Clinical and molecular characterization of a large primary hyperoxaluria cohort from Saudi Arabia: a retrospective study.

BACKGROUND: Primary hyperoxalurias (PHs) constitute rare disorders resulting in abnormal glyoxalate metabolism. PH-associated phenotypes range from progressive nephrocalcinosis and/or recurrent urolithiasis to early kidney failure. METHODS: A retrospective study was conducted for patients with confirmed PH diagnoses from three tertiary centers in Saudi Arabia. Detailed clinical molecular diagnosis was performed for 25 affected individuals. Whole exome sequencing (WES)-based molecular diagnosis was performed for all affected individuals. RESULTS: The male:female ratio was 52% male (n = 13) and 48% female (n = 12), and consanguinity was present in 88%. Nephrolithiasis and/or nephrocalcinosis were present in all patients. Kidney stones were present in 72%, nephrocalcinosis in 60%, hematuria in 32%, proteinuria in 16%, abdominal pain in 36%, developmental delay in 8%, and chronic kidney disease stage 5 (CKD stage 5) was observed in 28% of the patients. The most common PH disorder was type I caused by variants in the AGXT gene, accounting for 56%. The GRHPR gene variants were identified in 4 patients, 16% of the total cases. Seven patients did not reveal any associated variants. Missense variants were the most commonly observed variants (48%), followed by frame-shift duplication variants (28%). CONCLUSIONS: Characterization of the genetic and clinical aspects of PH in this unique population provides direction for improved patient management and further research. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical variability and outcome of succinyl-CoA:3-ketoacid CoA transferase deficiency caused by a single OXCT1 mutation: Report of 17 cases.

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is an inherited metabolic disease caused by mutated OXCT1 gene resulting in recurrent ketoacidosis. Analysis of longitudinal data in such an ultra-rare disease is warranted to delineate genotype-phenotype correlations and management outcome. A retrospective analysis of 17 patients, from nine unrelated families, with SCOT deficiency who were followed up in the Medical Genetics Clinic at King Faisal Specialist Hospital and Research Centre was conducted. All the patients were homozygous for p.R468C in OXCT1 gene. Most of the patients (n = 15, 88.2%) were symptomatic presenting with recurrent ketoacidosis, the onset of which ranged from 6 months to 4 years (median 2 years). A striking inter- and intrafamilial variability that ranged from being entirely asymptomatic to death during the first episode. All patients were instructed to avoid fasting, restrict protein in diet, and receive carnitine supplementation. However, there was no correlation between following instructions of chronic management and outcome. Most of the patients had their crises resolved and all of them had normal neurodevelopmental outcome. Our data suggest that SCOT deficiency caused by homozygous p.R468C has variable clinical presentation and incomplete penetrance. The apparent lack of correlation between protein restriction +/- carnitine supplementation and outcome suggests that chronic dietary restriction may not be warranted. However, a longer follow-up on larger and heterogenous cohort of cases is needed before a clear conclusion on the long-term management can be reached.

Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy.

BACKGROUND: Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale. METHODS: To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either (1) targeted genetic test with targeted mutation test, single-gene test, or multigene panel for Noonan syndrome, or (2) untargeted genetic test with whole-exome sequencing or whole-genome sequencing. Several bioinformatics tools were used to filter the variants. RESULTS: Two-hundred five unrelated probands with various forms of cardiomyopathy were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates (ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1). CONCLUSIONS: Our work demonstrates the impact of consanguinity on the genetics of childhood-onset cardiomyopathy, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting whole-exome sequencing/whole-genome sequencing as a first-line test should be considered.

A detailed musculoskeletal study of a fetus with anencephaly and spina bifida (craniorachischisis), and comparison with other cases of human congenital malformations.

