Early predictors of unfavourable outcome in progressive cholestasis of northwestern Quebec.

Background: Progressive cholestasis of northwestern Quebec (PCNQ) is a rare and severe form of cirrhosis affecting children from Quebec's First Nations. First described by our group in 1981 and historically named North American Indian childhood cirrhosis, such a condition often requires liver transplantation during the pediatric age. This study aimed at suggesting a more culturally sensitive name for the disease and identifying early prognostic factors for an unfavourable outcome. Methods: We retrospectively collected data of all 14 consecutive patients diagnosed with PCNQ over the last 20 years and compared children listed for liver transplant before 18 years of age (LT, n = 7) to those with milder disease progression (no-LT, n = 7). Results: Compared with the no-LT group, LT children developed serious complications with an unusually high incidence of gastrointestinal bleeding. Over the first 12 months from presentation, a greater increase of alanine aminotransferase plasma levels, decrease of total bilirubin, and increase of alanine aminotransferase-to-total bilirubin ratio was observed in the LT group. Bone mineral density was lower in LT children independently of vitamin D levels. Patients with PCNQ showed poorer bone health than age-matched children with other cholestatic disorders. Conclusions: In the name of cultural sensitivity, PCNQ should be the preferred name for this condition. Variation of alanine aminotransferase and total bilirubin plasma levels over the first 12 months from presentation might be used for the early identification of children with PCNQ who are at higher risk of unfavourable outcomes. This might help optimize clinical management to populations that are underserved by health care services.

Risk Factors of Clinical Relapses in Pediatric Luminal Crohn's Disease: A Retrospective Cohort Study.

INTRODUCTION: There is currently little knowledge on factors associated with the relapse of Crohn's disease (CD) in children. The aims of this study were to describe the risk factors associated with relapse in pediatric CD and the changes in the relapse rate over the past decade. METHODS: Patients younger than 18 years and diagnosed between 2009 and 2019 were included in this retrospective cohort study. Clinical, endoscopic, histological, and laboratory data, as well as induction and maintenance treatments, were collected from the medical records. Survival analyses and Cox regression models were used to assess the impact of these risk factors on relapse. RESULTS: Six hundred thirty-nine patients were included. There was a decrease in the clinical relapse rate over the past decade: 70.9% of the patients diagnosed between 2009 and 2014 relapsed as compared with 49.1% of the patients diagnosed between 2015 and 2019 (P < 0.0001). The following variables were associated with clinical relapse: female sex (adjusted hazard ratio [aHR] = 1.52, P = 0.0007), exposure to oral 5-ASA (aHR = 1.44, P = 0.04), use of immunomodulatory agents compared with tumor necrosis factor-alpha inhibitors (methotrexate aHR = 1.73, P = 0.003; thiopurines aHR = 1.63, P = 0.002), presence of granulomas (aHR = 1.34, P = 0.02) and increased eosinophils on intestinal biopsies (aHR = 1.36, P = 0.02), high levels of C-reactive protein (aHR = 1.01, P < 0.0001) and fecal calprotectin (aHR = 1.08, P < 0.0001), and low serum infliximab levels (aHR = 2.32, P = 0.001). DISCUSSION: Relapse of pediatric CD has decreased in the past decade. The risk of relapse is significantly associated with clinical, endoscopic, histological, and laboratory variables and treatment strategies.

Functional Luminal Imaging Probe in the Management of Pediatric Esophageal Disorders.

BACKGROUND: Functional luminal imaging probe (FLIP) measures pressure-geometry relationships of digestive luminal space. When used in esophageal disorders, it provides several luminal parameters that help better understand the pathophysiology. Data about the potential utility of FLIP in pediatrics are scarce and there is no standardized use in children. We aim to describe the use of FLIP in our center, its safety, feasibility, and clinical impact in esophageal disorders in children. METHODS: Consecutive FLIP recordings performed at the Centre Hospitalier Universitaire-Sainte-Justine, Montréal, Canada between February 2018 and January 2021 were extracted. A chart review was conducted for demographics and medical history. Symptomatology after the procedure was evaluated with validated dysphagia scores. KEY RESULTS: Nineteen patients were included (11 girls, median age 16 years, range 3.2-19.6) with achalasia (n = 5), post-Heller's myotomy dysphagia (n = 3), esophagogastric junction outflow obstruction (n = 3), congenital esophageal stenosis (n = 2); post-esophageal atresia repair stricture (n = 3), and post-fundoplication dysphagia (n = 3). There was no significant correlation between integrated relaxation pressure measured with high resolution manometry and distensibility index (DI). The use of FLIP made it possible to differentiate between dysphagia related to an esophageal obstruction (DI < 2.8 mm2/mmHg) and dysphagia without major motility disorder (DI > 2.8 mm2/mmHg) that guided the indication for dilation. FLIP led to a change in management in 47% of the patients. Forty-seven percent of the patients were symptom free at the time of the evaluation. CONCLUSIONS INFERENCES: FLIP provides key esophageal luminal values and therefore can play an important role in pediatric esophageal disorders management.

