Cystinuria is an inherited disorder characterized by defective renal reabsorption of cystine and dibasic amino acids leading to nephrolithiasis. This study was conducted to analyze the genotypes and phenotypes of pediatric patients with cystinuria. Eight children from Seoul National University Hospital and Asan Medical Center presenting with cystinuria from January 2003 to June 2016 were retrospectively analyzed. Mutational studies were performed by direct sequencing. Two of the 8 were male and 6 were female. The median ages at onset and diagnosis were 1.5 (range, 0.3–13.6) and 2.6 (range, 0.7–16.7) years, respectively. The median followed up was 7.7 (range, 3.4–14.0) years. Mutational analyses were performed in 7 patients and revealed biallelic SLC3A1 mutations (AA genotype) in 4 patients, a single heterozygous SLC3A1 mutation (A- genotype) in 1 patient, biallelic SLC7A9 mutations (BB genotype) in 1 patient, and a single heterozygous SLC7A9 mutation (B- genotype) in 1 patient. Two of the mutations were novel. No genotype-phenotype correlations were observed, except for earlier onset age in patients with non-AA genotypes than in patients with the AA genotype. All patients suffered from recurrent attacks of symptomatic nephrolithiasis, which lead to urologic interventions. At the last follow-up, 3 patients had a mild-to-moderate degree of renal dysfunction. This is the first study of genotypic and phenotypic analyses of patients with cystinuria in Korea.
Age of Onset ; Amino Acids, Diamino ; Child ; Chungcheongnam-do ; Cystine ; Cystinuria* ; Diagnosis ; Female ; Follow-Up Studies ; Genetic Association Studies ; Genotype* ; Humans ; Korea ; Male ; Nephrolithiasis ; Phenotype* ; Renal Reabsorption ; Retrospective Studies ; Seoul

PURPOSE: To document the experiences of a single institution in evaluating the clinical courses and treatment outcomes of patients with cystine stones. MATERIALS AND METHODS: The clinical data of 14 patients with cystine stones who were treated at our institution from March 1994 to July 2012 were reviewed. These data included age at first visit, gender, family history, body mass index, presence of a single kidney, stone locations, stone burden, routine urinalysis, and culture. In addition, we also analyzed data on surgery, shock wave lithotripsy, medical treatment, stone recurrence or regrowth, and overall treatment success rates. RESULTS: The mean age of our patients at their first visit was 19.6+/-5.0 years, and eight patients were males. The median stone burden and mean urine pH before each surgery were 6.5 cm2 and 6.5+/-0.9, respectively. Two patients had a family history of cystine stones. Patients underwent surgery an average of 2.7 times. The median interval between surgeries was 27.3 months, and 1 open surgery, 12 percutaneous nephrolithotomies, and 25 ureterorenoscopies were performed. Potassium citrate or sodium bicarbonate was used in nine cases. D-Penicillamine was continuously used in three patients. Patients had an average incidence of 3.2 recurrences or regrowth of stones during the median follow-up period of 60.5 months. CONCLUSIONS: Patients with cystine stones have high recurrence or regrowth rates and relatively large stone burdens. Adequate treatment schedules must therefore be established in these cases to prevent possible deterioration of renal function.
Adolescent ; Adult ; Child ; Combined Modality Therapy ; Cystine/*analysis ; Cystinuria/complications ; Female ; Humans ; Hydrogen-Ion Concentration ; Kidney Calculi/chemistry/pathology/therapy ; Lithotripsy/methods ; Male ; Nephrostomy, Percutaneous/methods ; Recurrence ; Reoperation ; Retrospective Studies ; Treatment Outcome ; Ureteral Calculi/chemistry/pathology/therapy ; Urinary Calculi/chemistry/etiology/pathology/*therapy ; Young Adult

