Considering Histologic Remission in Ulcerative Colitis as a Long-Term Target.

Monitoring disease activity in inflammatory bowel disease (IBD) is challenging since clinical manifestations do not represent reliable surrogates for an accurate reflection of the inflammatory burden. Endoscopic remission had been the most significant endpoint target in the last years; nevertheless, a remarkable proportion of patients continue to relapse despite a normal-appearing mucosa, highlighting that endoscopy may underestimate the true extent of the disease. A subtle hint of the importance that histology plays in the long-term course of the disease has been endorsed by the STRIDE-II consensus, which recommends considering histologic healing for ulcerative colitis (UC), even though it is not stated to be a compulsory formal target. It is a continuum-changing paradigm, and it is almost a certainty that in the near future, histologic healing may become the new formal target for ulcerative colitis. It must be emphasized that there is great heterogeneity in defining histological remission, and the main criteria or cut-off values for inflammatory markers are still in an ill-defined area. The complexity of some histologic scores is a source of confusion among clinicians and pathologists, leading to low adherence in clinical practice when it comes to a homogenous histopathological report. Therefore, a standardized and more practical approach is urgently needed.

Endometriosis as an Uncommon Cause of Intestinal Obstruction-A Comprehensive Literature Review.

The prevalence of intestinal endometriosis has been estimated to be between 3% and 37% of all endometriosis cases. Cases of intestinal occlusion due to endometriosis foci on the small bowel and on the large bowel are even rarer, with a reported prevalence of 0.1-0.7%. The aim of this literature review was to summarize the available published evidence on the diagnosis, characteristics, and management of intestinal occlusion due to endometriosis. The search on PubMed retrieved 295 records, of which 158 were rejected following a review of the title and abstract. After reviewing the full text, 97 studies met the Population, Intervention, Comparator, Outcomes, and Study (PICOS) criteria and were included in the analysis. The total number of patients with bowel occlusion due to endometriosis included in the studies was 107. The occlusive endometrial foci were localized on the ileum in 38.3% of the cases, on the rectosigmoid in 34.5% of the cases, at the ileocecal junction and the appendix in 14.9% of the cases, and at the rectum in 10.2% of the cases. Only one case reported large bowel obstruction by endometriosis of the hepatic flexure of the colon extending to the transverse colon (0.9%), and in one case the obstruction was caused by an omental giant endometrioid cyst compressing the intestines. We identified six cases of postmenopausal females with acute bowel obstruction due to endometriosis. Malignant degeneration of endometriosis was also identified as a cause of intestinal occlusion. The mechanisms of obstruction include the presence of a mass in the lumen of the intestine or in the wall of the intestine, extrinsic compression, adhesions, or intussusception.

Duodenal Gangliocytic Paragangliomas-Case Series and Literature Review.

Duodenal gangliocytic paragangliomas are rare neuroendocrine tumors primarily localized in the periampullary area. Though mostly asymptomatic, they can present with various symptoms, most often jaundice, anemia and abdominal pain. The present paper is a case series report, describing our personal experience with patients presenting to the Emergency Unit with different symptoms due to duodenal gangliocytic paraganglioma. Endoscopic resection is safe and indicated in most of the cases, being also associated with lower medical costs. EUS plays a central role in the pre-resection management and in surveillance, and immunostaining is decisive to ascertain the tumor histologic origin. In addition to reporting our experience, we researched the literature regarding these rare tumors and performed a comprehensive review.

Multidrug resistance in Helicobacter pylori infection.

Helicobacter pylori (Hp), a well-known human pathogen, causes one of the most common chronic bacterial infections and plays an important role in the emergence of chronic progressive gastric inflammation and a variety of gastrointestinal diseases. The prevalence of Hp infection varies worldwide and is indirectly proportional to socio-economic status, especially during childhood. The response to the eradication therapy significantly depends on the antibiotic resistance specific to each geographical region; thus, currently, given the increasing prevalence of antimicrobial resistance (especially to clarithromycin, metronidazole, and levofloxacin), successful treatment for Hp eradication has become a real challenge and a critical issue. The most incriminated factors associated with multidrug resistance (MDR) in Hp proved to be the overuse or the improper use of antibiotics, poor medication adherence, and bacterial-related factors including efflux pumps, mutations, and biofilms. Up to 30% of first-line therapy fails due to poor patient compliance, high gastric acidity, or high bacteremia levels. Hence, it is of great importance to consider new eradication regimens such as vonoprazan-containing triple therapies, quintuple therapies, high-dose dual therapies, and standard triple therapies with probiotics, requiring further studies and thorough assessment. Strain susceptibility testing is also necessary for an optimal approach.

