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INTRODUCTION: Improved outcome and longer life-expectancy in patients with cystinosis, and disease complexity itself, justify planning a guided-transition of affected patients from Pediatrics to adult medicine. The aims of the process are to guarantee the continuum of care and patient empowerment, moving from guardian-care to self-care. METHODS: review of articles, expert opinion and anonymous surveys of patients, relatives and patient advocacy groups. RESULTS: elaboration a new document to support and coordinate the transition of patients with cystinosis providing specific proposals in a variety of medical fields, and adherence promotion. Nephrologists play a key role in transition due the fact that most cystinotic patients suffer severe chronic kidney disease, and need kidney transplantation before adulthood. CONCLUSION: we present a document providing recommendations and suggesting a chronogram to help the process of transition of adolescents and young adults with cystinosis in our area.
Assuntos
Cistinose/terapia , Transição para Assistência do Adulto , Adolescente , Adulto , Criança , Humanos , Transplante de Rim , Pediatria , Insuficiência Renal Crônica/terapia , Autocuidado , Adulto JovemRESUMO
INTRODUCTION: Cystinosis is a rare lysosomal systemic disease that mainly affects the kidney and the eye. Patients with cystinosis begin renal replacement therapy during the first decade of life in absence of treatment. Prognosis of cystinosis depends on early diagnosis, and prompt starting and good compliance with cysteamine treatment. Kidney disease progression, extra-renal complications and shorter life expectancy are more pronounced in those patients that do not follow treatment. The objective of this work was to elaborate recommendations for the comprehensive care of cystinosis and the facilitation of patient transition from paediatric to adult treatment, based on clinical experience. The goal is to reduce the impact of the disease, and to improve patient quality of life and prognosis. METHODS: Bibliographic research and consensus meetings among a multidisciplinary professional team of experts in the clinical practice, with cystinotic patients (T-CiS.bcn group) from 5 hospitals located in Barcelona. RESULTS: This document gathers specific recommendations for diagnosis, treatment and multidisciplinary follow-up of cystinotic patients in the following areas: nephrology, dialysis,renal transplant, ophthalmology, endocrinology, neurology, laboratory, genetic counselling,nursing and pharmacy. CONCLUSIONS: A reference document for the comprehensive care of cystinosis represents a support tool for health professionals who take care of these patients. It is based on the following main pillars: (a) a multi-disciplinary approach, (b) appropriate disease monitoring and control of intracellular cystine levels in leukocytes, (c) the importance of adherence to treatment with cysteamine, and (d) the promotion of patient self-care by means of disease education programmes. All these recommendations will lead us, in a second phase, to create a coordinated transition model between paediatric and adult care services which will contemplate the specific needs of cystinosis.
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Assistência Integral à Saúde/normas , Cistinose/terapia , Transição para Assistência do Adulto/normas , Adolescente , Adulto , Sistemas de Transporte de Aminoácidos Neutros/deficiência , Sistemas de Transporte de Aminoácidos Neutros/genética , Doenças da Córnea/diagnóstico , Doenças da Córnea/etiologia , Doenças da Córnea/terapia , Cisteamina/uso terapêutico , Cistinose/complicações , Cistinose/diagnóstico , Cistinose/genética , Gerenciamento Clínico , Diagnóstico Precoce , Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/etiologia , Doenças do Sistema Endócrino/terapia , Aconselhamento Genético , Humanos , Comunicação Interdisciplinar , Falência Renal Crônica/etiologia , Falência Renal Crônica/prevenção & controle , Falência Renal Crônica/terapia , Transplante de Rim , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/terapia , Educação de Pacientes como Assunto , Qualidade de Vida , AutocuidadoRESUMO