Cystinuria is an autosomal recessive disease characterized by impaired transport of cystine and dibasic amino acids in the proximal renal tubule, resulting in the formation of cystine stones. It is believed to account for about 1% of all kidney stones and up to 10% of pediatric stones. Here we report a case of cystinuria with multiple renal stones confirmed by genetic mutational analysis. An 8-month-old girl was admitted to AMC with persistent fever and multiple renal stones. A renal sonogram showed multiple stones at the right renal pelvis, right distal ureter, and left renal medullary portion. An approximately 1 cm renal stone was extracted spontaneously, and stone analysis revealed it to be composed entirely of cystine. Cystinuria was confirmed by increased urine dibasic amino acid levels, including cysteine, and genetic mutational analysis showed the patient to be a homozygote for the pathogenic c. 1820del (p.L607fs) of SLC3A1. Despite treatment with oral hydration and urinary alkalinization, and restricted intake of animal protein, the stones increased in size and number. The patient has since been treated with tiopronin.
Amino Acids, Diamino ; Animals ; Cysteine ; Cystine ; Cystinuria* ; Female* ; Fever ; Homozygote ; Humans ; Infant* ; Kidney Calculi ; Kidney Pelvis ; Kidney Tubules, Proximal ; Tiopronin ; Ureter ; Urolithiasis

Cystinuria is an inherited renal and intestinal disease characterized by defective amino acids reabsorption and cystine urolithiasis. It is unusually associated with neurologic symptoms. Mutations in two genes, SLC3A1 and SLC7A9, have been identified in cystinuric patients. This report presents a 13-yr-old boy with cystinuria who manifested difficulty in walking, ataxia, and mental retardation. Somatosensory evoked potential of posterior tibial nerve stimulation showed the central conduction dysfunction through the posterior column of spinal cord. He was diagnosed non-type I cystinuria by urinary amino acid analysis and oral cystine loading test. We screened him and his family for gene mutation by direct sequencing of SLC3A1 and SLC7A9 genes. In this patient, we identified new missence mutation G173R in SLC7A9 gene.
Adolescent ; Amino Acid Substitution ; Amino Acid Transport Systems, Basic/*genetics ; Amino Acids/urine ; Ataxia/complications/diagnosis/*genetics ; Base Sequence ; Cystine/blood ; Cystinuria/complications/diagnosis/*genetics ; Humans ; Intellectual Disability/complications/diagnosis/*genetics ; Male ; *Mutation, Missense ; Pedigree ; Republic of Korea

Elastosis perforans serpiginosa (EPS) is a rare reactive perforating dermatosis that is characterized by the transepidermal elimination of abnormal elastic fibers. Penicillamine, which is one of the clear triggers for EPS, is a heavy metal chelator that is primarily used for disorders such as cystinuria and Wilson's disease. It may cause alterations in the dermal elastic tissue such as pseudo-pseudoxanthoma elasticum, acquired cutis laxa, EPS and anetoderma. Herein we present a case of cutis laxa and EPS in a 34-year-old man who was previously on a long-term, high-dose of penicillamine for Wilson's disease. The combination of EPS and cutis laxa induced by penicillamine has rarely been reported and we report the first such case in Korea.
Adult ; Anetoderma ; Cutis Laxa ; Cystinuria ; Elastic Tissue ; Hepatolenticular Degeneration ; Humans ; Korea ; Penicillamine ; Skin Diseases

