trasplante Homólogo , Adulto JovenRESUMEN
UNLABELLED: Despite the severity of HUS and the fact that it represents a leading cause of acute kidney injury in children, the general epidemiology of HUS is all but well documented. The present study provides updated, population-based, purely epidemiological information on HUS in childhood from a large and densely populated area of northern Italy (9.6 million inhabitants, 1.6 million children). We systematically reviewed the files concerning patients with STEC-HUS and atypical HUS (aHUS) over a 10-year observation period (January 2003-December 2012). We included all incident cases with a documented first episode of HUS before the age of 18 years. We identified 101 cases of HUS during the 10 years. The overall mean annual incidence was 6.3 cases/million children aged <18 years (range 1.9-11.9), and 15.7/million of age-related population (MARP) among subjects aged <5 years; aHUS accounted for 11.9 % of the cases (mean incidence 0.75/MARP). The overall case fatality rate was 4.0 % (3.4 % STEC-HUS, 8.3 % aHUS). CONCLUSION: Given the public health impact of HUS, this study provides recent, population-based epidemiological data useful for healthcare planning and particularly for estimating the financial burden that healthcare providers might have to face in treating HUS, whose incidence rate seems to increase in Northern Italy. WHAT IS KNOWN: ⢠HUS is a rare disease, but it represents the leading cause of acute kidney injury in children worldwide. ⢠STEC-HUS (also called typical, D + HUS) is more common compared to atypical HUS, but recent, population-based epidemiological data (incidence) are scanty. What is New: ⢠Comprehensive, population-based epidemiological data concerning both typical and atypical HUS based on a long observational period.
Asunto(s)
Infecciones por Escherichia coli/epidemiología , Escherichia coli/aislamiento & purificación , Síndrome Hemolítico-Urémico/epidemiología , Adolescente , Niño , Preescolar , Infecciones por Escherichia coli/complicaciones , Síndrome Hemolítico-Urémico/microbiología , Humanos , Incidencia , Lactante , Italia/epidemiologíaRESUMEN
BACKGROUND: Gitelman syndrome (GS) and Bartter syndrome (BS) are hereditary salt-losing tubulopathies (SLTs) resulting from defects of renal proteins involved in electrolyte reabsorption, as for sodium-chloride cotransporter (NCC) and furosemide-sensitive sodium-potassium-chloride cotransporter (NKCC2) cotransporters, affected in GS and BS Type 1 patients, respectively. Currently, definitive diagnosis is obtained through expensive and time-consuming genetic testing. Urinary exosomes (UE), nanovesicles released by every epithelial cell facing the urinary space, represent an ideal source of markers for renal dysfunction and injury, because UE molecular composition stands for the cell of origin. On these assumptions, the aim of this work is to evaluate the relevance of UE for the diagnosis of SLTs. METHODS: UE were purified from second morning urines collected from 32 patients with genetically proven SLTs (GS, BS1, BS2 and BS3 patients), 4 with unclassified SLTs and 22 control subjects (age and sex matched). The levels of NCC and NKCC2 were evaluated in UE by SDS-PAGE/western blotting with specific antibodies. RESULTS: Due to their location on the luminal side of tubular cells, NCC and NKCC2 are well represented in UE proteome. The NCC signal is significantly decreased/absent in UE of Gitelman patients compared with control subjects (Mann-Whitney t-test, P < 0.001) and, similarly, the NKCC2 in those of Bartter type 1 (P < 0.001). The difference in the levels of the two proteins allows recognition of Gitelman and Bartter type 1 patients from controls and, combined with clinical data, from other Bartter patients. Moreover, the receiver operating characteristic curve analysis using UE NCC densitometric values showed a good discriminating power of the test comparing GS patients versus controls and BS patients (area under the curve value = 0.92; sensitivity 84.2% and specificity 88.6%). CONCLUSIONS: UE phenotyping may be useful in the diagnosis of GS and BS, thus providing an alternative/complementary, urine-based diagnostic tool for SLT patient recognition and a diagnostic guidance in complex cases.