Changes in the clinical phenotype and behavior of pediatric luminal Crohn's disease at diagnosis in the last decade.

BACKGROUND AND AIMS: The aims of this study were to describe the trends in the behavior of pediatric CD during the last decade and to describe the seasonal variation of disease presentation. METHODS: Patients under 18 years old and diagnosed between 2009 and 2019 were included. The clinical, endoscopic, histological, and laboratory data were collected from the medical records. We analyzed the trends of these parameters according to the year and season of diagnosis. RESULTS: 654 patients were included in the study. The number of incident CD cases increased yearly. Patients diagnosed between 2015 and 2019 were younger at diagnosis (OR 2.53, p = 0.02), had more perianal diseases (OR: 2.30, p < 0.0001) and more granulomas (OR: 1.61, p = 0.003), but fewer eosinophils (OR: 0.35, p < 0.0001) and less chronic lymphoplasmacytic infiltrate (OR: 0.56, p = 0.008) as compared to the 2009-2014 cohort. There was fewer CD diagnosis during winter. Patients diagnosed in the fall had lower PCDAIs, less failure to thrive and less extensive digestive involvement. Colonic disease was significantly more frequent during summer and fall. CONCLUSION: The clinical and histological phenotype of CD has changed over time and there are important seasonal trends in the frequency and severity on disease behavior suggesting possible disease triggers.

Factors associated with time to clinical remission in pediatric luminal Crohn's disease: A retrospective cohort study.

BACKGROUND AND AIM: Data on factors influencing time to remission in pediatric Crohn's disease (CD) are very limited in the literature. The aim of this retrospective cohort study was to describe the trends of time to clinical remission over the past decade and to identify factors associated with time to clinical remission in children with luminal CD. METHODS: Patients under 18 years old diagnosed between 2009 and 2019 were included. All data were collected from the patients' medical records. Survival analyses and linear regression models were used to assess the impact of clinical, laboratory, endoscopic, histological, and therapeutic factors on time to clinical remission. RESULTS: A total of 654 patients were included in the study. There was no change in the time to clinical remission over the decade. Female sex in adolescents (adjusted bêta regression coefficient [aß] = 31.8 days, P = 0.02), upper digestive tract involvement (aß = 46.4 days, P = 0.04) perianal disease (aß = 32.2 days, P = 0.04), presence of active inflammation on biopsies at diagnosis (aß = 46.7 days, P = 0.01) and oral 5-aminosalicylates (5-ASA) exposure (aß = 56.6 days, P = 0.002) were associated with longer time to clinical remission. Antibiotic exposure (aß = -29.3 days, P = 0.04), increased eosinophils (aß = -29.6 days, P = 0.008) and combination of exclusive enteral nutrition with tumor-necrosis-factor-alpha (TNF-alpha) inhibitors as induction therapy (aß = -36.8 days, P = 0.04) were associated with shorter time to clinical remission. CONCLUSION: In children with newly diagnosed Crohn's disease, time to clinical remission did not shorten during the decade. It was associated with baseline clinical and histological data and treatment strategies. Combination of enteral nutrition and TNF-alpha inhibitors was associated with faster clinical remission.

The Mini-Med School and Its Impact on Future Health Care Professionals' Attitudes toward Indigenous People.