UNLABELLED: Molecular diagnosis is a useful diagnostic tool in primary nephrogenic diabetes insipidus (NDI), an inherited disease characterized by renal inability to concentrate urine. The AVPR2 and AQP2 genes were screened for mutations in a cohort of 25 patients with clinical diagnosis of NDI. Patients presented with dehydration, polyuria-polydipsia, failure to thrive (mean ± SD; Z-height -1.9 ± 2.1 and Z-weight -2.4 ± 1.7), severe hypernatremia (mean ± SD; Na 150 ± 10 mEq/L), increased plasma osmolality (mean ± SD; 311 ± 18 mOsm/Kg), but normal glomerular filtration rate. Genetic diagnosis revealed that 24 male patients were hemizygous for 17 different putative disease-causing mutations in the AVPR2 gene (each one in a different family). Of those, nine had not been previously reported, and eight were recurrent. Moreover, we found those same AVPR2 changes in 12 relatives who were heterozygous carriers. Further, in one female patient, AVPR2 gene study turned out to be negative and she was found to be homozygous for the novel AQP2 p.Ala86Val alteration. CONCLUSION: Genetic analysis presumably confirmed the diagnosis of nephrogenic diabetes insipidus in every patient of the studied cohort. We emphasize that we detected a high presence (50 %) of heterozygous females with clinical NDI symptoms. WHAT IS KNOWN: ⢠In most cases (90 %), inherited nephrogenic diabetes insipidus (NDI) is an X-linked disease, caused by mutations in the AVPR2 gene. ⢠In rare occasions (10 %), it is caused by mutations in the AQP2 gene. What is new: ⢠In this study, we report 10 novel mutations associated with NDI. ⢠We have detected a high presence (50 %) of heterozygous carriers with clinical NDI symptoms.
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Aquaporina 2/genética , DNA/genética , Diabetes Insípido Nefrogênico/genética , Mutação , Aquaporina 2/metabolismo , Criança , Pré-Escolar , Análise Mutacional de DNA , Diabetes Insípido Nefrogênico/diagnóstico , Diabetes Insípido Nefrogênico/metabolismo , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Masculino , LinhagemRESUMO
BACKGROUND: Genetic diagnosis of autosomal recessive polycystic kidney disease (ARPKD) is challenging due to the length and allelic heterogeneity of the PKHD1 gene. Mutations appear to be clustered at specific exons, depending on the geographic origin of the patient. We aimed to identify the PKHD1 exons most likely mutated in Spanish ARPKD patients. METHODS: Mutation analysis was performed in 50 ARPKD probands and nine ARPKD-suspicious patients by sequencing PKHD1 exons arranged by their reported mutation frequency. Haplotypes containing the most frequent mutations were analyzed. Other PKD genes (HNF1B, PKD1, PKD2) were sequenced in PKHD1-negative cases. RESULTS: Thirty-six different mutations (concentrated in 24 PKHD1 exons) were detected, giving a mutation detection rate of 86%. The screening of five exons (58, 32, 34, 36, 37) yielded a 54% chance of detecting one mutation; the screening of nine additional exons (3, 9, 39, 61, 5, 22, 26, 41, 57) increased the chance to 76%. The c.9689delA mutation was present in 17 (34%) patients, all of whom shared the same haplotype. Two HNF1B mutations and one PKD1 variant were detected in negative cases. CONCLUSIONS: Establishing a PKHD1 exon mutation profile in a specific population and starting the analysis with the most likely mutated exons might significantly enhance the efficacy of genetic testing in ARPKD. Analysis of other PKD genes might be considered, especially in suspicious cases.