Asunto(s)
Síndrome de Bartter/diagnóstico , Biomarcadores/orina , Exosomas/metabolismo , Síndrome de Gitelman/diagnóstico , Miembro 1 de la Familia de Transportadores de Soluto 12/orina , Adolescente , Adulto , Síndrome de Bartter/orina , Western Blotting , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Síndrome de Gitelman/orina , Humanos , Masculino , Miembro 3 de la Familia de Transportadores de Soluto 12/orina , Adulto JovenRESUMEN
BACKGROUND: Shigatoxin-associated hemolytic uremic syndrome (STEC-HUS) is a common thrombotic microangiopathy (TMA) in which central nervous system (CNS) involvement is responsible for the majority of deaths and for severe long-term sequelae. We have analyzed the role of hemoconcentration in disease severity. METHODS: This was a retrospective review of the records and laboratory data at presentation of all patients with STEC-HUS cases (n = 61) over a 10-year period. The patients were grouped into three severity classes: group A, comprising patients who did not require dialysis; group B, patients who were dialyzed without CNS involvement; group C, patients with CNS involvement. RESULTS: Patients with CNS involvement (group C) had a higher mean hemoglobin level (11.2 ± 2.3 g/dL) than those of group A or B ( 9.4 ± 2.1 and 7.5 ± 1.9 g/dL, respectively; p < 0.0001). We also observed that the higher the initial hemoglobin level, the more severe the long-term renal damage (p < 0.007). CONCLUSIONS: In patients with STEC-HUS, hemoconcentration and hypovolemia may be responsible for more severe ischemic organ damage (both short and long term) at disease onset, and these signs should be regarded as risk factors for CNS damage and for more severe TMA. Therefore, we recommend that hydration status should be actively monitored in HUS patients and that dehydration, when diagnosed, should be promptly corrected.
Asunto(s)
Síndrome Hemolítico-Urémico/sangre , Síndrome Hemolítico-Urémico/complicaciones , Enfermedades del Sistema Nervioso/etiología , Adolescente , Niño , Preescolar , Femenino , Fluidoterapia/efectos adversos , Hematócrito , Humanos , Lactante , Masculino , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy, and as many as 70% of patients with aHUS have mutations in the genes encoding complement regulatory proteins. Eculizumab, a humanized recombinant monoclonal antibody targeting C5, has been used successfully in patients with aHUS since 2009. The standard maintenance treatment requires life-long eculizumab therapy, but the possibility of discontinuation has not yet been tested systematically. We report the safety of discontinuing eculizumab treatment in 10 patients who stopped treatment with the aim of minimizing the risk of adverse reactions, reducing the risk of meningitis, and improving quality of life while also reducing the considerable treatment costs. Disease activity was monitored closely at home by means of urine dipstick testing for hemoglobin. During the cumulative observation period of 95 months, 3 of the 10 patients experienced relapse within 6 weeks of discontinuation, but then immediately resumed treatment and completely recovered. Our experience supports the possibility of discontinuing eculizumab therapy with strict home monitoring for early signs of relapse in patients with aHUS who achieve stable remission.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Síndrome Hemolítico Urémico Atípico , Costo de Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Hemoglobinuria , Calidad de Vida , Privación de Tratamiento , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/economía , Síndrome Hemolítico Urémico Atípico/diagnóstico , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Síndrome Hemolítico Urémico Atípico/economía , Síndrome Hemolítico Urémico Atípico/fisiopatología , Síndrome Hemolítico Urémico Atípico/psicología , Niño , Preescolar , Inactivadores del Complemento/administración & dosificación , Inactivadores del Complemento/efectos adversos , Inactivadores del Complemento/economía , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Femenino , Hemoglobinuria/diagnóstico , Hemoglobinuria/etiología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico/métodos , Recurrencia , Inducción de Remisión , Resultado del Tratamiento , Urinálisis/métodosRESUMEN