Mini-Med Schools (MiMS) are an opportunity for health sciences and social work undergraduates to discuss health-related topics with Innu and Atikamekw youth in Canada. More than 500 undergraduates and 1,000 students have taken part in the project since its beginning in 2011. This study aims to assess the impact of both 1) MiMS's predeparture training and 2) the MiMS themselves on undergraduates' prejudices toward Indigenous peoples. Satisfaction of the undergraduates taking part in the activity was also assessed. Seventy-eight undergraduates were recruited and completed the Old-fashioned and Modern Prejudiced Attitudes Toward Aboriginals Scales (O-PATAS and M-PATAS) at baseline, after the pre-departure training, and after the MiMS. They also completed satisfaction surveys. This study shows a reduction of prejudices after participating to a MiMS, but no effect of a pre-departure training. The activities were overall appreciated by undergraduates and most of them would like to take part again in the MiMS.

Innovating in teaching collaborative practice with a large student cohort at Université de Montréal.

Université de Montréal implemented an interprofessional education (IPE) curriculum on collaborative practice in a large cohort of students (>1,100) from 10 health sciences and psychosocial sciences training programs. It is made up of three one-credit undergraduate courses (CSS1900, CSS2900, CSS3900) spanning the first 3 years of training. The course content and activities aim for development of the six competency domains identified by the Canadian Interprofessional Health Collaborative. This paper describes the IPE curriculum and highlights the features contributing to its success and originality. Among main success key factors were: administrative cooperation among participating faculties, educators eager to develop innovative approaches, extensive use of clinical situations conducive to knowledge and skill application, strong logistic support, close cooperation with health care delivery organizations, and partnership between clinicians and patients. A distinguishing feature of this IPE curriculum is the concept of partnership in care between the patient and caregivers. Patients' representatives were involved in course planning, and patients were trained to become patients-as-trainers and cofacilitate interprofessional discussion workshops. They give feedback to students regarding integration and application of the patient partnership concept from a patient's point of view.

Inflammatory bowel disease and T cell lymphopenia in G6PC3 deficiency.

PURPOSE: G6PC3 deficiency presents as a complex and heterogeneous syndrome that classically associates severe congenital neutropenia with cardiac and urogenital developmental defects. Here we investigate the findings of T cell lymphopenia and inflammatory bowel disease in a child with G6PC3 deficiency due to compound heterozygous mutations in intron 3 (c.IVS3-1 G>A) and exon 6 (c.G778G/C; p.Gly260/Arg). METHODS: Histological examination was conducted on all biopsy specimens. Immunophenotyping and lymphocyte proliferation assays were performed. Immunoglobulin levels and vaccine responses were measured. RESULTS: The patient showed persistent global T cell lymphopenia, with only 8 to 13 % of thymic naive CD31(+)CD45RA(+) cells among CD4 T cells (normal range 27-60 %). Proliferation assays and vaccine responses were within normal limits. The gastrointestinal inflammatory lesions were very closely related to those of glycogen storage disease type 1b, with a Crohn's-like appearance but without granuloma or increased cryptic abscesses. The gastrointestinal disease responded to infliximab therapy. These findings were associated with a polyclonal hypergammaglobuliemia G. CONCLUSION: G6PC3 deficiency may present with inflammatory bowel disease and T cell lymphopenia. The diagnosis should thus be considered in a patient with chronic congenital neutropenia and gastrointestinal symptoms. Patients with confirmed disease should also undergo T cell phenotyping to rule out cellular immunodeficiency.

High prevalence of primary immune deficiencies in children with autoimmune disorders.

OBJECTIVES: Autoimmunity is a well-recognised manifestation of primary immunodeficiency disorders. However, the prevalence of primary immunodeficiency among children with autoimmune diseases is not well characterised. The objective of this retrospective study was to describe the prevalence of primary immunodeficiency disorders in a paediatric population with autoimmune diseases. METHODS: We retrospectively analysed a cohort of patients investigated for diverse autoimmune conditions from June 1st 2005 to December 31st 2006 in the Rheumatology and Immunology service of a tertiary care paediatric hospital in Canada. The clinical data of patients were reported. Independently of their baseline characteristics, patients underwent a systematic immunologic workup, which was performed before treatment initiation. RESULTS: Thirty-three patients were included in this study. We identified 5 patients (15%) with a primary immunodeficiency disorder: common variable immunodeficiency (n=2), combined immunodeficiency (n=1) and complement component deficiency (n=2). Four other patients (12%) displayed decreased levels of immunoglobulins, B-cell lymphopenia and/or abnormal vaccinal response but did not fulfil the criteria of a defined primary immunodeficiency disorder at the time of the study. Importantly, none of these 9 patients had a particular familial history and none had a history of recurrent infections. CONCLUSIONS: A significant proportion of patients presenting with an autoimmune condition have an underlying primary immunodeficiency disorder that may not be clinically obvious. Additional prospective investigations are needed to further define the role for routine immunologic testing in daily clinical rheumatologic practice.

