Long-term use of investigational ß-Hydroxybutyrate salts in children with multiple acyl-CoA dehydrogenase or pyruvate dehydrogenase deficiency.

Several disorders of energy metabolism have been treated with exogenous ketone bodies. The benefit of this treatment is best documented in multiple acyl-CoA dehydrogenase deficiency (MADD) (MIM#231680). One might also expect ketone bodies to help in other disorders with impaired ketogenesis or in conditions that profit from a ketogenic diet. Here, we report the use of a novel preparation of dextro-ß-hydroxybutyrate (D-ßHB) salts in two cases of MADD and one case of pyruvate dehydrogenase (PDH) deficiency (MIM#312170). The two patients with MADD had previously been on a racemic mixture of D- and L­sodium hydroxybutyrate. Patient #1 found D-ßHB more palatable, and the change in formulation corrected hypernatraemia in patient #2. The patient with PDH deficiency was on a ketogenic diet but had not previously been given hydroxybutyrate. In this case, the addition of D-ßHB improved ketosis. We conclude that NHS101 is a good candidate for further clinical studies in this group of diseases of inborn errors of metabolism.

Long-term outcomes in two adult siblings with Fucosidosis - Diagnostic odyssey and clinical manifestations.

Fucosidosis (OMIN# 230000) is a rare lysosomal storage disorder (LSDs) caused by mutations in the FUCA1 gene, leading to alpha-L-fucosidase deficiency; it is inherited as an autosomal recessive trait. Fucosidosis represents a disease spectrum with a wide variety of clinical features, but most affected patients have slow neurologic deterioration. Many patients die young and the long-term clinical outcomes in adult patients are poorly documented. Here, we report the long-term follow up of two Caucasian siblings, a 31-year-old man and 25-year-old woman. We describe the clinical, biochemical, radiological and genetic findings in two siblings affected by Fucosidosis and the differences between them after 19-years follow up. The dermatological features of the younger sibling have been reported previously by Bharati et al. (2007). Both patients have typical features of Fucosidosis, such as learning difficulties, ataxia, and angiokeratomas with differing severity. Case 1 presents severe ataxia with greater limitation of mobility, multiple dysostoses, angiokeratomas on his limbs, retinal vein enlargement and increased tortuosity in the eye and gastrointestinal symptoms. Biochemical analysis demonstrated a deficiency of alpha-fucosidase in leucocytes. Case 2 has a greater number of angiokeratomas and has suffered three psychotic episodes. The diagnosis of Fucosidosis was confirmed in cultured skin fibroblast at the age of 12 years. Molecular analysis of the FUCA1 gene showed a heterozygous mutation c.998G > A p.(Gly333Asp), with a pathogenic exon 4 deletion in the other allele in both patients. Conclusion. Fucosidosis presents a wide clinical heterogeneity and intrafamilial variability of symptoms. Psychosis and gastrointestinal symptoms have not been reported previously in Fucosidosis.

Liver transplantation in ornithine transcarbamylase deficiency: A retrospective multicentre cohort study.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked defect of ureagenesis and the most common urea cycle disorder. Patients present with hyperammonemia causing neurological symptoms, which can lead to coma and death. Liver transplantation (LT) is the only curative therapy, but has several limitations including organ shortage, significant morbidity and requirement of lifelong immunosuppression. This study aims to identify the characteristics and outcomes of patients who underwent LT for OTCD. We conducted a retrospective study for OTCD patients from 5 UK centres receiving LT in 3 transplantation centres between 2010 and 2022. Patients' demographics, family history, initial presentation, age at LT, graft type and pre- and post-LT clinical, metabolic, and neurocognitive profile were collected from medical records. A total of 20 OTCD patients (11 males, 9 females) were enrolled in this study. 6/20 had neonatal and 14/20 late-onset presentation. 2/20 patients had positive family history for OTCD and one of them was diagnosed antenatally and received prospective treatment. All patients were managed with standard of care based on protein-restricted diet, ammonia scavengers and supplementation with arginine and/or citrulline before LT. 15/20 patients had neurodevelopmental problems before LT. The indication for LT was presence (or family history) of recurrent metabolic decompensations occurring despite standard medical therapy leading to neurodisability and quality of life impairment. Median age at LT was 10.5 months (6-24) and 66 months (35-156) in neonatal and late onset patients, respectively. 15/20 patients had deceased donor LT (DDLT) and 5/20 had living related donor LT (LDLT). Overall survival was 95% with one patient dying 6 h after LT. 13/20 had complications after LT and 2/20 patients required re-transplantation. All patients discontinued dietary restriction and ammonia scavengers after LT and remained metabolically stable. Patients who had neurodevelopmental problems before LT persisted to have difficulties after LT. 1/5 patients who was reported to have normal neurodevelopment before LT developed behavioural problems after LT, while the remaining 4 maintained their abilities without any reported issues. LT was found to be effective in correcting the metabolic defect, eliminates the risk of hyperammonemia and prolongs patients' survival.