BACKGROUND: Bartter patients may be hypercalciuric. Additional abnormalities in the metabolism of calcium, phosphate, and calciotropic hormones have occasionally been reported. METHODS: The metabolism of calcium, phosphate, and calciotropic hormones was investigated in 15 patients with Bartter syndrome and 15 healthy subjects. RESULTS: Compared to the controls, Bartter patients had significantly reduced plasma phosphate {mean [interquartile range]:1.29 [1.16-1.46] vs. 1.61 [1.54-1.67] mmol/L} and maximal tubular phosphate reabsorption (1.16 [1.00-1.35] vs. 1.41 [1.37-1.47] mmol/L) and significantly increased parathyroid hormone (PTH) level (6.1 [4.5-7.7] vs. 2.8 [2.2-4.4] pmol/L). However, patients and controls did not differ in blood calcium, 25-hydroxyvitamin D, alkaline phosphatase, and osteocalcin levels. In patients, an inverse correlation (P < 0.05) was noted between total plasma calcium or glomerular filtration rate and PTH concentration. A positive correlation was also noted between PTH and osteocalcin concentrations (P < 0.005), as well as between chloriduria or natriuria and phosphaturia (P < 0.001). No correlation was noted between calciuria and PTH concentration or between urinary or circulating phosphate and PTH. CONCLUSIONS: The results of this study demonstrate a tendency towards renal phosphate wasting and elevated circulating PTH levels in Bartter patients.
Asunto(s)
Síndrome de Bartter/metabolismo , Fosfatos/metabolismo , Adolescente , Síndrome de Bartter/genética , Síndrome de Bartter/fisiopatología , Calcio/sangre , Calcio/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Canales de Cloruro/genética , Femenino , Tasa de Filtración Glomerular , Homeostasis , Hormonas/metabolismo , Humanos , Masculino , Osteocalcina/sangre , Hormona Paratiroidea/sangre , Miembro 1 de la Familia de Transportadores de Soluto 12/genéticaRESUMEN
BACKGROUND: Although Duchenne and Becker muscular dystrophies, X-linked recessive myopathies, predominantly affect males, a clinically significant proportion of females manifesting symptoms have also been reported. They represent an heterogeneous group characterized by variable degrees of muscle weakness and/or cardiac involvement. Though preferential inactivation of the normal X chromosome has long been considered the principal mechanism behind disease manifestation in these females, supporting evidence is controversial. METHODS: Eighteen females showing a mosaic pattern of dystrophin expression on muscle biopsy were recruited and classified as symptomatic (7) or asymptomatic (11), based on the presence or absence of muscle weakness. The causative DMD gene mutations were identified in all cases, and the X-inactivation pattern was assessed in muscle DNA. Transcriptional analysis in muscles was performed in all females, and relative quantification of wild-type and mutated transcripts was also performed in 9 carriers. Dystrophin protein was quantified by immunoblotting in 2 females. RESULTS: The study highlighted a lack of relationship between dystrophic phenotype and X-inactivation pattern in females; skewed X-inactivation was found in 2 out of 6 symptomatic carriers and in 5 out of 11 asymptomatic carriers. All females were characterized by biallelic transcription, but no association was found between X-inactivation pattern and allele transcriptional balancing. Either a prevalence of wild-type transcript or equal proportions of wild-type and mutated RNAs was observed in both symptomatic and asymptomatic females. Moreover, very similar levels of total and wild-type transcripts were identified in the two groups of carriers. CONCLUSIONS: This is the first study deeply exploring the DMD transcriptional behaviour in a cohort of female carriers. Notably, no relationship between X-inactivation pattern and transcriptional behaviour of DMD gene was observed, suggesting that the two mechanisms are regulated independently. Moreover, neither the total DMD transcript level, nor the relative proportion of the wild-type transcript do correlate with the symptomatic phenotype.