Chylomicron retention disease: a long term study of two cohorts.

Lipoprotein assembly is critical for the intestinal absorption of dietary lipids and of fat-soluble vitamins. Through their inhibition of chylomicron secretion, mutations of the Sar1B gene coding for Sar1 GTPase are associated with chylomicron retention disease (CRD). The aim of this study was to describe the phenotypic expression of CRD in two clinically and genetically well characterized cohorts, and to compare their long term evolution. The study in 7 children from France (X age 11.3+/-1.7 years) and 9 from Quebec, Canada (X age 12+/-2.5 years) involved data collection from medical records for growth evaluation, neurological and ophthalmological status as well as bone density over an average follow-up period of 4.9 years for the French cohort and of 10.6 years for the Canadian one. All CRD patients presented within the first few months of life with diarrhea and failure to thrive. Severe hypocholesterolemia coupled with normal triglycerides was associated with low LDL and HDL-cholesterol, as well as with low apolipoproteins A-I and B. Varying degrees of essential fatty acid and of vitamin E deficiency were observed. The earlier diagnosis in the Canadian cohort (1.3+/-0.04 years) than in the French one (6.3+/-1.3 years) was unrelated with the severity of presenting symptoms. The fact that the disease had more impact on growth and bone density in the latter group may be related to delayed diagnosis of the disease. Vitamin E deficiency led to functional neurological and ophthalmic changes in a small number of patients but only one developed areflexia. Finally, genotype-phenotype correlation is not obvious in our cohort with CRD; even if, the Canadian subjects with the allele 409G>A had a more severe degree (P<0.001) of hypocholesterolemia than the other patients, many clinical data are inconsistent with a hypothetical genotype-phenotype correlation. This study provides new insights on the phenotypic expression of CRD over time and emphasizes the need to screen the lipid profile of infants with chronic diarrhea and failure to thrive.

Design of predictive models for positive outcomes of upper and lower gastrointestinal endoscopies in children and adolescents.

OBJECTIVES: To develop models to accurately determine the outcomes of diagnostic endoscopies performed in children and adolescents without known gastrointestinal disease. MATERIALS AND METHODS: Retrospective chart review of all endoscopies performed in children 2 to 18 years of age without known gastrointestinal disease from January 1 to December 31, 2000. The association between age, presenting symptoms, physical examination findings, laboratory investigations, and endoscopy outcomes was assessed. Predictive models for positive outcomes on endoscopy were estimated for upper and lower endoscopies separately by use of multiple logistic regression. Receiver operating curves were constructed to evaluate the performance of the models. A model with a sensitivity of 95% and specificity of 40% was considered clinically significant. RESULTS: Positive findings on endoscopy were found in 191 (55%) of 346 and in 120 (59%) of 204 upper and lower endoscopies, respectively. Age above 13 years, vomiting, and hypoalbuminemia were significant predictors of positive upper endoscopies. Rectal bleeding, hypoalbuminemia, and elevated erythrocyte sedimentation rate were significant predictors of positive lower endoscopies. Extrapolating from the receiver operating curves, a sensitivity of 95% corresponded to a specificity of 10% for the upper endoscopy model and 30% for the lower endoscopy model. CONCLUSIONS: In our population of children and adolescents, several clinical characteristics were predictive of positive upper and lower endoscopy outcomes. Predictive models composed of these clinical variables were statistically, but not clinically, significant. The inclusion of additional clinical characteristics that could be assessed in prospective studies will likely improve the clinical significance of endoscopy outcome prediction.

Canadian pediatric gastroenterology workforce: current status, concerns and future projections.