Application of an Interactive, Hands-On Nutritional Curriculum for Pediatric Residents.

Currently, there exists a scarcity of suitable nutrition training resources for the primary care physician (PCP) and a paucity of educational materials for pediatric residency programs. Barriers to nutritional education include: a lack of well-defined competencies, a dearth of centralized resources for nutritional education, and a reliance on didactic teaching methodology. Because PCPs often cite a lack of confidence as a primary reason for not providing nutritional counseling, we created an interactive 3-pronged nutritional curriculum for pediatric residents with the aim of increasing their confidence to provide nutritional counseling to patients. This curriculum included an in-person visit to a local supermarket, an online, interactive case during the resident's continuity clinic, and an interactive lecture. There was a statistically significant change in pediatric residents' confidence to manage issues of outpatient nutrition management. We find this particularly relevant as increasing physician confidence is key to increasing nutritional counseling in a clinical setting.

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study.

OBJECTIVE: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. METHODS: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data. RESULTS: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy. SIGNIFICANCE: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria.

Predictors of Perianal Fistula Healing in Children With Newly Diagnosed Crohn Disease.

OBJECTIVES: Perianal fistulas are among the most severe complications of Crohn disease, but limited data regarding their outcomes are available in children. Our objective was to determine predictors of perianal fistula healing among pediatric patients newly diagnosed with Crohn disease. METHODS: This single-center retrospective study followed patients with perianal fistulas at Crohn disease diagnosis until fistula healing. Time to healing was analyzed using Cox proportional hazard regression models considering relevant covariates including patient demographics, disease characteristics, medical therapies [no anti-tumor necrosis factor (TNF)α therapy, anti-TNFα therapy ±therapeutic drug monitoring], and perianal surgical procedures including fistulotomy, fistulectomy, removal of perianal lesions, seton placement, and incision and drainage. RESULTS: Of 485 patients identified, 107 (22%) had a perianal fistula at Crohn disease diagnosis. Multivariate analysis identified that perianal fistulotomy, fistulectomy, and lesion removal [hazard ratio (HR) 0.46; P = 0.028], non-White race (HR 0.30, P < 0.01), and male sex (HR 0.42; P = 0.02) were associated with delayed fistula healing. Faster fistula healing was associated with treatment with anti-TNFα with therapeutic drug monitoring (HR 1.78, P = 0.009). There were no other differences in healing by treatment. CONCLUSIONS: Fistulotomy, fistulectomy, and perianal lesion removal as well as non-White race were associated with delayed fistula healing. Anti-TNFα therapy was associated with faster fistula healing when combined with therapeutic drug monitoring, compared to all other medical treatment groups, including anti-TNFα therapy without therapeutic drug monitoring.

Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria: A comparison between two genetic disorders affecting the same metabolic pathway.

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism.

Postauthorization safety study of betaine anhydrous.

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013-2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 µmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.

Quantification of Mucosal Activity from Colonoscopy Reports via the Simplified Endoscopic Mucosal Assessment for Crohn's Disease.