Asunto(s)
Compensación de Dosificación (Genética) , Distrofina/genética , Debilidad Muscular/genética , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patología , Mutación/genética , Transcripción Genética , Inactivación del Cromosoma X/genética , Adolescente , Adulto , Alelos , Western Blotting , Niño , Preescolar , Hibridación Genómica Comparativa , Distrofina/metabolismo , Femenino , Heterocigoto , Humanos , Persona de Mediana Edad , Debilidad Muscular/patología , Osteopontina/genética , Fenotipo , Reacción en Cadena de la Polimerasa , Adulto JovenRESUMEN
Thrombotic microangiopathy (TMA) is a complication that may occur after autologous or allogeneic hematopoietic stem cell transplantation (HSCT) and is conventionally called transplant-associated thrombotic microangiopathy (TA-TMA). Despite the many efforts made to understand the mechanisms of TA-TMA, its pathogenesis is largely unknown, its diagnosis is challenging and the case-fatality rate remains high. The hallmarks of TA-TMA, as for any TMA, are platelet consumption, hemolysis, and organ dysfunction, particularly the kidney, leading also to hypertension. However, coexisting complications, such as infections and/or immune-mediated injury and/or drug toxicity, together with the heterogeneity of diagnostic criteria, render the diagnosis difficult. During the last 10 years, evidence has been provided on the involvement of the complement system in the pathophysiology of TA-TMA, supported by functional, genetic, and therapeutic data. Complement dysregulation is believed to collaborate with other proinflammatory and procoagulant factors to cause endothelial injury and consequent microvascular thrombosis and tissue damage. However, data on complement activation in TA-TMA are not sufficient to support a systematic use of complement inhibition therapy in all patients. Thus, it seems reasonable to propose complement inhibition therapy only to those patients exhibiting a clear complement activation according to the available biomarkers. Several agents are now available to inhibit complement activity: two drugs have been successfully used in TA-TMA, particularly in pediatric cases (eculizumab and narsoplimab) and others are at different stages of development (ravulizumab, coversin, pegcetacoplan, crovalimab, avacopan, iptacopan, danicopan, BCX9930, and AMY-101).
RESUMEN
BACKGROUND: Duchenne and Becker Muscular dystrophies (DMD/BMD) are allelic disorders caused by mutations in the dystrophin gene, which encodes a sarcolemmal protein responsible for muscle integrity. Deletions and duplications account for approximately 75% of mutations in DMD and 85% in BMD. The implementation of techniques allowing complete gene sequencing has focused attention on small point mutations and other mechanisms underlying complex rearrangements. METHODS: We selected 47 patients (41 families; 35 DMD, 6 BMD) without deletions and duplications in DMD gene (excluded by multiplex ligation-dependent probe amplification and multiplex polymerase chain reaction analysis). This cohort was investigated by systematic direct sequence analysis to study sequence variation. We focused our attention on rare mutational events which were further studied through transcript analysis. RESULTS: We identified 40 different nucleotide alterations in DMD gene and their clinical correlates; altogether, 16 mutations were novel. DMD probands carried 9 microinsertions/microdeletions, 19 nonsense mutations, and 7 splice-site mutations. BMD patients carried 2 nonsense mutations, 2 splice-site mutations, 1 missense substitution, and 1 single base insertion. The most frequent stop codon was TGA (n=10 patients), followed by TAG (n=7) and TAA (n=4). We also analyzed the molecular mechanisms of five rare mutational events. They are two frame-shifting mutations in the DMD gene 3'end in BMD and three novel splicing defects: IVS42: c.6118-3C>A, which causes a leaky splice-site; c.9560A>G, which determines a cryptic splice-site activation and c.9564-426 T>G, which creates pseudoexon retention within IVS65. CONCLUSION: The analysis of our patients' sample, carrying point mutations or complex rearrangements in DMD gene, contributes to the knowledge on phenotypic correlations in dystrophinopatic patients and can provide a better understanding of pre-mRNA maturation defects and dystrophin functional domains. These data can have a prognostic relevance and can be useful in directing new therapeutic approaches, which rely on a precise definition of the genetic defects as well as their molecular consequences.