Clinical presentation and management of nephrotic syndrome in the first year of life: A report from the Pediatric Nephrology Research Consortium.

Background and objectives: Nephrotic syndrome (NS) in the first year of life is called congenital (CNS) if diagnosed between 0-3 months, or infantile (INS) if diagnosed between 3-12 months of age. The aim of this study was to determine if there were clinically meaningful differences between CNS and INS patients, regarding clinical presentation, management and outcomes. Design setting participants and measurements: Eleven Pediatric Nephrology Research Consortium sites participated in the study, using IRB-approved retrospective chart reviews of CNS and INS patients born between 1998 and 2019. Data were collected on patient characteristics, pertinent laboratory tests, provided therapy, timing of unilateral/bilateral nephrectomy and initiation of renal replacement therapy (RRT). Results: The study included 69 patients, 49 with CNS and 20 with INS, with a median age at diagnosis of 1 and 6 months, respectively. Management for the two groups was similar regarding nutrition, thyroxin supplementation, immunoglobulin administration, and thrombosis prophylaxis. Within the first 2 months after diagnosis, daily albumin infusions were used more often in CNS vs. INS patients (79 vs. 30%; p = 0.006), while weekly infusions were more common in INS patients (INS vs. CNS: 50 vs. 3%; p = 0.001). During the 6 months preceding RRT, albumin infusions were more frequently prescribed in CNS vs. INS (51 vs. 15%; p = 0.007). Nephrectomy was performed more often in CNS (78%) than in INS (50%; p = 0.02). End-stage kidney disease tended to be more common in children with CNS (80%) vs. INS (60%; p = 0.09). Conclusion: Compared to INS, patients with CNS had a more severe disease course, requiring more frequent albumin infusions, and earlier nephrectomy and RRT. Despite center-specific variations in patient care, 20-40% of these patients did not require nephrectomy or RRT.

Efficacy of Endobiliary Radiofrequency Ablation in Preserving Survival, Performance Status and Chemotherapy Eligibility of Patients with Unresectable Distal Cholangiocarcinoma: A Case-Control Study.

BACKGROUND: Cholangiocarcinoma is the most common malignancy of the bile ducts causing intrahepatic, hilar, or distal bile duct obstruction. Most jaundiced patients are diagnosed with unresectable tumors in need for palliative bile duct drainage and chemotherapy. Endobiliary radiofrequency ablation (RFA) is an adjuvant technique that may be applied prior to biliary stenting. The aim of our study was to assess the efficacy of endobiliary RFA prior to stent insertion in patients with unresectable distal cholangiocarcinomas. METHODS: Twenty-five patients (eight treated with RFA and stenting and 17 treated with stenting alone) were included in a case-controlled study. We prospectively assessed the impact of RFA on the survival rate, the patient performance status, and the preservation of eligibility for chemotherapy based on the patient laboratory profile. RESULTS: Patients treated with RFA prior to stenting proved to have a significantly longer survival interval (19 vs. 16 months, p = 0.04, 95% CI) and significantly better performance status. Moreover, the laboratory profiles of patients treated with RFA has been proven superior in terms of total bilirubin, liver enzymes, and kidney function, thus making patients likely eligible for palliative chemotherapy. Post-ERCP adverse events were scarce in both the study group and the control group. CONCLUSION: Given the isolated adverse events and the impact on the patient survival, performance, and laboratory profile, RFA can be considered safe and efficient in the management of patients with unresectable distal cholangiocarcinomas.

Utility of the 2018 revised ISN/RPS thresholds for glomerular crescents in childhood-onset lupus nephritis: a Pediatric Nephrology Research Consortium study.

