Computational structural genomics and clinical evidence suggest BCKDK gain-of-function may cause a potentially asymptomatic maple syrup urine disease phenotype.

Maple syrup urine disease (MSUD) is a disorder of branched-chain amino acid metabolism caused by a defect in the branched-chain α-ketoacid dehydrogenase (BCKD) complex (OMIM #248600). The hallmark presentation is encephalopathic crisis in neonates, but can also present with metabolic decompensation, developmental delays, and feeding difficulties. Biochemical evidence for MSUD includes elevated branched-chain amino acids (BCAA) and the pathognomonic presence of alloisoleucine. The BCKD complex contains several subunits associated with autosomal recessive MSUD, while its regulatory proteins have less well-defined disease associations. We report on two families with the same BCKDK variant (c.1115C>G (p.Thr372Arg)). Probands were detected on newborn screening and demonstrated biochemical evidence of MSUD. The variant was identified in reportedly asymptomatic parents and additional family members who had elevated BCAA and alloisoleucine, following an autosomal dominant pattern of inheritance. To better define the functional effect of the variant on the kinase, we completed molecular modeling using sequence-based (2D), structural-based (3D), and dynamic-based (4D) analyses. The BCKDK variant modeling indicated a gain-of-function which leads to impaired BCAA catabolism consistent with the biochemical evidence in this cohort. Combining the evidence gained from molecular modeling with the absence of metabolic decompensation in our patients and several adult family members, despite encountering stressors typically problematic in classic MSUD, we suggest that heterozygous gain-of-function variants in BCKDK may represent a novel biochemical phenotype of MSUD with a benign clinical course.

Screening for Methylmalonic and Propionic Acidemia: Clinical Outcomes and Follow-Up Recommendations.

Wisconsin's newborn screening program implemented second-tier testing on specimens with elevated propionylcarnitine (C3) to aid in the identification of newborns with propionic and methylmalonic acidemias. The differential diagnosis for elevated C3 also includes acquired vitamin B12 deficiency, which is currently categorized as a false positive screen. The goal of this study was to summarize screening data and evaluate their effectiveness at establishing diagnoses and categorizing false positive cases. All Wisconsin newborns born between 2013 and 2019 with a positive first-tier screen for C3 were included in this study. For each case the first- and second-tier newborn screening data and confirmatory test results were compiled. The clinical determination for each case was reviewed and categorized into groups: inborn error of metabolism, maternal B12 deficiency, infant B12 deficiency, and false positive. A review of the screening data showed a significant overlap in the concentration of biomarkers for newborns with genetic versus acquired disease. Additionally, a review of confirmatory test results showed incomplete ascertainment of maternal vitamin B12 status. The Wisconsin newborn screening program recommended a confirmatory testing algorithm to aid in the diagnosis of inborn errors of metabolism and acquired vitamin B12 deficiency.

CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum.

We describe the clinical features of nine unrelated individuals with rare de novo missense or in-frame deletions/duplications within the "HX motif" of exon 7 of ATN1. We previously proposed that individuals with such variants should be considered as being affected by the syndromic condition of congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA), distinct from dentatorubral-pallidoluysian atrophy (DRPLA) secondary to expansion variants in exon 5 of ATN1. We confirm that the universal phenotypic features of CHEDDA are distinctive facial features and global developmental delay. Infantile hypotonia and minor hand and feet differences are common and can present as arthrogryposis. Common comorbidities include severe feeding difficulties, often requiring gastrostomy support, as well as visual and hearing impairments. Epilepsy and congenital malformations of the brain, heart, and genitourinary systems are frequent but not universal. Our study confirms the clinical entity of CHEDDA secondary to a mutational signature restricted to exon 7 of ATN1. We propose a clinical schedule for assessment upon diagnosis, surveillance, and early intervention including the potential of neuroimaging for prognostication.

An Autoimmune Protocol Diet Improves Patient-Reported Quality of Life in Inflammatory Bowel Disease.

BACKGROUND: Prior studies suggest dietary modification may improve clinical response or remission rates in patients with inflammatory bowel disease (IBD). Our aim was to examine whether an autoimmune protocol diet improves quality of life in patients with active Crohn disease (CD) and ulcerative colitis (UC). METHODS: We conducted an uncontrolled clinical trial of the autoimmune protocol diet in adult patients with active IBD (Harvey-Bradshaw Index ≥ 5 for CD or partial Mayo score ≥ 3 for UC, and erosions/ulcers on endoscopy and/or elevated fecal calprotectin). The dietary intervention consisted of a 6-week elimination phase, followed by a 5-week maintenance phase. Short Inflammatory Bowel Disease Questionnaire (SIBDQ) was completed at baseline, and weeks 3, 6, 9, and 11. RESULTS: The final cohort included 6 UC and 9 CD participants. Mean SIBDQ score improved significantly from baseline (46.5) to weeks 3 (54.0, P = 0.02), 6 (53.3, P = 0.02), 9 (62.0, P = 0.03), and 11 (60.5, P = 0.05). Among participants completing all 5 surveys, mean SIBDQ increased from 46.5 to 61.5 by week 11 (P = 0.03). By week 3, participants experienced significant improvements in bowel movement frequency (36%, P = 0.04), stress (28%, P = 0.01), and ability to perform leisure/sport activities (29%, P = 0.02). Effects were not significantly different between CD and UC participants. CONCLUSIONS: Dietary modification can improve quality of life as early as week 3 in patients with active IBD. Larger randomized controlled trials are needed to examine dietary interventions in IBD.