Asunto(s)
Distrofina/genética , Distrofia Muscular de Duchenne/genética , Adolescente , Adulto , Alelos , Empalme Alternativo , Niño , Preescolar , Codón sin Sentido , Codón de Terminación , Estudios de Cohortes , Mutación del Sistema de Lectura , Humanos , Persona de Mediana Edad , Distrofia Muscular de Duchenne/diagnóstico , Mutagénesis Insercional , Mutación Missense , Fenotipo , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Inactivating mutations in the SLC12A3 gene are the main cause of Gitelman's syndrome (GS), a renal tubular disorder inherited as an autosomal recessive trait. In our cohort of patients, we identified 11 probands from 11 apparently unrelated Italian families that carry the c.1196_1202dup7bp mutation, which appears to be more frequent than other mutations in Italian GS patients. Therefore, we characterized in greater detail the SLC12A3 locus and its vicinity in those patients that carry this mutation in order to detect a possible shared haplotype. Three further probands characterized in France, carrying the same mutation, were also included in this study. METHODS: Sequence or fragment analyses were carried out to investigate seven intragenic polymorphisms (rs3217425, rs3816119, rs2304483, rs2278490, rs2278489, rs2289116 and rs2289115) that flank the mutation, as well as two extragenic markers, D16S3071 and D16S3057, flanking the SLC12A3 locus in the 5' and 3' termini, respectively. RESULTS: A shared haplotype co-segregates with the mutation both in Italian and French probands. Moreover, all the Italian families originate from a restricted area of Italy. Likewise, the French probands come from an area of France close to the north of Italy. CONCLUSION: It is likely that the c.1196_1202dup7bp mutation in the SLC12A3 gene reflects the presence of a common ancestor in an area covering the northern-central part of Italy and eastern France. A modified genotyping strategy for GS patients originating from this area has to be considered.
Asunto(s)
Síndrome de Gitelman/genética , Receptores de Droga/genética , Simportadores/genética , Familia , Femenino , Mutación del Sistema de Lectura , Francia , Haplotipos , Humanos , Italia , Masculino , Familia de Multigenes , Polimorfismo Genético , Miembro 3 de la Familia de Transportadores de Soluto 12RESUMEN
INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is mainly due to complement regulatory gene abnormalities with a dominant pattern but incomplete penetrance. Thus, healthy carriers can be identified in any family of aHUS patients, but it is unpredictable if they will eventually develop aHUS. METHODS: Patients are screened for 10 complement regulatory gene abnormalities and once a genetic alteration is identified, the search is extended to at-risk family members. The present cohort study includes 257 subjects from 71 families: 99 aHUS patients (71 index cases + 28 affected family members) and 158 healthy relatives with a documented complement gene abnormality. RESULTS: Fourteen families (19.7%) experienced multiple cases. Over a cumulative observation period of 7595 person-years, only 28 family members carrying gene mutations experienced aHUS (overall penetrance of 20%), leading to a disease rate of 3.69 events for 1000 person-years. The disease rate was 7.47 per 1000 person-years among siblings, 6.29 among offspring, 2.01 among parents, 1.84 among carriers of variants of uncertain significance, and 4.43 among carriers of causative variants. CONCLUSIONS: The penetrance of aHUS seems a lot lower than previously reported. Moreover, the disease risk is higher in carriers of causative variants and is not equally distributed among generations: siblings and the offspring of patients have a much greater disease risk than parents. However, risk calculation may depend on variant classification that could change over time.
