RESUMEN
BACKGROUND: Nephropathic cystinosis (NC) is a rare lysosomal disease, leading to early kidney failure and extra-renal comorbidities. Its prognosis strongly relies on early diagnosis and treatment by cysteamine. Developing economies (DEing) face many challenges when treating patients for rare and chronic diseases. The aim here is to evaluate the access to investigations and treatment in DEing, and to assess for potential inequalities with Developed Economies (DEed). METHODS: In this international cross-sectional study, a questionnaire on access, price and reimbursement of genetic, biological analyses, and treatment was sent to nephrology centers worldwide during 2022. RESULTS: A total of 109 centers responded, coming from 49 countries and managing 741 patients: 43 centers from 30 DEing and Economies in transition (TrE), and 66 from 19 DEed. In 2022, genetics availability was 63% in DEing and 100% in DEed, whereas intra leukocytes cystine levels (IL-CL) were available for 30% of DEing patients, and 94% of DEed patients, both increasing over the last decade, as has access to immediate release cysteamine and to cysteamine eye drops in DEing. However, delayed released cysteamine can be delivered to only 7% vs. 74% of patients from DEing and DEed, respectively, and is still poorly reimbursed in DEing. CONCLUSIONS: Over the last decade, access to investigations (namely genetics and IL-CL) and to cysteamine have improved in DEing and TrE. However, discrepancies remain with DEed: access to delayed released cysteamine is limited, and reimbursement is still profoundly insufficient, therefore limiting their current use.
Asunto(s)
Cistinosis , Síndrome de Fanconi , Humanos , Cistinosis/diagnóstico , Cistinosis/tratamiento farmacológico , Cistinosis/epidemiología , Cisteamina/uso terapéutico , Estudios Transversales , Cistina , Accesibilidad a los Servicios de SaludRESUMEN
Cystinosis is an autosomally inherited rare genetic disorder in which cystine accumulates in the lysosome. The defect arises from a mutation in the lysosomal efflux pump, cystinosin (or CTNS). Despite the disease being known for more than a century, research, diagnosis, and treatment in India have been very minimal. In recent years, however, some research on cystinosis has been carried out on understanding the pathophysiology and in the development of a humanized yeast model for interrogating the CTNS protein. There has also been a greater awareness of the disease that has been facilitated by the formation of the Cystinosis Foundation of India just over a decade ago. Awareness among primary physicians is critical for early diagnosis, which in turn is critical for proper treatment. Eight different mutations have been observed in cystinosis patients in India, and the mutation spectrum seems different to what has been seen in the US and Europe. Despite these positive developments, there are immense hurdles still to be surmounted. This includes ensuring that the diagnosis is done sooner, making cysteamine more easily available, and, also for the future, to make accessible the promise of gene therapy to cystinosis patients.
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Cistinosis , Humanos , Cistinosis/diagnóstico , Cistinosis/epidemiología , Cistinosis/genética , Cistina/genética , Cistina/metabolismo , Cisteamina/efectos adversos , Mutación , India/epidemiologíaRESUMEN
INTRODUCTION: Nephropathic cystinosis (NC) is a rare, autosomal recessive disorder leading to lysosomal accumulation of cystine. It is caused by mutations in the CTNS gene encoding a cystine cotransporter cystinosin. The infantile (INC) and juvenile (JNC) forms are distinguished. The former, responsible for 95% of cases, is characterized by development of renal Fanconi syndrome, end-stage kidney disease (ESKD), and extrarenal complications. A therapy with cysteamine significantly improves outcomes. There are limited data on NC in the Central Eastern European countries. OBJECTIVES: We aimed to evaluate the prevalence, genetic background, and clinical course of NC in the Polish population. PATIENTS AND METHODS: We performed a retrospective analysis of data of all identified NC patients in Poland. RESULTS: Between 1982 and 2017, 15 patients with NC (13 ICN, 2 JCN) were identified. The most common mutations of the CTNS gene were c.18_c.21delGACT and c.681+1G>A, whereas only 2 patients carried the 57 kb deletion. The majority (11/13) of INC patients with limited access to the cysteamine therapy developed ESKD at a median age of 11 years and 9 of them received kidney transplants. Three INC patients died at a median age of 24 years. In contrast, 2 INC patients treated adequately present normal kidney function and growth at the age of 13 and 11 years. Two JNC patients presented a milder course. CONCLUSIONS: The prevalence of NC in Poland is much lower than in the Western countries and its molecular background appears to be different. The unfavorable course in the majority of INC patients was caused by a limited access to the cysteamine treatment.
