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Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4). We have identified a new transcript, encoding a protein (bo, +AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.

Objetivo: Evaluar un nuevo enfoque en el análisis de la litiasis urinaria en función de la combinación de sus componentes. Material y métodos: Se analizaron un total de 7.949 litiasis y sus componentes principales y combinaciones, y se clasificaron en función del sexo y la edad. El análisis estadístico fue mediante el test de ji cuadrado. Resultados: Oxalato cálcico monohidrato (OCM) fue el componente más frecuente en hombres (39%) y mujeres (37,4%), seguido de oxalato cálcico dihidrato (OCD) (28%) y ácido úrico (URI) (14,6%) en hombres y de fosfato (FOS) (22,2%) y OCD (19,6%) en mujeres (p=0,0001). En la gente joven OCD y FOS fueron los componentes más frecuentes en hombres y mujeres, respectivamente (p=0,0001). En los pacientes mayores OCM y URI (por este orden) fueron los componentes más frecuentes en ambos sexos (p=0,0001). OCM es oxalatodependiente y está relacionado con las dietas de alto contenido en oxalato y baja ingesta de agua. El aumento progresivo de URI con la edad se relaciona principalmente con el sobrepeso y el síndrome metabólico. Respecto a la combinación de componentes, las más frecuentes fueron OCM (26,3%), OCD+Apatita (APA) (15,5%), URI (10%) y OCM+OCD (7,5%) (p=0,0001). Conclusiones: Este estudio presenta no sólo la composición de las litiasis, sino también las principales combinaciones de componentes en función de la edad y el sexo. Los resultados muestran que la composición de la litiasis está relacionada con los cambios en los hábitos dietéticos y de estilo de vida que ocurren durante la vida, y la estructura morfológica de las litiasis es indicativa de los mecanismos etiopatogénicos. Objective: To evaluate a new approach to urinary stone analysis according to the combination of the components. Materials and methods: A total of 7949 stones were analysed and their main components and combinations of components were classified according to gender and age. Statistical analysis was performed using the chi-square test. Results: Calcium oxalate monohydrate (COM) was the most frequent component in both males (39%) and females (37.4%), followed by calcium oxalate dihydrate (COD) (28%) and uric acid (URI) (14.6%) in males and by phosphate (PHO) (22.2%) and COD (19.6%) in females (p=0.0001). In young people, COD and PHO were the most frequent components in males and females respectively (p=0.0001). In older patients, COM and URI (in that order) were the most frequent components in both genders (p=0.0001). COM is oxalate dependent and is related to diets with a high oxalate content and low water intake. The progressive increase in URI with age is related mainly to overweight and metabolic syndrome. Regarding the combinations of components, the most frequent were COM (26.3%), COD+Apatite (APA) (15.5%), URI (10%) and COM+COD (7.5%) (p=0.0001). Conclusions: This study reports not only the composition of stones but also the main combinations of components according to age and gender. The results prove that stone composition is related to the changes in dietary habits and life-style that occur over a lifetime, and the morphological structure of stones is indicative of the aetiopathogenic mechanisms.

The use of preoperative imaging in patients with hyperparathyroidism remains controversial. The aim of this study is to assess the usefulness of the double-phase 99mTc-sestamibi scintigraphy in the diagnosis of abnormal parathyroid glands in patients with primary hyperparathyroidism.We studied 60 patients presenting with primary hyperparathyroidism who were referred to surgery; four of them had been unsuccessfully operated. 99mTc-sestamibi scintigraphy were performed in all patients previously to surgery. Scintigraphic technique: planar imaging of the neck and thorax was done in the anterior view at 15 and 150 min postinjection of 740 MBq (20 mCi) of 99mTc-sestamibi.Surgery found 57 adenomas (2.59 [SD, 5.84] g; range 0.160-40), 6 hyperplastic glands (0.34 [SD, 0.26] g) and one carcinoma 8.2 g. The 99mTc-sestamibi was able to localize correctly 60 out of 64 lesions (55/57 adenomas, 4/6 hyperplastic glands and 1/1 carcinoma) (global sensitivity of 94%, adenomas sensitivity of 96%, positive predictive value of 97% and specificity of 98%). Isotopic imaging detected the abnormal tissue in all patients who had undergone unsuccessful previous surgery. PTH (4 [SD, 1.51] pmol/l) and calcium postoperative serum levels (2.13 [SD, 0.22] mmol/l) showed curation of all patients.Double phase parathyroid scintigraphy with 99mTc-sestamibi is the method of choice to localize abnormal parathyroid glands.

Cystinuria is an amino acid disease due to a defect of intestinal and renal tubular transport of cystine and various basic amino acids (lysine, arginine and ornithine). The disease is transmitted horizontally according to an autosomal recessive pattern. The overall prevalence is one per 7,000 live births. It is the commonest hereditary disease affecting amino acid transport (MIM 220100). This disease is characterized by excessive urinary excretion of cystine and basic amino acids. From a clinical point of view, almost 50% of homozygotes will develop cystine renal stones with urinary tract infection, renal colic, partial or total obstruction of the urinary tract and possibly loss of renal function.

A cystinuria disease gene (rBAT) has been recently identified, and some mutations causing the disease have been described. The frequency of these mutations has been investigated in a large sample of 51 Italian and Spanish cystinuric patients. In addition, to identify new mutated alleles, genomic DNA has been analyzed by an accurate and sensitive method able to detect nucleotide changes. Because of the lack of information available on the genomic structure of rBAT gene, the study was carried out using the sequence data so far obtained by us. More than 70% of the entire coding sequence and 8 intron-exon boundaries have been analyzed. Four new mutations and seven intragenic polymorphisms have been detected. All mutations so far identified in rBAT belong only to cystinuria type I alleles, accounting for approximately 44% of all type I cystinuric chromosomes. Mutation M467T is the most common mutated allele in the Italian and Spanish populations. After analysis of 70% of the rBAT coding region, we have detected normal sequences in cystinuria type II and type III chromosomes. The presence of rBAT mutated alleles only in type I chromosomes of homozygous (type I/I) and heterozygous (type I/III) patients provides evidence for genetic heterogeneity where rBAT would be responsible only for type I cystinuria and suggests a complementation mechanism to explain the intermediate type I/type III phenotype.

Cystine renal stone is the only clinical consequence of cystinuria, an autosomal recessive hereditary disease that affects an average of 1 out of 7,000 newborns, and whose geographical distribution varies significantly. The diagnosis and treatment of this condition is reviewed in the light of the advances in genetics and molecular biology.The evolution of current knowledge about this disease is reviewed.The advances over the last 8 years have led to the characterization, at the present time, of two genes responsible for this disease, which demonstrates its polygenic origin. By phenotype, cystinuria can be classified into two types: type 1 and non-type 1. Both types show genetic and biochemical, but not clinical differences. From the therapeutic viewpoint, the main objective is to eliminate existing calculi and, above all, prevent recurrence by acting on the pathophysiologic mechanisms of renal cystine. Experience shows that despite the correct use of our current therapeutic armamentarium and the application of the general guidelines discussed in this paper, some cystinuric patients still maintain an important stone-forming activity. Patient clinical evaluation and a genetic study of both patient and family will be decisive for phenotyping.