RESUMEN
RATIONALE AND OBJECTIVE: Patients with atypical hemolytic uremic syndrome (aHUS) have long been considered ineligible for kidney transplantation (KTx) in several centers due to the high risk of disease recurrence, graft loss and life-threatening complications. The availability of Eculizumab (ECU) has now overcome this problem. However, the best approach towards timing, maintenance schedule, the possibility of discontinuation and patient monitoring has not yet been clearly established. STUDY DESIGN: This is a single center case series presenting our experience with KTx in aHUS. SETTING AND PARTICIPANTS: This study included 26 patients (16 females) with a diagnosis of aHUS, who spent a median of 5.5 years on kidney replacement therapy before undergoing KTx. We compared the aHUS relapse rate in three groups of patients who underwent KTx: patients who received no prophylaxis, patients who underwent plasma exchange, those who received Eculizumab prophylaxis. Complement factor H-related disease was by far the most frequent etiology (n = 19 patients). RESULTS: Untreated patients and patients undergoing pre-KTx plasma exchange prophylaxis had a relapse rate of 0.81 (CI 0.30-1.76) and 3.1 (CI 0.64-9.16) events per 10 years cumulative observation, respectively, as opposed to 0 events among patients receiving Eculizumab prophylaxis. The time between Eculizumab doses was tailored based on classic complement pathway activity (target to < 30%). Using this strategy, 12 patients are currently receiving Eculizumab every 28 days, 5 every 24-25 days, and 3 every 21 days. CONCLUSION: Our experience supports the prophylactic use of Eculizumab in patients with a previous history of aHUS undergoing KTx, especially when complement dysregulation is well documented by molecular biology.
Asunto(s)
Síndrome Hemolítico Urémico Atípico , Trasplante de Riñón , Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome Hemolítico Urémico Atípico/diagnóstico , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Femenino , Humanos , Trasplante de Riñón/efectos adversos , PlasmaféresisRESUMEN
BACKGROUND: Little information is available on a long-term follow-up in Bartter syndrome type I and II. METHODS: Clinical presentation, treatment and long-term follow-up (5.0-21, median 11 years) were evaluated in 15 Italian patients with homozygous (n = 7) or compound heterozygous (n = 8) mutations in the SLC12A1 (n = 10) or KCNJ1 (n = 5) genes. RESULTS: Thirteen new mutations were identified. The 15 children were born pre-term with a normal for gestational age body weight. Medical treatment at the last follow-up control included supplementation with potassium in 13, non-steroidal anti-inflammatory agents in 12 and gastroprotective drugs in five patients. At last follow-up, body weight and height were within normal ranges in the patients. Glomerular filtration rate was <90 mL/min/1.73 m(2) in four patients (one of them with a pathologically increased urinary protein excretion). In three patients, abdominal ultrasound detected gallstones. The group of patients with antenatal Bartter syndrome had a lower renin ratio (P < 0.05) and a higher standard deviation score (SDS) for height (P < 0.05) than a previously studied group of patients with classical Bartter syndrome. CONCLUSIONS: Patients with Bartter syndrome type I and II tend to present a satisfactory prognosis after a median follow-up of more than 10 years. Gallstones might represent a new complication of antenatal Bartter syndrome.