BACKGROUND: Endoscopic mucosal healing is the gold standard for evaluating Crohn's disease (CD) treatment efficacy. Standard endoscopic indices are not routinely used in clinical practice, limiting the quality of retrospective research. A method for retrospectively quantifying mucosal activity from documentation is needed. We evaluated the simplified endoscopic mucosal assessment for CD (SEMA-CD) to determine if it can accurately quantify mucosal severity recorded in colonoscopy reports. METHODS: Pediatric patients with CD underwent colonoscopy that was video recorded and evaluated via Simple Endoscopic Score for CD (SES-CD) and SEMA-CD by central readers. Corresponding colonoscopy reports were de-identified. Central readers blinded to clinical history and video scoring were randomly assigned colonoscopy reports with and without images. The SEMA-CD was scored for each report. Correlation with video SES-CD and SEMA-CD were assessed with Spearman rho, inter-rater, and intrarater reliability with kappa statistics. RESULTS: Fifty-seven colonoscopy reports were read a total of 347 times. The simplified endoscopic mucosal assessment for CD without images correlated with both SES-CD and SEMA-CD from videos (rho = 0.82, P < .0001 for each). The addition of images provided similar correlation. Inter-rater and intrarater reliability were 0.93 and 0.92, respectively. CONCLUSIONS: The SEMA-CD applied to retrospective evaluation of colonoscopy reports accurately and reproducibly correlates with SES-CD and SEMA-CD of colonoscopy videos. The SEMA-CD for evaluating colonoscopy reports will enable quantifying mucosal healing in retrospective research. Having objective outcome data will enable higher-quality research to be conducted across multicenter collaboratives and in clinical registries. External validation is needed.

Granulomas in Diagnostic Biopsies Associated With High Risk of Crohn's Complications-But May Be Preventable.

BACKGROUND: Granulomatous intestinal inflammation may be associated with aggressive Crohn's disease (CD) behavior. However, this has not been confirmed, and it is unknown if associated disease complications are preventable. METHODS: This is a retrospective cohort of patients younger than 21 years at CD diagnosis (November 1, 2005 to November 11, 2015). Clinical information was abstracted, including dates of starting medications and the timing of perianal fistula or stricture development, if any. Diagnostic pathology reports were reviewed, and a subset of biopsy slides were evaluated by a blinded pathologist. Patients were excluded if perianal fistula or stricture developed within 30 days after CD diagnosis. Medications were included in analyses only if started >90 days before development of perianal fistula or stricture. RESULTS: In total, 198 patients were included. Half (54%) had granulomas at diagnosis. Granulomas were associated with a greater than 3-fold increased risk of perianal fistula (hazard ration [HR] = 3.24; 95% confidence interval CI], 1.40-7.48). Immunomodulator and anti-tumor necrosis factor-α (anti-TNF) therapy were associated with 90% (HR, = 0.10; 95% CI, 0.03-0.42) and 98% (HR, = 0.02; 95% CI, 0.01-0.10) reduced risk of perianal fistula, respectively. Patients with granulomatous inflammation preferentially responded to anti-TNF therapy with reduced risk of perianal fistula. The presence of granulomas was not associated with risk of stricture. Immunomodulator and anti-TNF therapy were associated with 96% (HR, = 0.04; 95% CI, 0.01-0.22) and 94% (HR, = 0.06; 95% CI, 0.02-0.20) reduced risk of stricture, respectively. CONCLUSIONS: Granulomas are associated with increased risk of perianal fistula but not stricture. Steroid sparing therapies seem to reduce the risk of both perianal fistula and stricture. For those with granulomas, anti-TNF-α therapy greatly reduced the risk of perianal fistula development, whereas immunomodulators did not.

Correction: Multi-stage feature selection (MSFS) algorithm for UWB-based early breast cancer size prediction.

[This corrects the article DOI: 10.1371/journal.pone.0229367.].

Development and Testing of a New Simplified Endoscopic Mucosal Assessment for Crohn's Disease: The SEMA-CD.

OBJECTIVES: Endoscopic mucosal improvement is the gold standard for assessing treatment efficacy in clinical trials of Crohn's disease. Current endoscopic indices are not routinely used in clinical practice. The lack of endoscopic information in large clinical registries limits their use for research. A quick, easy, and accurate method is needed for assessing mucosal improvement for clinicians in real-world practice. We developed and tested a novel simplified endoscopic mucosal assessment for Crohn's disease (SEMA-CD). METHODS: We developed a 5-point scale for ranking endoscopic severity of ileum and colon based on Simple Endoscopic Score for Crohn's disease (SES-CD). Central readers were trained to perform SES-CD and SEMA-CD. Pediatric patients with Crohn's disease undergoing colonoscopy were enrolled. Video recordings of colonoscopies were de-identified and randomly assigned to blinded central readers. The SES-CD and SEMA-CD were scored for each video. The SES-CD was considered the validated standard for comparison. Correlation was assessed with Spearman rho, inter- and intrarater reliability with kappa statistics. RESULTS: Fifty-seven colonoscopies were read a total of 212 times. Correlation between SEMA-CD and SES-CD was strong (rho = 0.98, P < 0.0001). Inter-rater reliability for SEMA-CD was 0.80, and intrarater reliability was 0.83. Central readers rated SEMA-CD as easier than SES-CD. CONCLUSION: The SEMA-CD accurately and reproducibly correlates with the standard SES-CD. Central readers viewed SEMA-CD as easier than SES-CD. Use of SEMA-CD in practice should enable collecting mucosal improvement information in large populations of patients. This will improve the quality of research that can be conducted in clinical registries. External validation is needed.