BACKGROUND: The revised 2018 ISN/RPS Classification System for lupus nephritis (LN) includes calculations for both activity index (A.I.) and chronicity index (C.I.). Unchanged were the thresholds of < 25%, 25-50%, and > 50% crescents to distinguish between mild, moderate, and severe activity/chronicity. We aimed to evaluate these thresholds for percent crescents in childhood-onset LN. METHODS: Eighty-six subjects < 21 years of age were enrolled from the Pediatric Glomerulonephritis with Crescents Registry, a retrospective multi-center cohort sponsored by the Pediatric Nephrology Research Consortium. Thresholds of 10%, 25%, and 50% for both cellular/fibrocellular and fibrous crescents were interrogated for primary outcomes of kidney failure, eGFR, and eGFR slope. RESULTS: Median age at time of initial biopsy was 14 years (range 1-21). Median follow-up time was 3 years (range 1-11). Cumulative incidence of kidney failure was 6% at 1 year and 10% at latest follow-up. Median eGFR slope was - 18 mL/1.73 m2/min (IQR - 51 to + 8) at 1 year and - 3 mL/min/1.73 m2/year (IQR - 19 to + 6) at latest follow-up. We found no difference in kidney failure at the proposed < 25% and 25-50% cellular crescents thresholds, and thus added a new provisional threshold of 10% that better predicted outcomes in children. Moreover, use of 10% and 25% thresholds for fibrous crescents showed a fourfold and sevenfold increase in risk of kidney failure. CONCLUSIONS: In children with crescentic LN, use of 10% and 25% thresholds for cellular crescents better reflects disease activity, while these thresholds for fibrous crescents better discriminates kidney disease outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information.

Impact of biliary stenting in endoscopic ultrasound-guided tissue acquisition among patients with pancreatic cancer.

INTRODUCTION: Pancreatic malignancies represent highly fatal diseases with poor prognosis and constantly increasing incidence despite modern diagnostic and therapeutic options. Both endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) are regarded as mainstays in pancreatic cancer management. The present study aims to evaluate whether accuracy EUS with fine-needle aspiration or biopsy (FNA or FNB) in pancreatic cancer diagnosis is influenced by prior biliary stenting or by technical or anatomical features (stent type, number of needle passes, common bile duct or Wirsung's diameter, topographical characteristics and diameter of the pancreatic tumor). MATERIALS AND METHODS: This retrospective study includes 243 patients with pancreatic cancer who underwent ERCP and EUS with fine-needle aspiration or biopsy (FNA or FNB). RESULTS AND DISCUSSION: Out of the total number of patients, 68 were stented prior to EUS. We found that the EUS-FNA diagnostic yield is not influenced either by the presence of biliary stent, nor by the type of stent (plastic or metallic). Moreover, the mean needle passes required were similar for both stented patients and not stented ones. CONCLUSIONS: Ultimately, given our results, we can state that EUS-FNA/FNB can be safely and accurately performed in the presence of biliary stents.

Primary treatment of ocular surface squamous neoplasia with topical interferon alpha-2b: Comparative analysis of outcomes based on original tumor configuration.

Purpose: The aim of this study was to evaluate tumor control of OSSN with topical IFNα2b alone based on tumor configuration (flat versus (vs.) dome-shaped). Methods: Retrospective, nonrandomized, interventional cohort study on 64 consecutive tumors in 63 patients with OSSN treated with topical IFNα2b. Topical IFNα2b (1 million international units/cc) was compounded and provided by the Thomas Jefferson University Hospital Pharmacy to be refrigerated and applied 4 times daily until biomicroscopic evidence of tumor resolution was observed. Results: The tumor configuration was flat (n = 15, 23%) or dome-shaped (n = 49, 77%). A comparison (flat vs. dome-shaped) revealed dome-shaped with older mean patient age at presentation (62 vs. 70 years, P = 0.04), greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (7% vs. 82%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean thickness (1.9 vs. 4.3, P = 0.002), and longer mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002). There was no difference in mean follow-up time (22.2 vs 23.1 months) or time to complete response (5.0 vs. 6.1 months). There was no difference in achievement of complete tumor control with IFNα2b alone (93% vs. 96%). There were no cases with metastasis or death. Conclusion: Topical IFNα2b alone shows excellent overall tumor control of 95% with no difference in efficacy based on tumor configuration.

A morphological and immunohistochemical study of the endoscopic ultrasound-fine-needle biopsy samples from solid pancreatic masses: a single center study.