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Análise Mutacional de DNA/métodos , Testes Genéticos/economia , Rim Policístico Autossômico Recessivo/diagnóstico , Rim Policístico Autossômico Recessivo/genética , Receptores de Superfície Celular/genética , Análise Custo-Benefício , Éxons/genética , Haplótipos , Humanos , MutaçãoRESUMO
BACKGROUND: Mutations in the TRPC6 gene have been reported in six families with adult-onset (17-57 years) autosomal dominant focal segmental glomerulosclerosis (FSGS). Electrophysiology studies confirmed augmented calcium influx only in three of these six TRPC6 mutations. To date, the role of TRPC6 in childhood and adulthood non-familial forms is unknown. METHODS: TRPC6 mutation analysis was performed by direct sequencing in 130 Spanish patients from 115 unrelated families with FSGS. An in silico scoring matrix was developed to evaluate the pathogenicity of amino acid substitutions, by using the bio-physical and bio-chemical differences between wild-type and mutant amino acid, the evolutionary conservation of the amino acid residue in orthologues, homologues and defined domains, with the addition of contextual information. RESULTS: Three new missense substitutions were identified in two clinically non-familial cases and in one familial case. The analysis by means of this scoring system allowed us to classify these variants as likely pathogenic mutations. One of them was detected in a female patient with unusual clinical features: mesangial proliferative FSGS in childhood (7 years) and partial response to immunosupressive therapy (CsA + MMF). Asymptomatic carriers of this likely mutation were found within her family. CONCLUSIONS: We describe for the first time TRPC6 mutations in children and adults with non-familial FSGS. It seems that TRPC6 is a gene with a very variable penetrance that may contribute to glomerular diseases in a multi-hit setting.
Assuntos
Glomerulosclerose Segmentar e Focal/genética , Canais de Cátion TRPC/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Pessoa de Meia-Idade , Canal de Cátion TRPC6 , Adulto JovemRESUMO
We report on a 16-day-old male with metabolic acidosis, hyperuricemia, hyperuricosuria, and nephrocalcinosis caused by Lesch-Nyhan syndrome. Activity of the hypoxanthine-guanine phosphoribosyl transferase (HPRT) enzyme in lysed erythrocytes was undetectable, and molecular DNA analysis confirmed the presence of a 4-base pair deletion at the 5' end of intervening sequence 8 in the HPRT1 gene, a change that affects a 5' splice site consensus sequence. Rasburicase, a urate oxidase enzyme, was administered on day 26 of life, with an endovenous dose of 0.20 mg/kg/d for 3 days. Plasma urate concentrations normalized (2.96 mg/dL) at 38 days of life. Kidney function was preserved in our patient. In summary, rasburicase proved to be a safe and effective treatment in a patient with Lesch-Nyhan syndrome with uric acid nephropathy in the neonatal period.
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Supressores da Gota/uso terapêutico , Hiperuricemia/tratamento farmacológico , Hiperuricemia/etiologia , Síndrome de Lesch-Nyhan/complicações , Urato Oxidase/uso terapêutico , Relação Dose-Resposta a Droga , Deleção de Genes , Supressores da Gota/efeitos adversos , Humanos , Hipoxantina Fosforribosiltransferase/genética , Recém-Nascido , Rim/fisiopatologia , Síndrome de Lesch-Nyhan/genética , Masculino , Resultado do Tratamento , Urato Oxidase/efeitos adversos , Ácido Úrico/sangueRESUMO
Familial benign hematuria (FBH) is a common autosomal dominant disorder characterized by the presence of persistent or recurrent hematuria. The clinical and pathologic features of this syndrome resemble those of early Alport syndrome (AS), and for this reason a common molecular defect has been proposed. The COL4A3/4 genes seem to be involved in both autosomal AS and FBH. This study involves a linkage analysis for the COL4A3/4 loci and a search for mutations within these genes in 11 biopsy-proven FBH families. Haplotype analysis showed that linkage to the COL4A3/4 locus could not be excluded in eight of nine families. One family was not linked to this locus; however, it included three affected women who could be X-linked AS carriers. Two families were too small to perform linkage analysis. COL4A3 and COL4A4 mutation screening disclosed six new pathogenic mutations, two in the COL4A3 gene (G985V and G1015E) and four in the COL4A4 gene (3222insA, IVS23-1G>C, 31del11, and G960R). It is the first time that mutations within the COL4A3 gene are described in families with FBH. This study clearly demonstrates the main role of the COL4A4 and COL4A3 genes in the pathogenesis of FBH.