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Cistinosis , Síndrome de Fanconi , Fallo Renal Crónico , Humanos , Niño , Adulto Joven , Adulto , Cistinosis/complicaciones , Cistinosis/tratamiento farmacológico , Cistinosis/epidemiología , Síndrome de Fanconi/inducido químicamente , Síndrome de Fanconi/tratamiento farmacológico , Síndrome de Fanconi/genética , Estudios Retrospectivos , Cisteamina/uso terapéutico , Polonia/epidemiología , Cistina/uso terapéutico , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/etiologíaRESUMEN
Background Cystinosis is a rare autosomal-recessive disorder caused by a defective transport of cystine across the lysosomal membrane. Previous studies have mapped cystinosis to the CTNS gene which is located on chromosome 17p13, and various CTNS mutations have been identified to correlate them with this disease. Methods We analyzed six patients from five unrelated families who were diagnosed with cystinosis in our hospital. We described the diagnostic procedures for all the patients and proposed alternative therapies for cystinosis patients instead of using cysteamine, an orphan drug which was commercially unavailable in China. Moreover, genetic analysis of all patients' samples was carried out to identify novel CTNS gene mutations. Results and conclusions The patients in this study were followed up from 1 to more than 10 years to monitor their growth and development, which indicated that the alternative therapies we used were helpful to ameliorate the complications of the cystinosis patients without cysteamine. Furthermore, by sequencing the patients' genome, we identified novel mutations in the CTNS gene including: c.477C > G (p.S159R), c.274C > T (p.Q92X) and c.680A > T (p.E227V); these mutations were only observed in cystinosis patients and had never been reported in any other populations, suggesting they might be specific to Chinese cystinosis patients.
Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/genética , Cistinosis/diagnóstico , Genética de Población , Mutación , Adolescente , Niño , Preescolar , China/epidemiología , Cistinosis/tratamiento farmacológico , Cistinosis/epidemiología , Cistinosis/genética , Femenino , Estudios de Seguimiento , Hormona de Crecimiento Humana/administración & dosificación , Humanos , Lactante , Masculino , Linaje , PronósticoRESUMEN
Mutations in the CTNS gene encoding the lysosomal membrane cystine transporter cystinosin are the cause of cystinosis, an autosomal recessive lysosomal storage disease. More than 140 CTNS mutations have been reported worldwide. Recent studies have discovered that cystinosin exerts other key cellular functions beyond cystine transport such as regulation of oxidative state, lysosomal dynamics and autophagy. Here, we review the different mutations described in the CTNS gene and the geographical distribution of incidence. In addition, the characteristics of the various mutations in relation to the functions of cystinosin needs to be further elucidated. In this review, we highlight the functional consequences of the different mutations in correlation with the clinical phenotypes. Moreover, we propose how this understanding would be fundamental for the development of new technologies through targeted gene therapy, holding promises for a possible cure of the kidney and extra-renal phenotypes of cystinosis.
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Sistemas de Transporte de Aminoácidos Neutros/genética , Cistinosis/genética , Reparación del ADN , Mutación , Animales , Cistinosis/epidemiología , Modelos Animales de Enfermedad , Genotipo , Geografía , Humanos , Incidencia , FenotipoRESUMEN
Objetivo: Describir el caso clínico de un paciente con Cistinosis Nefropática diagnosticado a muy temprana edad. Método: Reporte de caso. Resultados: Se reporta el caso de una paciente de 7 meses de edad, quien consulta con poliuria, piolidipsia, glucosuria y bajo peso para la edad. De acuerdo a protocolos de evaluación interdisciplinaria establecidos con el servicio de Pediatría se logra evidenciar hallazgos oculares que orientan al diagnóstico final de la paciente. Conclusión: La Cistinosis es una enfermedad rara, cursa con manifestaciones oculares que podrían orientar un diagnóstico temprano e incluso predecir la severidad de la enfermedad y brindar la posibilidad de un tratamiento temprano. Es importante establecer protocolos interdisciplinarios, de apoyo diagnóstico, ante la sospecha de enfermedades sistémicas con posible compromiso ocular, en lugar de desistir ante la dificultad para valorar a los niños en la consulta de oftalmología, sobre todo en aquellos menores de un año. Se demuestra este caso con fines académicos teniendo en cuenta la baja incidencia de la enfermedad, pero también para destacar la importancia de contar con protocolos de atención interdisciplinaria ante la sospecha de enfermedades metabólicas en todas las edades.