OBJECTIVE: The purpose of this study was to present the experience of a single center on endoscopic ultrasound-fine-needle biopsy (EUS-FNB) of pancreatic solid tumors amenable to immunohistochemistry (IHC) assay. PATIENTS, MATERIALS AND METHODS: Inclusion criterion for this prospective study was identifying patients with pancreatic solid tumors, by means of imaging methods, from January 2018 to February 2020, within the Department of Gastroenterology, Emergency Clinical Hospital, Bucharest, Romania. All patients underwent EUS-FNB and the harvested tissue was sent to the Department of Pathology for histopathological (HP) diagnosis and IHC assessment if tumoral origin remained undetermined. RESULTS: A total of 57 patients were ultimately selected to take part in our study. We performed immunohistochemical analysis based on the morphological diagnosis of the pancreatic tumors and assessed cytokeratin (CK)7, CK20, caudal type homeobox 2 (CDX2), MutL homolog 1 (MLH1), MutS homolog (MSH)2, MSH6, postmeiotic segregation 2 (PMS2) for all histopathologically uncertain pancreatic ductal adenocarcinoma (PDAC) and chromogranin A, synaptophysin, pan-CK AE1∕AE3 for pancreatic neuroendocrine tumors (pNETs). Cox hazard regression was performed to identify the factors influencing the survival rate. In univariate analysis, patient survival time was significantly associated with stage, location, surgical management and CK7 positivity. Our data show a statistically significant predictive relationship between stage (regional or metastatic) and hazard for survival (p=0.015). Tumoral location in the tail (p=0.015) and radicality surgery (p=0.015) significantly decrease the survival of pancreatic cancer (PAC) patients. The presence of CK7 (p=0.015) significantly increases the survival of pancreas cancer patients. CONCLUSIONS: EUS-FNB has opened up a new path for pancreatic tumor diagnosis providing enough tissue for HP examination and IHC. A panel of several immunomarkers might aid in providing new therapies for PAC patients.

Ocular Surface Squamous Neoplasia Managed With Primary Interferon α2b: A Comparative Analysis of 212 Tumors in Smokers Versus Nonsmokers.

PURPOSE: To explore clinical features and outcomes of ocular surface squamous neoplasia (OSSN) treated with primary interferon (IFN)-α2b, based on patient cigarette smoking status. METHODS: Retrospective nonrandomized, interventional cohort study on 212 consecutive tumors in 194 patients, all of whom were treated with topical and/or injection IFNα2b. RESULTS: There were 88 tumors in 76 patients with current or past smoking history (smokers) and 124 tumors in 118 nonsmoking patients (nonsmokers). A comparison (smokers vs. nonsmokers) revealed smokers with more frequent bilateral disease (16% vs. 3%, P = 0.003), more frequent involvement of inferior forniceal (34% vs. 21%, P = 0.03) and inferior tarsal conjunctiva (38% vs. 24%, P = 0.04), greater mean number of clock hour involvement (4.1 vs. 3.5 clock hours, P = 0.04), and greater dome growth pattern (30% vs. 15%, P = 0.01). There was no difference regarding method of IFNα2b administration as topical (61% vs. 71%, P = 0.14), injection (10% vs. 6%, P = 0.32), or combination topical/injection (28% vs. 23%, P = 0.33). A comparison revealed smokers with more frequent recurrence after initial response (23% vs. 13%, P = 0.04). There was no difference regarding initial tumor response or time to response, treatment side effects, or systemic outcomes. CONCLUSIONS: Regarding ocular surface squamous neoplasia, smokers more often display bilateral, dome-shaped tumors with inferior forniceal or tarsal involvement, and greater extent than nonsmokers. After treatment with topical and/or injection IFNα2b, control is equivalent, but smokers show greater recurrence.

Delayed Management of Zollinger-Ellison Syndrome in a Noncompliant Patient.

We present a case of a 60-year-old male diagnosed with Zollinger-Ellison syndrome (ZES) after a protracted multicentric workup for chronic diarrhea and unexplained weight loss. ZES is intrinsically difficult to diagnose due to nonspecific symptoms, which are mimicked by other more frequent pathologies, such as peptic ulcer disease secondary to Helicobacter pylori or nonsteroidal anti-inflammatory drugs. The diagnostic challenge can be further complicated by patient noncompliance, resulting in delayed management and unnecessary health care. In our case report, the patient did not adhere to the care plan preceding endoscopy and failed to maintain communication with the treating doctor. As a result, crucial information was missing, and establishing the diagnosis of ZES took six months. Delay in appropriate management also contributed to poor disease course, heavy necrotic ulceration of the duodenum and proximal jejunum that was discovered on repeat endoscopy.