Few descriptions of the musculoskeletal system of humans with anencephaly or spina bifida exist in the literature. Even less is published about individuals in which both phenomena occur together, i.e. about craniorachischisis. Here we provide a detailed report on the musculoskeletal structures of a fetus with craniorachischisis, as well as comparisons with the few descriptions for anencephaly and with musculoskeletal anomalies found in other congenital malformations. We focused in particular on the comparison with trisomies 13, 18, and 21 because neural tube defects have been associated with such chromosomal defects. Our results showed that many of the defects found in the fetus with craniorachischisis are similar not only to anomalies previously described in the available works on musculoskeletal phenotypes seen in fetuses with anencephaly and spina bifida, but also to a wide range of other different conditions/syndromes including trisomies 13, 18 and 21, and cyclopia. The fact that similar anomalies are seen commonly not only in a wide range of different syndromes, but also as variants of the normal human population and as the 'normal' phenotype of other animals, supports Pere Alberch's unfortunately named idea of a 'logic of monsters'. That is, it supports the idea that development is so constrained that both in 'normal' and abnormal development one sees certain outcomes being produced again and again because ontogenetic constraints only allow a few possible outcomes, thus also leading to cases where the anatomical defects of some organisms are similar to the 'normal' phenotype of other organisms. In fact, this applies not only to specific anomalies but also to general patterns, such as the fact that in pathological conditions affecting different regions of the body, one consistently sees more defects on the upper limbs than on the lower limbs. Such general patterns are, again, seen in the fetus examined for this study, which had 29 muscle anomalies on the right upper limb and 22 muscle anomalies on the left upper limb, vs. seven muscle anomalies on the right lower limb and two on the left lower limb. It is therefore hoped that this work, which is part of our effort to describe and compile information on human musculoskeletal defects found in a wide range of conditions, will contribute not only to a better understanding of craniorachischisis in particular and of human congenital malformations in general, but also to broader discussions on the fields of comparative anatomy, and developmental and evolutionary biology.

Inflammatory bowel disease: An evaluation of health information on the internet.

AIM: To evaluate the quality and accuracy of websites written to the public on inflammatory bowel disease (IBD) (Crohn's disease and ulcerative colitis) and assess their readability level. METHODS: Google™, Bing™, and Yahoo™ search engines were searched independently by three researchers in December 2014. Only English-language websites were selected on the basis of predetermined inclusion and exclusion criteria. Researchers independently evaluated the quality of each website by using the DISCERN and the HONcode instruments. The readability levels were calculated using two formulas; the Flesch-Kincaid Grade Level Index, and the Coleman-Liau Readability Index. The agreement between the evaluators was calculated using Cohen kappa coefficient. RESULTS: Eighty-four websites were finally identified. Scores varied from a minimum DISCERN score of 18 to a maximum of 68 [mean ± SD, 42.2 ± 10.7; median = 41.5, interquartile range, interquartile range (IQR) = 15.8] and a minimum score of HONcode of 0.14 and a maximum of 0.95 (mean ± SD, 0.16 ± 0.19; median = 0.45, IQR = 0.29). Most of these websites were reviewed in 2014 and 2015 (n = 51). The creators of these websites were: universities and research centers (n = 25, 30%), foundations and associations (n = 15, 18%), commercial and pharmaceutical companies (n = 25, 30%), charities and volunteer work (n = 9, 10%), and non-university educational bodies (n = 10, 12%). The Flesch-Kincaid Grade Level readability score (mean ± SD) was 11.9 ± 2.4 and the Coleman-Liau Readability Index score was 12.6 ± 1.5. Significant correlation was found between the two readability scores (R2 = 0.509, P = 0.001). The overall agreement between evaluators measured by Cohen kappa coefficient was in the range of 0.804-0.876; rated as "Good". CONCLUSION: The DISCERN and the HONcode scores of websites varied and the readability levels of most websites were above the public readability level. The study highlights the areas that need further improvement and development in patient education online materials about IBD.

An untold story: The important contributions of Muslim scholars for the understanding of human anatomy.

It is usually assumed that Galen is one of the fathers of anatomy and that between the Corpus Galenicum and the Renaissance there was no major advance in anatomical knowledge. However, it is also consensually accepted that Muslim scholars had the intellectual leadership from the 8th/9th to 13th centuries, and that they made remarkable progresses in numerous scientific fields including medicine. So, how is it possible that they did not contribute to advance human anatomy during that period? According to the dominant view, Muslim scholars exclusively had a passive role: their transmission of knowledge from the Greeks to the West. Here, we summarize, for the first time in a single paper, the studies of major Muslim scholars that published on human anatomy before Vesalius. This summary is based on analyses of original Arabic texts and of more recent publications by anatomists and historians, and on comparisons between the descriptions provided by Galen and by these Muslim scholars. We show that Arabic speakers and Persians made important advances in human anatomy well before Vesalius. The most notable exception concerns the muscular system: strikingly, there were apparently neither advances made by Muslims nor by Westerners for more than 1000 years. Unbiased discussions of these and other related issues, and particularly of the mainly untold story about the major contributions of Muslim scholars to anatomy, are crucial to our knowledge of the history of anatomy, biology and sciences, and also of our way of thinking, biases, and prejudices. Anat Rec, 300:986-1008, 2017. © 2017 Wiley Periodicals, Inc.