Purpose: To describe a case of an infant with Nephropathic Cystinosis and the ocular fi ndings that leads to the diagnosis. Method: Case report. Results: Th is report describe a prompt and accurate diagnosis of a 7 months old patient, who consults with polyuria, piolidipsia, glucosuria and low weight. According to interdisciplinary evaluation protocols previusly established with Pediatrics services, it was possible to demonstrate ocular fi ndings of the disease, guiding the physician to the fi nal diagnosis. Conclusion: Cystinosis is a rare disease, its clinical presentation has ocular manifestations that could guide diagnosis and even predict its severity, off ering the possibility of an early treatment. When one suspect a systemic disease, It is important to establish interdisciplinary protocol, instead of surrendering to the challenge of an ophthalmological examination of an infant. We choose this case due to its low incidence, but also to highlight the importance of having interdisciplinary care protocols when a metabolic disease is suspected.
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Cistinosis/epidemiología , Cistinosis/diagnóstico , OftalmopatíasRESUMEN
BACKGROUND: Nephropathic cystinosis is a rare inherited metabolic disorder leading to progressive renal failure and extra-renal comorbidity. The prognosis relies on early adherence to cysteamine treatment and symptomatic therapies. Developing nations [DiN] experience many challenges for management of cystinosis. The aim of this study was to assess the management characteristics in DiN compared with developed nations [DeN]. METHODS: A questionnaire was sent between April 2010 and May 2011 to 87 members of the International Pediatric Nephrology Association, in 50 countries. RESULTS: A total of 213 patients were included from 41 centres in 30 nations (109 from 17 DiN and 104 from 13 DeN). 7% of DiN patients died at a median age of 5 years whereas no death was observed in DeN. DiN patients were older at the time of diagnosis. In DiN, leukocyte cystine measurement was only available in selected cases for diagnosis but never for continuous monitoring. More patients had reached end-stage renal disease in DiN (53.2 vs. 37.9%, p = 0.03), within a shorter time of evolution (8 vs. 10 yrs., p = 0.0008). The earlier the cysteamine treatment, the better the renal outcome, since the median renal survival increased up to 16.1 [12.5-/] yrs. in patients from DeN treated before the age of 2.5 years of age (p = 0.0001). However, the renal survival was not statistically different between DeN and DiN when patients initiated cysteamine after 2.5 years of age. The number of transplantations and the time from onset of ESRD to transplantation were not different in DeN and DiN. More patients were kept under maintenance dialysis in DiN (26% vs.19%, p = 0.02); 79% of patients from DiN vs. 45% in DeN underwent peritoneal dialysis. CONCLUSIONS: Major discrepancies between DiN and DeN in the management of nephropathic cystinosis remain a current concern for many patients living in countries with limited financial resources.