Renal Survival in Children with Glomerulonephritis with Crescents: A Pediatric Nephrology Research Consortium Cohort Study.

There is no evidence-based definition for diagnosing crescentic glomerulonephritis. The prognostic implications of crescentic lesions on kidney biopsy have not been quantified. Our objective was to determine risk factors for end-stage kidney disease (ESKD) in patients with glomerulonephritis and crescents on kidney biopsy. A query of the Pediatric Nephrology Research Consortium's Pediatric Glomerulonephritis with Crescents registry identified 305 patients from 15 centers. A retrospective cohort study was performed with ESKD as the primary outcome. Median age at biopsy was 11 years (range 1-21). The percentage of crescents was 3-100% (median 20%). Etiologies included IgA nephropathy (23%), lupus (21%), IgA vasculitis (19%) and ANCA-associated GN (13%), post-infectious GN (5%), and anti-glomerular basement membrane disease (3%). The prevalence of ESKD was 12% at one year and 16% at last follow-up (median = 3 years, range 1-11). Median time to ESKD was 100 days. Risk factors for ESKD included %crescents, presence of fibrous crescents, estimated GFR, and hypertension at biopsy. For each 1% increase in %crescents, there was a 3% decrease in log odds of 1-year renal survival (p = 0.003) and a 2% decrease in log odds of renal survival at last follow-up (p < 0.001). These findings provide an evidence base for enrollment criteria for crescentic glomerulonephritis in future clinical trials.

Biliary Stenting for Malignant Biliary Obstruction Secondary to Pancreatic Cancer.

Despite progresses made in oncology, pancreatic adenocarcinoma has a grim prognosis and commonly presents with rapidly advancing jaundice which requires endoscopic treatment. AIM: Our objective was to show the perspective of a high ERCP volume dedicated Center on endoscopic stenting for malignant biliary obstruction consecutive to pancreatic cancer. METHODS: We conducted a retrospective study, between October 2017 and October 2020, and enrolled hospitalized patients within the Gastroenterology Department of the Clinical Emergency Hospital Bucharest, diagnosed with pancreatic cancer with secondary malignant biliary obstruction which underwent ERCP stenting. RESULTS: We identified 269 patients which were admitted in our Clinic with a pancreatic lesion on computed tomography or magnetic resonance imaging and underwent EUS-FNA. 115 patients with proven pancreatic malignancy were selected and underwent ERCP stenting. 69 received plastic stents and 46 metal biliary stents, with the stent chosen based on patient's characteristics and availability at the time of the procedure. Per total 234 stents were used for relief of the cholestasis syndrome. The number of ERCP procedures was higher in the plastic stents group with a median of 1,8 whereas the SEMS had 1,5 range of procedures. Procedures were successful in 54 patients following plastic stents and 33 that underwent SEMS. At 30 days, overall mortality rate was of 5%. CONCLUSIONS: Malignant obstruction secondary to pancreatic cancer is amenable by ERCP. However, choosing the right stents still varies. SEMS seem to be more efficient on a long term with fewer complications rates and further studies should be performed.

Uveal Metastasis: Clinical Features and Survival Outcome of 2214 Tumors in 1111 Patients Based on Primary Tumor Origin.

PURPOSE: The purpose of this study is to evaluate patients with uveal metastasis based on primary tumor site. METHODS: Retrospective analysis from Wills Eye Hospital, Philadelphia, PA, USA, for uveal metastasis clinical features and outcomes based on the primary tumor site. RESULTS: There were 2214 uveal metastases diagnosed in 1111 consecutive patients. The demographics included mean age of 60 years (median 61 years), Caucasian race (88%), and female gender (64%). The tumor was unilateral (82%) and primary site was established before uveal metastasis (67%). The primary tumor originated in the breast (37%), lung (26%), kidney (4%), gastrointestinal (GI) tract (4%), cutaneous melanoma (2%), lung carcinoid (2%), prostate (2%), thyroid (1%), pancreas (1%), other sites (3%), and unknown (16%). Comparative analysis of the 5 most common primary sites (breast, lung, kidney, GI tract, and cutaneous melanoma), revealed metastasis at mean age (57, 62, 66, 61, 59 years), as unilateral tumor (74%, 86%, 85%, 93%, 85%), with mean number of metastasis/eye (1.9, 1.7, 1.0, 1.1, 2.0), and in females (99%, 46%, 26%, 25%, 30%). Choroidal metastases measured mean base (9.3, 10.2, 9.1, 11.0, 7.3 mm), mean thickness (2.4, 3.6, 4.4, 4.0, 2.9 mm), and demonstrated predominant color yellow (94%, 91%, 56%, 97%, 36%). Of the 769 patients with documented follow-up, mean patient survival was poor (22.2, 11.5, 8.6, 12.4, 11.4 months) and Kaplan-Meier analysis revealed 3-year survival (33%, 19%, 0%, 14%, 21%) and 5-year survival (24%, 13%, 0%, 14%, 21%). The worst survival was found in patients with pancreatic metastasis (mean 4.2 months) and best survival with lung carcinoid (92% at 5 years). CONCLUSION: In a tertiary referral service, uveal metastasis originates from cancer in the breast, lung, kidney, GI tract, cutaneous melanoma, or others. Overall prognosis is poor with 5-year survival at 23% and worst survival with pancreatic metastasis whereas best survival with lung carcinoid metastasis.