Asunto(s)
Síndrome de Bartter/genética , Mutación/genética , Canales de Potasio de Rectificación Interna/genética , Simportadores de Cloruro de Sodio-Potasio/genética , Síndrome de Bartter/clasificación , Síndrome de Bartter/tratamiento farmacológico , Estatura , Peso Corporal , Preescolar , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Heterocigoto , Homocigoto , Humanos , Lactante , Recién Nacido , Masculino , Pronóstico , Miembro 1 de la Familia de Transportadores de Soluto 12 , Factores de TiempoRESUMEN
Inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive co-transporter causes Gitelman syndrome. The main features of this syndrome include normal or low blood pressure, hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and hyperreninemia. These patients are at low risk for preterm birth and do not present with symptoms before school age. As a consequence, the condition is usually diagnosed in late childhood or in adult life. We report on four patients, two pairs of prematurely born twins, in whom hypokalemia was demonstrated early in life. In these children, a tendency towards hypokalemia was first noted during the third week of life. Overt hypokalemia subsequently appeared associated with normal blood pressure, hypochloremia, hyperreninemia, and an inappropriately high fractional excretion of potassium and chloride. Molecular biology studies failed to detect mutations in the SLC12A1, KCNJ1, and CLCNKB genes responsible for the Bartter syndromes type I, II and III, respectively. Compound heterozygous mutations in the SLC12A3 gene were detected in both pairs of twins: a frameshift mutation in exon 10 (c.1196_1202dup7bp), leading to the truncated protein p.Ser402X, and a missense mutation in exon 11, p.Ser475Cys (c.1424C>G) in the first pair; two missense mutations, p.Thr392Ile (c.1175C>T) in exon 9 and p.Ser615Leu in exon 15 (c.1844C>T), in the second pair. In conclusion, the diagnosis of Gitelman syndrome deserves consideration in infants with unexplained hypokalemia.
Asunto(s)
Síndrome de Gitelman/complicaciones , Hipopotasemia/etiología , Preescolar , Femenino , Síndrome de Gitelman/genética , Humanos , Recién Nacido , Recien Nacido Prematuro , Masculino , Mutación , Receptores de Droga/genética , Miembro 3 de la Familia de Transportadores de Soluto 12 , Simportadores/genéticaRESUMEN
AIM: We report a case of Gitelman Syndrome (GS) in a 9-year-old girl, previously diagnosed as a Bartter syndrome at one year of life. METHODS: She had been treated with potassium, for over 8 years and was admitted because of fatigue, numbness and weakness of both legs. The patient has typical laboratory findings, including hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria, thus GS was suspected. RESULTS: Genetic analysis was performed two mutations IVS9(+1)G>T were detected in the thiazide-sensitive Na-Cl cotransporter (TSC) gene (SLC12A3), thus she was diagnosed as having GS. She was treated with oral potassium and magnesium supplements with resolution of the symptoms. CONCLUSION: This case reminded us that doctors should be alert to the initial presentation of renal tubular diseases. Detailed electrolyte analysis, hormone evaluations and clinic follow-up are mandatory for their correct differential diagnosis.
Asunto(s)
Insuficiencia de Crecimiento/etiología , Síndrome de Gitelman/diagnóstico , Hipopotasemia/fisiopatología , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/etiología , Síndrome de Bartter/fisiopatología , Niño , Diagnóstico Diferencial , Femenino , Síndrome de Gitelman/complicaciones , Síndrome de Gitelman/etiología , Síndrome de Gitelman/fisiopatología , HumanosRESUMEN
BACKGROUND: HELLP (Hemolysis, elevated liver enzymes and low platelets) syndrome is a severe and acute pregnancy-related disorder that occurs in approximately 2.5 per 1000 deliveries and represents a major cause of maternal and perinatal morbidity and mortality. This syndrome has been suggested to be a microangiopathy and delivery is the only effective treatment. OBJECTIVES: The aim of this study was to investigate the pathophysiology of HELLP syndrome by simultaneously exploring complement, haemostasis, autoimmunity and inflammation in relation to the clinical outcome. METHODS: We investigated 19 HELLP patients at the time of diagnosis and 3 months after delivery, for complement function, haemostasis and inflammation with immunoenzymatic methods. Complement-related gene variants were also analyzed by next generation sequencing and multiplex ligation-dependent probe amplification. Nineteen age-matched healthy pregnant women served as controls. RESULTS: At diagnosis, HELLP patients, compared to controls, showed significantly higher plasma levels of SC5b-9 (median 710 ng/ml [range 216-1499] vs 253 ng/ml [19-371], P < 0.0001) and of C5a (20.8 ng/ml [5.6-27.5] vs 12.7 ng/ml [3.2-24.6]; P = 0.004), which decreased three months after delivery (SC5b9: 190 ng/ml [83-446] vs 160 ng/ml [107-219]; C5a: 9.28 ng/ml [2.3-21.6] vs 10.7 ng/ml [2.5-21.2]). A significantly higher frequency of genetic variants involving complement regulatory genes was also observed (52.6% vs 15.8%; P = 0.016). Moreover, at HELLP diagnosis, patients showed increased coagulation markers (fragment F1 + 2 and D-dimer; P = 0.0001) while both patients and controls had high thrombin-generation potential that decreased after delivery. CONCLUSIONS: In the pathophysiology of HELLP syndrome, complement dysregulation, in addition to coagulation activation, is involved and may represent a potential target for treatment with the aim of delaying delivery.