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Cistinosis/epidemiología , Salud Global , Internacionalidad , Fallo Renal Crónico/epidemiología , Médicos , Encuestas y Cuestionarios , Adolescente , Adulto , Niño , Preescolar , Cistinosis/diagnóstico , Cistinosis/terapia , Países en Desarrollo , Femenino , Estudios de Seguimiento , Humanos , Lactante , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/terapia , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: This study was conducted to investigate CTNS (cystinosin, lysosomal cystine transporter) gene mutations and the clinical spectrum of nephropathic cystinosis among patients diagnosed with the disease in a single center in Turkey. METHODS: Patients' clinical and laboratory data were extracted from an electronic health registry. Molecular CTNS gene analysis was performed using either next-generation sequencing or Sanger sequencing. RESULTS: Eleven patients (age range: 1.5-12 years) from nine families were identified. The presenting complaint was growth retardation in seven patients; polydipsia and polyuria in three patients; and vomiting in two patients. At presentation, electrolyte loss was noted in all patients, of which eight patients presented with metabolic acidosis, and three patients presented with metabolic alkalosis. All patients also presented with proteinuria and glucosuria, and four patients developed varying degrees of renal insufficiency, for which peritoneal dialysis was initiated in one patient. Cystine crystals were detected via ocular examination in one patient at presentation. No cystine crystals were detected among patients who underwent bone marrow aspiration. In the CTNS gene, a p.T7FX7 (c.18-21del4bp) mutation was detected in three patients, whereas a p.E227E (c.681 G>A) (homozygous) mutation was detected in eight patients. CONCLUSIONS: We detected two distinct mutations, p.T7FX7 (c.18-21del4bp) and p.E227E (c.681 G>A) (homozygous), in the CTNS gene in 11 patients with cystinosis from the East Anatolian region of Turkey. Patients with a homozygous c.681 G>A (p.E227E) mutation are more likely to develop chronic renal failure and should be monitored closely, whereas patients with a p.T7FX7 (c.18-21del4bp) mutation have a milder phenotype. Additionally, metabolic alkalosis does not exclude cystinosis, although cystinosis is a cause of proximal renal tubular acidosis.
Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/genética , Biomarcadores/metabolismo , Cistinosis/genética , Mutación/genética , Niño , Preescolar , Cistinosis/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Pronóstico , Turquía/epidemiologíaRESUMEN
OBJECTIVE: Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder that is characterised by the accumulation of the amino acid cystine in several body tissues due to a mutation in the CTNS gene, which encodes the cystinosin protein. The aim of this study was to sequence the coding exons of the CTNS gene in five different Jordanian families and one family from Sudan with nephropathic cystinosis. METHODS: Probands initially presented with Fanconi syndrome symptoms. An eye examination showed the accumulation of cystine crystals in the cornea by the age of 2 years, suggesting cystinosis. All of the coding exons and flanking intronic sequences and the promoter region of the CTNS gene were amplified using polymerase chain reaction and subjected to sequencing. RESULTS: None of the probands in this study carried the European 57-kb deletion in the CTNS gene. Seven variants in the coding and promoter sequence of the CTNS gene were identified in the probands of this study. Two of these variants were a CTNS mutation that was previously identified in a heterozygous genotype in two different patients of European descendant. The two mutations were c.829dupA in exon 10 and c.890G>A in exon 11. The proband of family 2 was compound-heterozygous for the two mutations. CONCLUSION: This study is the first molecular study of infantile nephropathic cystinosis in Jordan. We successfully identified the causative CTNS mutations in Jordanian families. The results provide a basis for the early detection of the disease using molecular tools in a highly consanguineous Jordanian population.
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Sistemas de Transporte de Aminoácidos Neutros/genética , Cistinosis/genética , Adulto , Alelos , Niño , Preescolar , Consanguinidad , Cistinosis/epidemiología , Cistinosis/etnología , Análisis Mutacional de ADN , Exones/genética , Femenino , Mutación del Sistema de Lectura , Duplicación de Gen , Genotipo , Humanos , Lactante , Jordania/epidemiología , Masculino , Mutación Missense , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Sudán/etnologíaAsunto(s)
Sistemas de Transporte de Aminoácidos Neutros/genética , Cistinosis/genética , Cistinosis/diagnóstico , Cistinosis/epidemiología , Análisis Mutacional de ADN , Diagnóstico Diferencial , Humanos , Incidencia , Mutación , Diagnóstico Prenatal , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadAsunto(s)
Cistinosis/epidemiología , Países en Desarrollo , Síndrome de Fanconi/epidemiología , Síndrome Nefrótico/epidemiología , Cistinosis/diagnóstico , Diagnóstico Diferencial , Egipto/epidemiología , Síndrome de Fanconi/diagnóstico , Femenino , Humanos , Incidencia , Lactante , Masculino , Síndrome Nefrótico/diagnósticoAsunto(s)
Cistinosis , Adulto , Factores de Edad , Enfermedad Crónica , Cistinosis/epidemiología , HumanosRESUMEN
We report the molecular findings for the CTNS gene in 12 Turkish cystinosis patients aged 7-29 years. All presented initially with severe failure to thrive, polyuria, and polydipsia. Cystinosis was diagnosed at age 1 month to 9 years. Seven patients reached end-stage renal failure at ages ranging from 6.5 to 15 years. Whereas three of the remaining five have renal Fanconi syndrome with proteinuria, two have had kidney failure of varying degrees. Molecular analyses involved an initial multiplex polymerase chain reaction (PCR) to determine the presence or absence of the 57-kb northern European founder deletion in CTNS, followed by sequencing of the ten coding exons of CTNS. Comprehensive mutation analysis verified that none of the 12 patients carried the common 57-kb deletion. We identified four previously reported nucleotide variations associated with cystinosis and five new variants: a 10-kb deletion, three missense variants, and a nucleotide substitution in a potential branch point site of intron 4. This study is the first molecular analysis of Turkish cystinosis patients and provides guidance for the molecular diagnosis of cystinosis in this population.