PURPOSE: Urinary lithiasis is uncommon in children, however, it may lead to chronic renal insufficiency and even end stage renal disease. The etiology of stone formation in children is largely unknown; although the most common causes are known to be associated with congenital anomalies of the genito-urinary(G-U) tract, urinary tract infections(UTI), and metabolic diseases. METHODS: A total of 73 children(male:female=42:31, mean age 6.6+/-5.3 years) presented with urinary lithiasis between Sep. 1998 and Jul. 2007 at Seoul National University Children's Hospital. The medical records were reviewed retrospectively. RESULTS: The most common presenting symptoms were gross hematuria(28/73, 38%) and flank or abdominal pain(23/73, 32%). The stones were located in the upper urinary tract in 48 patients(66%), in the bladder in 18(24%), and in both the bladder and upper urinary tract in 2 (3%). Congenital anomalies of the G-U tract with/without UTI were detected in 30 children (41%), hypercalciuria with/without hypercalcemia in 15(20%), and other metabolic diseases in 8(11%). In 17 patients(23%), no underlying cause of stone formation was detected. The majority of stones were infected stones(24/36, 67%), which were followed by calcium stones(8/36, 22%), uric acid stones(3/36, 8%), and cystine stones(1/36, 3%). Thirty-four patients(46%) underwent surgical procedures and/or extracorporeal shockwave lithotripsy for stone removal, and 13(18%) passed stones spontaneously with/without medical management. Stones recurred in 6 patients(8%): 4 with neurogenic bladder augmented by ileocystoplasty, 1 with cystinuria, and 1 with unknown etiology. CONCLUSION: The common causes of urinary lithiasis in children were congenital anomalies of the G-U tract with/without UTI and metabolic disorders including hypercalciuria/hypercalcemia. For the management of stones, minimally invasive procedures should be chosen on the basis of accompanying symptoms and the composition, locations and etiology of stones.
Calcium ; Child* ; Cystine ; Cystinuria ; Humans ; Hypercalcemia ; Hypercalciuria ; Kidney Failure, Chronic ; Lithotripsy ; Medical Records ; Metabolic Diseases ; Recurrence ; Renal Insufficiency, Chronic ; Retrospective Studies ; Seoul ; Uric Acid ; Urinary Bladder ; Urinary Bladder, Neurogenic ; Urinary Tract ; Urolithiasis*

The heterodimeric amino acid transporter family is a subfamily of SLC7 solute transporter family which includes 14-transmembrane cationic amino acid transporters and 12-transmembrane heterodimeric amino acid transporters. The members of heterodimeric amino acid transporter family are linked via a disulfide bond to single membrane spanning glycoproteins such as 4F2hc (4F2 heavy chain) and rBAT (related to b0, +-amino acid transporter). Six members are associated with 4F2hc and one is linked to rBAT. Two additional members were identified as ones associated with unknown heavy chains. The members of heterodimeric amino acid transporter family exhibit diverse substrate selectivity and are expressed in variety of tissues. They play variety of physiological roles including epithelial transport of amino acids as well as the roles to provide cells in general with amino acids for cellular nutrition. The dysfunction or hyperfunction of the members of the heterodimeric amino acid transporter family are involved in some diseases and pathologic conditions. The genetic defects of the renal and intestinal transporters b0, +AT/BAT1 (b0, +-type amino acid transporter/b0, +-type amino acid transporter 1) and y+LAT1 (y+L-type amino acid transporter 1) result in the amino aciduria with sever clinical symptoms such as cystinuria and lysin uric protein intolerance, respectively. LAT1 is proposed to be involved in the progression of malignant tumor. xCT (x-C-type transporter) functions to protect cells against oxidative stress, while its over-function may be damaging neurons leading to the exacerbation of brain damage after brain ischemia. Because of broad substrate selectivity, system L transporters such as LAT1 transport amino acid-related compounds including L-Dopa and function as a drug transporter. System L also interacts with some environmental toxins with amino acid-related structure such as cysteine-conjugated methylmercury. Therefore, these transporter would be candidates for drug targets based on new therapeutic strategies.
Amino Acid Transport Systems* ; Amino Acid Transport Systems, Basic ; Amino Acids ; Brain ; Brain Ischemia ; Cystinuria ; Glycoproteins ; Humans ; Levodopa ; Membranes ; Neurons ; Oxidative Stress

Penicillamine dermatopathy refers to the characteristic hemorrhagic skin lesions found in persons receiving long-term penicillamine therapy for either Wilson's disease or cystinuria. These lesions are thought to develop as a result of faulty collagen and elastin synthesis. We described a 31-year-old woman with Wilson's disease who developed mild pruritic grouped matchhead-sized cream-colored papules on the dark reddish plaques on both knees and elbows.
Adult ; Collagen ; Cystinuria ; Elastin ; Elbow ; Female ; Hepatolenticular Degeneration ; Humans ; Knee ; Penicillamine* ; Skin