BACKGROUND: There is concern that the Canadian pediatric gastroenterology workforce is inadequate to meet health care demands of the pediatric population. The Canadian Association of Gastroenterology Pediatric Committee performed a survey to determine characteristics and future plans of the Canadian pediatric gastroenterology workforce and trainees. METHODS: Estimates of total and pediatric populations were obtained from the 2001 Census of Population, Statistics Canada (with estimates to July 1, 2005). Data on Canadian pediatric gastroenterologists, including clinical full-time equivalents, sex, work interests, opinions on workforce adequacy, retirement plans, fellowship training programs and future employment plans of fellows, were gathered through e-mail surveys and telephone correspondence in 2005 and 2006. RESULTS: Canada had an estimated population of 32,270,507 in 2005 (6,967,853 people aged zero to 17 years). The pediatric gastroenterology workforce was estimated at 9.2 specialists per million children. Women accounted for 50% of the workforce. Physician to pediatric population ratios varied, with Alberta demonstrating the highest and Saskatchewan the lowest ratios (1:69,404 versus 1:240,950, respectively). Between 1998 and 2005, Canadian pediatric gastroenterology fellowship programs trained 65 fellows (65% international trainees). Twenty-two fellows (34%) entered the Canadian workforce. CONCLUSIONS: The survey highlights the variable and overall low numbers of pediatric gastroenterologists across Canada, an increasingly female workforce, a greater percentage of part-time physicians and a small cohort of Canadian trainees. In conjunction with high projected retirement rates, greater demands on the workforce and desires to partake in nonclinical activities, there is concern for an increasing shortage of pediatric gastroenterologists in Canada in future years.

Recurrent pancreatitis in mitochondrial cytopathy.

Diabetes mellitus and exocrine insufficiency are the commonest pancreatic manifestations of mitochondrial diseases. In contrast, pancreatitis has rarely been described in mitochondrial syndromes. We report on a patient with Kearns-Sayre syndrome and recurrent episodes of acute pancreatitis for which no explanation could be found other than the associated mitochondrial dysfunction. Interestingly, pharmacological disruption of mitochondrial metabolism in various models as well as in patients can cause pancreatitis, further supporting this association. A diagnosis of pancreatitis should be considered in any patients with mitochondrial disease and recurrent abdominal pain.

Abnormal intracellular lipid processing contributes to fat malabsorption in cystic fibrosis patients.

A common feature of cystic fibrosis (CF) is the functional derangement of the exocrine pancreas, which affects output of pancreatic lipase. This condition results in severe dietary malabsorption due to the poor hydrolysis of triacylglycerol (TG) in the lumen of the small intestine. Despite the benefits of pancreatic enzyme supplements, patients with CF present with persistent intestinal fat malabsorption. The aim of the present investigation was to determine whether defects in the intracellular phase of lipid transport occur in this pathophysiology in addition to the known disturbed digestive processes. Our hypothesis was tested by incubating intestinal biopsies from six CF and six healthy subjects with radiolabeled lipid and protein precursors. Lipid esterification and secretion were markedly decreased by 22-31% and 38-42%, respectively, in CF samples, as noted by the low incorporation of [(14)C]palmitic acid into TGs, phospholipids, and cholesteryl esters in patients' duodenal explants and culture media compared with controls (100%). Accordingly, the output of TG-rich lipoproteins was substantially reduced (P < 0.05), and a similar trend was observed for high-density lipoproteins. Because intestinal lipoprotein assembly/secretion shows an absolute requirement for apolipoprotein (apo) B-48, radioactive labeling experiments were performed; these experiments demonstrated a significantly (P < 0.05) diminished synthesis of apoB-48 (40%) and apoA-I (30%). Given the critical role of microsomal triglyceride transfer protein in the formation of apoB-containing lipoproteins, its activity was determined and not found to be altered in CF intestinal tissue. Together, these results suggest that CF malabsorption may also be caused by defects in mucosal mechanisms leading to abnormal lipoprotein delivery into the blood circulation.

A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).