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Sistemas de Transporte de Aminoácidos Neutros/genética , Cistinosis/genética , Mutación , Adolescente , Adulto , Niño , Cistinosis/complicaciones , Cistinosis/epidemiología , Análisis Mutacional de ADN , Progresión de la Enfermedad , Exones , Insuficiencia de Crecimiento/genética , Síndrome de Fanconi/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Intrones , Fallo Renal Crónico/genética , Masculino , Mutación Missense , Fenotipo , Mutación Puntual , Polidipsia/genética , Reacción en Cadena de la Polimerasa , Poliuria/genética , Proteinuria/genética , Insuficiencia Renal/genética , Eliminación de Secuencia , Turquía/epidemiología , Adulto JovenRESUMEN
INTRODUCTION: Cystinosis is an autosomal recessive disorder leading to intralysosomal cystine accumulation in various tissues. It causes renal Fanconi syndrome and end stage renal failure around the age of 10 years if not treated with cysteamine. Children with cystinosis seem to have a normal intelligence but frequently show learning difficulties. These problems may be due to specific neurocognitive deficits rather than impaired renal function. Whether cysteamine treatment can improve cognitive functioning of cystinosis patients is thus far unknown. We aim to analyze neurocognitive functioning of school-aged cystinosis patients treated with cysteamine in order to identify specific deficits that can lead to learning difficulties. PATIENTS AND METHODS: Fourteen Dutch and Belgian school-aged cystinosis patients were included. Glomerular filtration rate was estimated using the Schwartz formula. Children were tested for general intelligence, visual-motor integration, inhibition, interference, sustained attention, accuracy, planning, visual memory, processing speed, motor planning, fluency and speed, and behavioural and emotional functioning using standardized methods. RESULTS: Glomerular filtration rate ranged from 22 to 120 ml min(-1) 1.73 m(-2). Median full-scale intelligence was below the average of a normal population (87, range 60-132), with a discrepancy between verbal (median 95, range 60-125) and performance (median 87, range 65-130) intelligence. Over 50% of the patients scored poorly on visual-motor integration, sustained attention, visual memory, planning, or motor speed. The other tested areas showed no differences between patients' and normal values. CONCLUSION: Neurocognitive diagnostics are indicated in cystinosis patients. Early recognition of specific deficits and supervision from special education services might reduce learning difficulties and improve school careers.