In an outpatient setting, 107 patients were evaluated using a single 24-hour specimen with StoneRisk Diagnostic Profile on a random diet before medication and treatment and updated the classification of nephrolithiasis. For specific subclassification of hypercalciuric calcium(Ca) nephrolithiasis, calcium and sodium restricted diet and sodium cellulose phosphate screening test were underwent. Abnormal urinary biochemistry was classified into one or more of 20 etiologic categories. A single diagnosis was documented in 37(34.6%) patients and the remaining 65.4% had more than one diagnosis. Hypercalciuric Ca nephrolithiasis occurred in 41 (38.3%) patients and specific subclassification of 6 variants was performed. In this study, hypercalciuric Ca nephrolithiasis occurred less frequently in comparison to the incidence of U.S.A. reported by Dr. Pak. Hyperuricosuric Ca nephrolithiasis (HUCN) and gouty diathesis(GD) accounted for 47(43.9%) and 8(7.4%) patients, respectively. Hyperoxaluric Ca nephrolithiasis was in 25(23.4%) patients and all were dietary origin following an oxalate-restricted diet. Hypocitraturic Ca nephrolithiasis was seen in 51(47.6%) patients in idiopathic variant. Hypocitraturia due to RTA and chronic diarrheal syndrome occurred in 1(0.9%) and 2(1.8%) patients. Hypomagnesiuric Ca nephrolithiasis and acquired problem of low urine volume(<1 L/d) were accounted in 3(2.8%) and 13(12.2%) patients, respectively. Infection stones or cystinuria were not detected. No metabolic abnormality was found in 12(11.2%) patients. High sodium take was detected in 60(56.1%) patients, reflecting that Koreans take high sodium containing foods. We think that StoneRisk Diagnostic Profile using a single 24-hour urine specimen is very useful in detecting stone-forming risk factors and providing specific therapeutic guidelines. Additionally, recurrence associated with high cost of medical care can be reduced through adequate diagnostic evaluation as part of the treatment regimen.
Biochemistry ; Calcium ; Cellulose ; Classification ; Cystinuria ; Diagnosis ; Diet ; Humans ; Incidence ; Korea* ; Mass Screening ; Nephrolithiasis* ; Outpatients ; Recurrence ; Risk Factors ; Sodium

We report three cases of cystinuria, presenting with urinary stones. A 2-year-old girl presented with urinary difficulty, hematuria, dysuria of sudden onset, and her 7-month-old younger brother also was presented with urinary difficulty, irritability on urination & stone passage. Other 6-month-old boy was admitted due to sudden onset anuria. They had radioopague renal & ureter stones and stone analysis revealed mixed cystine stones. The diagnosis of cystinuria was confirmed metabolic studies and stone analysis. Lrinary amino acid analysis showed excessive excretion of dibasic amino acids(cystine, ornithine, lysine, arginine). And they all had hypercalciuria and hyperuricosuria. They were treated with combination of percutaneous lithotripsy for large obstructing senes a nd an oral drug therapy with sodium bicarbonate for rendering the urine more alkaline, and alpha-mercaptopropionylglycine(ThiolaR). This form of treatment was sucessful in our three cases with elimination of recurrent nephrolithiasis, but in one patient, nephrotic syndrome possibly caused by ThiolaR was developed. The nephrotic syndrome was recovered spontaneously after cessation of Thiola. A review of literatures was also attempted briefly.
Anuria ; Child, Preschool ; Cystine ; Cystinuria* ; Diagnosis ; Drug Therapy ; Dysuria ; Female ; Hematuria ; Humans ; Hypercalciuria ; Infant ; Lithotripsy ; Lysine ; Male ; Nephrolithiasis ; Nephrotic Syndrome ; Ornithine ; Siblings ; Sodium Bicarbonate ; Tiopronin ; Ureter ; Urinary Calculi ; Urination