Asunto(s)
Síndrome HELLP , Biomarcadores , Coagulación Sanguínea , Femenino , Síndrome HELLP/genética , Hemólisis , Humanos , EmbarazoRESUMEN
Type III and IV Bartter syndromes (BS) are rare kidney tubulopathies caused by loss-of-function mutations in the CLCNKB and BSND genes coding respectively for the ClC-Kb chloride channels and accessory subunit barttin. ClC-K channels are expressed in the Henle's loop, distal convoluted tubule, and cortical collecting ducts of the kidney and contribute to chloride absorption and urine concentration. In our Italian cohort, we identified two new mutations in CLCNKB, G167V and G289R, in children affected by BS and previously reported genetic variants, A242E, a chimeric gene and the deletion of the whole CLCNKB. All the patients had hypokalemia and metabolic alkalosis, increased serum renin and aldosterone levels and were treated with a symptomatic therapy. In order to define the molecular mechanisms responsible for BS, we co-expressed ClC-Kb wild type and channels with point mutations with barttin in HEK 293 cells and characterized chloride currents through the patch-clamp technique. In addition, we attempted to revert the functional defect caused by BS mutations through barttin overexpression. G167V and A242E channels showed a drastic current reduction compared to wild type, likely suggesting compromised expression of mutant channels at the plasma membrane. Conversely, G289R channel was similar to wild type raising the doubt that an additional mutation in another gene or other mechanisms could account for the clinical phenotype. Interestingly, increasing ClC-K/barttin ratio augmented G167V and A242E mutants' chloride current amplitudes towards wild type levels. These results confirm a genotype-phenotype correlation in BS and represent a preliminary proof of concept that molecules functioning as molecular chaperones can restore channel function in expression-defective ClC-Kb mutants.
RESUMEN
Dystrophinopathies are inherited diseases caused by mutations in the dystrophin (DMD) gene for which testing is mandatory for genetic diagnosis, reproductive choices and eligibility for personalized trials. We genotyped the DMD gene in our Italian cohort of 1902 patients (BMD n = 740, 39%; DMD n =1162, 61%) within a nationwide study involving 11 diagnostic centers in a 10-year window (2008-2017). In DMD patients, we found deletions in 57%, duplications in 11% and small mutations in 32%. In BMD, we found deletions in 78%, duplications in 9% and small mutations in 13%. In BMD, there are a higher number of deletions, and small mutations are more frequent than duplications. Among small mutations that are generally frequent in both phenotypes, 44% of DMD and 36% of BMD are nonsense, thus, eligible for stop codon read-through therapy; 63% of all out-of-frame deletions are eligible for single exon skipping. Patients were also assigned to Italian regions and showed interesting regional differences in mutation distribution. The full genetic characterization in this large, nationwide cohort has allowed us to draw several correlations between DMD/BMD genotype landscapes and mutation frequency, mutation types, mutation locations along the gene, exon/intron architecture, and relevant protein domain, with effects on population genetic characteristics and new personalized therapies.