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Cognición/fisiología , Cistinosis/fisiopatología , Cistinosis/psicología , Adolescente , Bélgica , Niño , Conducta Infantil/fisiología , Cistinosis/epidemiología , Emociones/fisiología , Femenino , Humanos , Pruebas de Inteligencia , Masculino , Memoria a Corto Plazo/fisiología , Recuerdo Mental/fisiología , Fenómenos Fisiológicos del Sistema Nervioso , Países Bajos , PoblaciónRESUMEN
INTRODUCTION: The Brazilian Multicenter Nephropathic Study Group, founded in 1999, is currently composed of 16 pediatric nephrology units, which are coordinated by the Pediatric Nephrology Unit of Instituto da Criança--HCFMUSP. This Study Group intends to better know our patients, their special characteristics and facilitates the treatment. OBJECTIVE: To present an update on the demographics of the ongoing study participants with interest on renal function status, response to therapy, and extra-renal complications. METHODS: Patient recruitment to the study is based on informed consent and has been supported by the Brazilian Society of Nephrology, by the creation of an electronic homepage and by the participation in medical meetings and publications in medical periodicals. Our study protocol involves the initial and follow-up questionnaire, the measurement of intraleukocyte cystine content, initiation and follow-up therapy with cysteamine, and clinical patient follow-up based on a protocol of subsidiary exams. RESULTS: We identified 102 patients (42 females) with nephropathic cystinosis in Brazil since 1999. Forty-six children are followed at the Instituto da Criança/SP, 15 at the Hospital Pequeno Príncipe/PR, 12 at the UNICAMP/SP, 10 at the Unidade de Transplante Renal - HCFMUSP/SP and 3 at the Santa Casa/SP; the remaining patients are followed at the Instituto da Criança and at their respective doctors' offices in different nephrology services in Brazil. Of these patients, 23/102 (22.5%) have normal renal function, 19/102 (18.6%) are in chronic renal failure with conservative treatment, 26/102 are on dialysis (18 on peritoneal dialysis and 8 on hemodialysis), and 34/102 received a renal transplant. The extra-renal involvement diagnosed was: hypothyroidism in 63 patients, diabetes mellitus in 8 patients, muscular involvement in 7 patients, a compromised central nervous system in 5 patients, hepatic complications in 5 patients, and deglutition dysfunction in 2 patients. During this period, 10/102 patients died. Cysteamine has been used by 81/102 patients (20 children started the therapy under 2 years of age). Growth parameters were improved by cysteamine, mainly in the youngest patients. We used recombinant growth hormone in 15 patients with persistent low growth velocity and stature z score under 2.5%. We could also observe a delay in appearance of extra-renal complications in patients receiving cysteamine. CONCLUSION: Our study demonstrates the importance of a multi-center study for recruitment, diagnosis and management of rare diseases. This study promotes access to the adequate treatment with profound impact on the quality of life.
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Cistinosis/epidemiología , Enfermedades Renales/epidemiología , Adolescente , Adulto , Brasil/epidemiología , Niño , Preescolar , Comorbilidad , Cisteamina/administración & dosificación , Cisteamina/uso terapéutico , Cistinosis/tratamiento farmacológico , Femenino , Tasa de Filtración Glomerular , Humanos , Hipotiroidismo/epidemiología , Lactante , Enfermedades Renales/tratamiento farmacológico , Leucocitos/química , Masculino , Adulto JovenRESUMEN
OBJECTIVES: Infantile nephropathic cystinosis is associated with a specific cognitive deficit in visual spatial processing in older children and adults. The cause of this deficit is unknown. This study was designed to determine whether the cognitive deficit is present in young children with cystinosis, suggesting an early effect of the genetic disorder on brain development. STUDY DESIGN: Young children (n = 25; age, 3-8 years) with cystinosis and 25 matched control subjects underwent cognitive testing, including tests of intelligence, visual perceptual, visual spatial, and visual motor functions. RESULTS: Children with cystinosis performed significantly more poorly on tests of visual spatial and visual motor function than did control subjects. Visual perceptual abilities were equivalent in the 2 groups. CONCLUSION: The same pattern of visual spatial deficit is present in young children with cystinosis as has previously been demonstrated in older children and adults, which suggests that there may be an influence of the cystinosis gene on brain development, rather than an adverse effect of prolonged cystine accumulation in the brain during childhood.
