A Slc38a8 Mouse Model of FHONDA Syndrome Faithfully Recapitulates the Visual Deficits of Albinism Without Pigmentation Defects.

Purpose: We aimed to generate and phenotype a mouse model of foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis (FHONDA), a rare disease associated with mutations in Slc38a8 that causes severe visual alterations similar to albinism without affecting pigmentation. Methods: The FHONDA mouse model was generated with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology using an RNA guide targeting the Scl38a8 murine locus. The resulting mice were backcrossed to C57BL/6J. Melanin content was measured using spectrophotometry. Retinal cell architecture was analyzed through light and electron microscopy. Retinal projections to the brain were evaluated with anterograde labelling in embryos and adults. Visual function was assessed by electroretinography (ERG) and the optomotor test (OT). Results: From numerous Slc38a8 mouse mutant alleles generated, we selected one that encodes a truncated protein (p.196Pro*, equivalent to p.199Pro* in the human protein) closely resembling a mutant allele described in patients (p.200Gln*). Slc38a8 mutant mice exhibit wild-type eye and coat pigmentation with comparable melanin content. Subcellular abnormalities were observed in retinal pigment epithelium cells of Slc38a8 mutant mice. Anterograde labeling experiments of retinal projections in embryos and adults showed a reduction of ipsilateral fibers. Functional visual analyses revealed a decreased ERG response in scotopic conditions and a reduction of visual acuity in mutant mice measured by OT. Conclusions: Slc38a8 mutant mice recapitulate the phenotype of patients with FHONDA concerning their normal pigmentation and their abnormal visual system, in the latter being a hallmark of all types of albinism. These mice will be helpful in better understanding the pathophysiology of this genetic condition.

Imbalances in dietary consumption of fatty acids, vegetables, and fruits are associated with risk for Crohn's disease in children.

BACKGROUND AND OBJECTIVES: The role of dietary factors in the etiology of Crohn's disease (CD) is inconsistent largely due to difficulties in acquiring valid information on consumption habits. We examined the impact of diet on new onset CD in children using a validated food-frequency questionnaire (FFQ). METHODOLOGY: A case-control study was carried out. Children < or =20 yr, newly diagnosed with CD, were recruited from 3 pediatric gastroenterology clinics across Canada. Population or hospital controls were selected matched to cases for time of diagnosis (+/-6 months) and area of residence. Dietary consumption 1 yr prior to disease diagnosis was evaluated using a validated FFQ, administered within 1 month of diagnosis. Conditional logistic regression analysis adjusting for potential confounding variables (energy intake, age, gender, body mass index) was carried out. RESULTS: A total of 130 CD patients and 202 controls were studied. Mean age at diagnosis (+/-SD) was 14.2 (2.7). There were more male patients (59%). Comparing the highest to the lowest levels of consumption, higher amounts of vegetables (OR 0.69, 95% CI 0.33-1.44, P= 0.03), fruits (OR 0.49, 95% CI 0.25-0.96, P= 0.02), fish (OR 0.46, 95% CI 0.20-1.06, P= 0.02), and dietary fiber (OR 0.12, 95% CI 0.04-0.37, P < 0.001) protected from CD. Consumption of long-chain omega-3 fatty acids (LCN-omega-3) was negatively associated with CD (OR 0.44, 95% CI 0.19-1.00, P < 0.001). A higher ratio of LCN-omega-3/omega-6 fatty acids was significantly associated with lower risks for CD (OR 0.32, 95% CI 0.14-0.71, P= 0.02). CONCLUSIONS: Our findings indicate that an imbalance in consumption of fatty acids, vegetables, and fruits is associated with increased risks for CD among Canadian children.

Investigating the hygiene hypothesis as a risk factor in pediatric onset Crohn's disease: a case-control study.

BACKGROUND AND OBJECTIVES: Evidence for the hygiene hypothesis in the etiology of Crohn's disease (CD) is unclear. We investigated the relationship between infection-related exposures and risk for CD in children. METHODS: A hospital-based case-control was carried out. Newly-diagnosed cases of CD (n = 194), less than 20 yr of age were recruited from the gastroenterology clinic of a large-pediatric inflammatory bowel disease (IBD) center in Montreal, Canada. Orthopedic patients pair-matched (n = 194) for timing of diagnosis and area of residence were recruited as controls. Information on infection-related exposures between birth and disease diagnosis was ascertained by administering a structured questionnaire to the mother and the index subject. The relationship between the frequency and timing of infection-related exposures with CD was studied. RESULTS: The mean age (SD) at diagnosis was 12.3 (5.1). CD was more common after 10 yr of age. Gender distribution was similar between comparison groups. In multivariate conditional logistic regression, family history of IBD (odds ratio (OR) = 4.6; 95% confidence interval (CI) = 1.6-13.3), age (OR = 1.2; 95% CI = 1.1-1.3), and owning a pet (OR = 2.0; 95% CI = 0.9-4.5) were associated with risk for CD, whereas regular use of a personal towel (OR = 0.5; 95% CI = 0.2-0.9) and lesser crowding in homes (OR = 0.3; 95% CI = 0.1-0.8) were protective. Day-care attendance during the first 6 months of life and "physician-diagnosed infections" between 5 and 10 yr of age were associated with increased risks for CD. CONCLUSIONS: Infection-related exposures seem to enhance risk for CD in children. The timing of these exposures during early childhood may be relevant to the etiology of pediatric CD.