BACKGROUND: Juvenile polyposis and hereditary haemorrhagic telangiectasia are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in MADH4 (encoding SMAD4) or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG (endoglin) or ACVRL1 (ALK1). All four genes encode proteins involved in the transforming-growth-factor-beta signalling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic aetiology of this association is unknown. METHODS: Blood samples were collected from seven unrelated families segregating both phenotypes. DNA from the proband of each family was sequenced for the ACVRL1, ENG, and MADH4 genes. Mutations were examined for familial cosegregation with phenotype and presence or absence in population controls. Findings No patient had mutations in the ENG or ACVRL1 genes; all had MADH4 mutations. Three cases of de-novo MADH4 mutations were found. In one, the mutation was passed on to a similarly affected child. Each mutation cosegregated with the syndromic phenotype in other affected family members. INTERPRETATION: Mutations in MADH4 can cause a syndrome consisting of both juvenile polyposis and hereditary haemorrhagic telangiectasia phenotypes. Since patients with these disorders are generally ascertained through distinct medical specialties, genetic testing is recommended for patients presenting with either phenotype to identify those at risk of this syndrome. Patients with juvenile polyposis who have an MADH4 mutation should be screened for the vascular lesions associated with hereditary haemorrhagic telangiectasia, especially occult arteriovenous malformations in visceral organs that may otherwise present suddenly with serious medical consequences.

Pharmacokinetics of omeprazole in healthy adults and in children with gastroesophageal reflux disease.

Studies of the pharmacokinetics of omeprazole in children with gastroesophageal reflux disease (GERD) remain scarce despite the vast number of reports on its efficacy. The objectives of this study were to assess the pharmacokinetics of omeprazole in healthy adults and in children with GERD. Omeprazole (Losec, delayed-release capsules) was administered orally to 18 healthy adults (mean age 36.8 years) and 12 children with GERD (mean age 6.1 years). Blood samples were collected over 5 hours, and plasma concentrations were assessed using liquid chromatography. Population pharmacokinetic parameters were calculated using NONMEM. A 1-compartment model with zero-order absorption and a lag time was used. The population approach was well suited to the limited number of samples available, and residual variability was low. Oral clearance (CL/F) and apparent volume of distribution (V(ss)/F) in healthy adults (Mean +/- SD: 0.62 +/- 0.27 L/h/kg and 0.76 +/- 0.26 L/kg, respectively) were not significantly different than those in children with GERD (0.51 +/- 0.34 L/h/kg and 0.66 +/- 0.25 L/kg, respectively). Healthy adults displayed a statistically significantly longer delay in drug absorption (Lag time: 0.62 +/- 0.15 hours) as compared with that observed in children with GERD (0.12 +/- 0.03 hours, P < 0.05). On the basis of these findings, omeprazole dosings on a milligram-per-kilogram basis are recommended with no further adjustments for the treatment of GERD in children.

Feeding management of children with severe cerebral palsy and eating impairment: an exploratory study.

Some children with cerebral palsy and severe feeding impairment experience pulmonary complications from aspiration and gastroesophageal reflux. This exploratory study examined whether pulmonary function would improve following one year of intervention with optimal positioning for feeding, control of gastroesophageal reflux and use of food textures that would minimize aspiration from swallowing. Two children showed a 28% and 45% improvement, respectively, in functional residual capacity. One child experienced a 37% improvement in total respiratory resistance and a 284% improvement in respiratory compliance. All children gained sufficient weight to maintain their growth trajectories but only one who was changed from oral to tube feeding due to aspiration showed catch-up growth in length. One child showed pathological gastroesophageal reflux that was controlled medically throughout the study period. Although all children experienced pulmonary illnesses during the one year of follow up, control of aspiration permitted a clinically significant improvement of their pulmonary obstructive syndrome Further study is needed to more fully determine the effect of this treatment approach on pulmonary function.

A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis.

North American Indian childhood cirrhosis (CIRH1A, or NAIC), a severe autosomal recessive intrahepatic cholestasis described in Ojibway-Cree children from northwestern Quebec, is one of several familial cholestases with unknown molecular etiology. It typically presents with transient neonatal jaundice, in a child who is otherwise healthy, and progresses to biliary cirrhosis and portal hypertension. Clinical and physiological investigations have not revealed the underlying cause of the disease. Currently, liver transplantation is the only effective therapy for patients with advanced disease. We previously identified the NAIC locus by homozygosity mapping to chromosome 16q22. Here we report that an exon 15 mutation in gene FLJ14728 (alias Cirhin) causes NAIC: c.1741C-->T in GenBank cDNA sequence NM_032830, found in all NAIC chromosomes, changes the conserved arginine 565 codon to a tryptophan, altering the predicted secondary structure of the protein. Cirhin is preferentially expressed in embryonic liver, is predicted to localize to mitochondria, and contains WD repeats, which are structural motifs frequently associated with molecular scaffolds.