Efficacy of the Autoimmune Protocol Diet for Inflammatory Bowel Disease.

INTRODUCTION: Data suggest dietary modification can improve clinical responses in inflammatory bowel disease (IBD). The goal of this study was to determine the efficacy of an autoimmune protocol diet in patients with Crohn's disease and ulcerative colitis. METHODS: We enrolled adults with active IBD (Harvey-Bradshaw index ≥ 5 or partial Mayo score ≥3 and erosions on endoscopy and/or elevated fecal calprotectin). For the autoimmune protocol, patients underwent 6-week elimination followed by 5-week maintenance phase. Clinical indices, laboratories, and biomarkers were assessed at baseline and weeks 6 and 11. Endoscopy was performed at study completion. RESULTS: The final cohort included 15 patients with IBD, with mean disease duration 19 years (SD 14.6) and active biological use in 7 (47%) patients. Nutrient repletion was initiated for deficiencies in vitamin D (n = 3) and iron (n = 6). From week 0 to weeks 6 and 11, mean partial Mayo score significantly improved from 5.8 (SD 1.2) to 1.2 (SD 2.0) and 1.0 (SD 2.0) for ulcerative colitis, and mean Harvey-Bradshaw index significantly improved from 7 (SD 1.5) to 3.6 (SD 2.1) and 3.4 (SD 2.6) for Crohn's disease. C-reactive protein did not significantly change during study. Mean fecal calprotectin improved from 471 (SD 562) to 112 (SD 104) at week 11 (P = 0.12). Among those with follow-up endoscopy at week 11 (n = 7), improvements were noted in simple endoscopic score for Crohn's disease (n = 1), Rutgeerts score (n = 1), and Mayo endoscopy subscore (n = 4). DISCUSSION: Dietary elimination can improve symptoms and endoscopic inflammation in patients with IBD. Randomized controlled trials are warranted.

Colorectal cancer screening in women with endometrial cancer: are we following the guidelines?

INTRODUCTION: Colorectal cancer (CRC) is the most common gastrointestinal malignancy. There is an association between CRC and endometrial cancer (EC). Up to 10% of this linkage may be due to hereditary non-polyposis colorectal cancer but in the majority of patients a genetic disorder is not found. The National Comprehensive Cancer Network (NCCN) guidelines on CRC since 2005 have suggested that women with endometrial or ovarian cancer diagnosed at less than 60 years of age have CRC screening with colonoscopy beginning at age 40 or at time of diagnosis of the gynecologic tumor. We assessed our population of women with EC to determine if women were receiving CRC screening after a diagnosis of EC. METHODS: Electronic medical records of all women diagnosed at our institution with EC predominantly between 1997 and 2007 were reviewed. We assessed age at diagnosis, tumor type, family history of malignancy, CRC screening, and findings at CRC screening and recorded the information in a database. Patients were evaluated for the Amsterdam and Bethesda criteria. This study was approved by the Institutional Review Board. RESULTS: Two hundred sixty-seven women with EC were evaluated. The median age was 66; 39% were less than age 60 at diagnosis. Family history of CRC was present in 25 (9.4%) of EC patients. Of these women, 125 (46.8%) had CRC screening, with 12 (9.6%) being screened for CRC within 1 year of diagnosis and 33 (26.4%) screened for CRC before diagnosis of endometrial cancer. Of the women, 142 (53.2%) did not have CRC screening reported. Of the women screened, ten had adenomatous polyps with one of those polyps being greater than 1 cm, four had tubulovillous histology, and three had CRC. Colonoscopy was performed in 59.2% of women who underwent CRC screening. One woman met criteria for Amsterdam and Bethesda criteria. CONCLUSIONS: Less than half of women with EC received screening for CRC. Women who were screened had significant pathology in 13.6% of cases and 2.4% had colon cancer. The NCCN guidelines should be more aggressively followed by physicians who care for women. A prospective colonoscopy screening study on these women with EC to assess the yield and utility in screening in this population is needed.

Prophylaxis for travelers' diarrhea.

Travelers' diarrhea affects more than 10 million people per year and is usually contracted through the ingestion of microbially contaminated food or water. Although most cases resolve in 3 to 5 days, chronic conditions are associated with acute infections. Prevention encompasses avoidance of ingesting contaminated products and, in certain situations, taking prophylactic medications. The available prophylactic antibiotics are very effective in prevention, but are recommended only for specific at-risk individuals and are contraindicated for most travelers.