EUS-Guided Transgastric Drainage of Intraabdominal Fluid Collections.

Intraabdominal fluid collections can be a significant cause of morbi-mortality among patients with acute pancreatitis and those who underwent surgery, especially oncological ones. Nowadays, the treatment tends to be minimally invasive, so that the patient's recovery would be shorter and the quality of life higher. EUS (endoscopic ultrasound) has emerged in the last decade to fulfill that demand, alongside percutaneous and surgical drainage in the management of perigastric collections. Objectives: The main objective of this paper is to evaluate the efficacy of EUS guided drainage in terms of techincal and clinical success. Secondary objectives refer to the assessment of complete resolution of intraabdominal collection, presence of infection after drainage, overall survival. Methods: We conducted a prospective study by enrolling 31 patients who were diagnosed using EUS with perigastric intraabdominal fluid collections, from an overall of 788 EUS performed over a period of 2 years. We analyzed their evolution during 6 months after treatment, by regular examinations (ultrasound/endoscopic/computed tomography). All of them were in-patients of Bucharest Clinical Emergency Hospital, either in Endoscopy or in Surgery Departments. Data collected was processed in IBM SPSS Statistics 20. Results: Overall mean age was 51 year and intraabdominal collections average was 109 mm (range 34 250 mm) and was correlated with the method of treatment (p 0.005). Patients underwent different methods for their intraabdominal collections: EUS drainage, CT (computed-tomography)- guided percutaneous drainage, surgical intervention, alone or combined when needed. Overall mortality was 9,3% and was mainly related to the severity of the case and sepsis. Conclusions: We conclude that endoscopic ultrasound can be the first choice for drainage of intraabdominal perigastric fluid collections because it is a safe and effective technique with 100 % technical success, and with over 80 % clinical success assures a better quality of life. For collections with a diameter larger than 127 mm, we can expect however the need of combined treatment, EUS and surgery.

Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child.

The human sodium-dependent multivitamin transporter (hSMVT) is a product of the SLC5A6 gene and mediates biotin, pantothenic acid, and lipoate uptake in a variety of cellular systems. We report here the identification of mutations R94X, a premature termination, and R123L, a dysfunctional amino acid change, both in exon 3 of the SLC5A6 gene in a child using whole genome-scanning. At 15 months of age, the child showed failure to thrive, microcephaly and brain changes on MRI, cerebral palsy and developmental delay, variable immunodeficiency, and severe gastro-esophageal reflux requiring a gastrostomy tube/fundoplication, osteoporosis, and pathologic bone fractures. After identification of the SLC5A6 mutations, he responded clinically to supplemental administration of excess biotin, pantothenic acid, and lipoate with improvement in clinical findings. Functionality of the two mutants was examined by 3H-biotin uptake assay following expression of the mutants in human-derived intestinal HuTu-80 and brain U87 cells. The results showed severe impairment in biotin uptake in cells expressing the mutants compared to those expressing wild-type hSMVT. Live cell confocal imaging of cells expressing the mutants showed the R94X mutant to be poorly tolerated and localized in the cytoplasm, while the R123L mutant was predominantly retained in the endoplasmic reticulum. This is the first reporting of mutations in the SLC5A6 gene in man, and suggests that this gene is important for brain development and a wide variety of clinical functions.