Factors Associated With Development of Perianal Fistulas in Pediatric Patients With Crohn's Disease.

Perianal fistulizing complications (PFCs) develop among 15%-40% of patients with Crohn's disease (CD), are difficult to treat, commonly recur, and increase healthcare costs.1-4 Few reliable predictors of PFCs are known, and no evidence-based preventive strategies exist. Studies often rely on inconsistent methods for identifying PFCs.3-5 Rigorous study design is essential. Occult PFCs may be present at CD diagnosis but may not become apparent until later, leading to PFCs being erroneously misclassified as developing later. We therefore sought to determine the risk factors for developing PFCs among children with CD in whom PFCs were conclusively ruled out with cross-sectional imaging at diagnosis.

Cystathionine ß-synthase deficiency in the E-HOD registry-part I: pyridoxine responsiveness as a determinant of biochemical and clinical phenotype at diagnosis.

Cystathionine ß-synthase (CBS) deficiency has a wide clinical spectrum, ranging from neurodevelopmental problems, lens dislocation and marfanoid features in early childhood to adult onset disease with predominantly thromboembolic complications. We have analysed clinical and laboratory data at the time of diagnosis in 328 patients with CBS deficiency from the E-HOD (European network and registry for Homocystinurias and methylation Defects) registry. We developed comprehensive criteria to classify patients into four groups of pyridoxine responsivity: non-responders (NR), partial, full and extreme responders (PR, FR and ER, respectively). All groups showed overlapping concentrations of plasma total homocysteine while pyridoxine responsiveness inversely correlated with plasma/serum methionine concentrations. The FR and ER groups had a later age of onset and diagnosis and a longer diagnostic delay than NR and PR patients. Lens dislocation was common in all groups except ER but the age of dislocation increased with increasing responsiveness. Developmental delay was commonest in the NR group while no ER patient had cognitive impairment. Thromboembolism was the commonest presenting feature in ER patients, whereas it was least likely at presentation in the NR group. This probably is due to the differences in ages at presentation: all groups had a similar number of thromboembolic events per 1000 patient-years. Clinical severity of CBS deficiency depends on the degree of pyridoxine responsiveness. Therefore, a standardised pyridoxine-responsiveness test in newly diagnosed patients and a critical review of previous assessments is indispensable to ensure adequate therapy and to prevent or reduce long-term complications.

Multi-stage feature selection (MSFS) algorithm for UWB-based early breast cancer size prediction.

Breast cancer is the most common cancer among women and it is one of the main causes of death for women worldwide. To attain an optimum medical treatment for breast cancer, an early breast cancer detection is crucial. This paper proposes a multi- stage feature selection method that extracts statistically significant features for breast cancer size detection using proposed data normalization techniques. Ultra-wideband (UWB) signals, controlled using microcontroller are transmitted via an antenna from one end of the breast phantom and are received on the other end. These ultra-wideband analogue signals are represented in both time and frequency domain. The preprocessed digital data is passed to the proposed multi- stage feature selection algorithm. This algorithm has four selection stages. It comprises of data normalization methods, feature extraction, data dimensional reduction and feature fusion. The output data is fused together to form the proposed datasets, namely, 8-HybridFeature, 9-HybridFeature and 10-HybridFeature datasets. The classification performance of these datasets is tested using the Support Vector Machine, Probabilistic Neural Network and Naïve Bayes classifiers for breast cancer size classification. The research findings indicate that the 8-HybridFeature dataset performs better in comparison to the other two datasets. For the 8-HybridFeature dataset, the Naïve Bayes classifier (91.98%) outperformed the Support Vector Machine (90.44%) and Probabilistic Neural Network (80.05%) classifiers in terms of classification accuracy. The finalized method is tested and visualized in the MATLAB based 2D and 3D environment.