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Sistemas de Transporte de Aminoácidos Neutros/genética , Trastornos del Conocimiento/genética , Cistinosis/genética , Regulación del Desarrollo de la Expresión Génica , Trastornos de la Percepción/genética , Distribución por Edad , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/epidemiología , Comorbilidad , Cistinosis/diagnóstico , Cistinosis/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Pruebas de Inteligencia , Masculino , Análisis Multivariante , Pruebas Neuropsicológicas , Trastornos de la Percepción/diagnóstico , Trastornos de la Percepción/epidemiología , Probabilidad , Valores de Referencia , Medición de Riesgo , Índice de Severidad de la Enfermedad , Distribución por Sexo , Factores de Tiempo , Percepción Visual/fisiologíaRESUMEN
Many of the end-organ effects of cystinosis are known to be risk factors for osteopenia; these include deposition of cystine crystals in bone, hypothyroidism, diabetes mellitus, primary hypogonadism, urinary phosphate wasting, and chronic renal failure. While transplantation may correct the latter, it exposes the child to other risk factors for diminished bone mass, notably the use of high-dose glucocorticoids. Our objective was to determine if these multiple risk factors translate into an increased occurrence of osteopenia, as measured by dual-energy X-ray absorptiometry (DEXA), and/or fractures in this population. We examined the charts, X-rays, and bone mineral density (BMD) of all cystinotic patients post renal transplant for whom this information was available. Lumbar spine BMD was measured by DEXA scan (Hologic 4500). Z-scores were corrected for growth parameters using previously published reference data. Fracture history and pertinent serum markers of bone metabolism were also analyzed. Of the 63 renal transplants performed at our institution, 11 children were transplanted due to cystinosis. Nine of these patients, 5 male and 4 female, had had BMD evaluations, with an average age of 14.3 years (range 5-17 years) at the time of initial BMD post transplant. The mean interval between transplant and BMD evaluation was 39 months (range 3-90 months). Surprisingly, 7 of 9 patients had normal uncorrected BMD values (z-scores -1.92 to +0.02) and 7 of 9 patients had normal corrected values (z-scores -1.20 to +1.93). Three patients suffered from a total of eight fractures. Of the 3 fracture patients, 2 had normal BMD. All patients maintained good graft function and had normal calcium/phosphate mineral status. Of note, 3 of 5 male patients had evidence of primary testicular failure at earlier ages than often described, and this may be an unrecognized risk factor for bone disease in this population. Despite the numerous risk factors for developing osteopenia, these results suggest that the majority of cystinotic patients post renal transplant do not experience reduced bone mineral content as measured by DEXA. However, the significant fracture history among these patients demonstrates that DEXA cannot be used to assess fracture risk in patients with nephropathic cystinosis.
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Enfermedades Óseas Metabólicas/epidemiología , Cistinosis/epidemiología , Fracturas Óseas/epidemiología , Trasplante de Riñón , Absorciometría de Fotón , Adolescente , Biomarcadores , Densidad Ósea , Enfermedades Óseas Metabólicas/diagnóstico por imagen , Enfermedades Óseas Metabólicas/etiología , Niño , Cistinosis/diagnóstico por imagen , Femenino , Fracturas Óseas/diagnóstico por imagen , Fracturas Óseas/etiología , Trastornos del Crecimiento/epidemiología , Trastornos del Crecimiento/etiología , Humanos , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/cirugía , Pruebas de Función Renal , Masculino , Valor Predictivo de las Pruebas , Factores de RiesgoAsunto(s)
Cistinosis/genética , Etnicidad/genética , Glicoproteínas , Proteínas de la Membrana/genética , Mutación Missense/genética , Sistemas de Transporte de Aminoácidos Neutros , Secuencia de Bases , Cristianismo , Cistinosis/epidemiología , Análisis Mutacional de ADN , Exones/genética , Femenino , Frecuencia de los Genes/genética , Pruebas Genéticas , Homocigoto , Humanos , Lactante , Masculino , Proteínas de Transporte de Membrana , Ontario/epidemiología , Eliminación de Secuencia/genéticaRESUMEN
Cystinosis is an autosomal recessive disorder, characterized by an accumulation of intralysosomal cystine, with an incidence of 1 in 100,000 to 200,000 live births. A higher incidence of cystinosis, 1 in 26,000 live births, has been reported in the western French province of Brittany. PCR amplification and sequencing has identified a 27-bp deletion starting 3 bp before the end of exon 8 and continuing into intron 8, 898-900+24del27, which has only been detected in families from this region. Reverse transcription-PCR amplification of RNA from an affected individual has shown that this mutation is indeed a splice-site mutation and results in the production of aberrant transcripts. These transcripts are predicted to either severely truncate cystinosin or alter its topology, thus accounting for the severe phenotype of these individuals. The mutation 898-900+24del27 has been identified in 7 of 18 alleles studied. This mutation is likely to be a founder mutation and would account for the higher incidence of cystinosis in Brittany.(1)