Mohammed H. Alghamdi

Identification of a truncation mutation of acylglycerol kinase (AGK) gene in a novel autosomal recessive cataract locus

Hereditary forms of cataract are genetically heterogeneous. Mutations in crystallin genes account for most Mendelian forms, but identification of other cataract genes has provided insights into additional molecular mechanisms that control lens transparency. In a multiplex consanguineous family with isolated congenital cataract, we identified a novel autosomal recessive cataract locus on 7q33‐q36.1. Exome sequencing revealed a splice‐site mutation in AGK, encoding acylglycerol kinase, which we confirm led to aberrant splicing and predicted premature truncation. This is the first mutation in this lipid metabolism gene to be implicated in the development of isolated cataract, although it remains to be seen if the mechanism involves perturbation of lenticular lipid composition or aberrant signaling during lens morphogenesis. Hum Mutat 33:960–962, 2012.

Can Simple Echocardiographic Measures Reduce the Number of Cardiac Magnetic Resonance Imaging Studies to Diagnose Right Ventricular Enlargement in Congenital Heart Disease

BACKGROUND Right ventricular (RV) enlargement is used as a criterion for the treatment of RV outflow tract dysfunction in patients with congenital heart disease. Although RV volumes are most accurately measured by cardiac magnetic resonance (CMR), CMR is a limited resource. The aim of this study was to investigate whether simple echocardiographic measurements can adequately predict RV volumes below clinical thresholds, thereby reducing the need for CMR in some patients. METHODS Children with repaired tetralogy of Fallot, double-outlet right ventricle, or truncus arteriosus who underwent CMR and echocardiography within a 4-week interval were retrospectively studied. From the four-chamber view, indexed RV lateral wall length, indexed RV end-diastolic perimeter length, and indexed RV end-diastolic area (RVEDAi), were measured. Results were compared with CMR indexed RV volume. The sensitivity and specifity of echocardiographic threshold values predicting RV volumes < 170 mL/m(2) were determined. RESULTS Fifty-one children (mean age, 12.7 ± 3.5 years; 25 male, 26 female) were reviewed. RVEDAi was correlated with CMR indexed RV volume (r = 0.60, P < .0001). Indexed RV end-diastolic perimeter length and indexed RV lateral wall length were not correlated with CMR. RVEDAi < 20 cm(2)/m(2) had 100% specificity to predict indexed RV volume ≤ 170 mL/m(2) (area under the curve, 0.79), reducing the need for CMR in 15 of 51 patients (29%). A threshold RVEDAi of 22 cm(2)/m(2) would reduce the need for CMR in 21 of 51 patients (41%) at the expense of one false-negative result. The coefficients of variation were 14.7% for intraobserver variability and 9.6% for interobserver variability. CONCLUSIONS The specificity of echocardiography-measured RVEDAi can be set to predict RV volumes below a 170 mL/m(2) threshold in 100% of cases. This may reduce the need for CMR to determine RV volumes in ≥25% of patients with congenital heart disease, potentially reducing patient burden and costs.

Longitudinal right ventricular function is a better predictor of right ventricular contribution to exercise performance than global or outflow tract ejection fraction in tetralogy of Fallot: A combined echocardiography and Magnetic Resonance Study

AIMS The contribution of the systolic function of the right ventricular (RV) outflow tract (RVOT) and of longitudinal shortening of the body of the right ventricle to global RV systolic function and exercise capacity in patients after tetralogy of Fallot (TOF) repair is unclear. Our aim was to characterize the functional role of the RVOT and to identify the most suitable method of assessing RV systolic function in clinical practice. METHODS The cardiac magnetic resonance (CMR) studies, echocardiograms, and medical records of 50 consecutive patients with repaired TOF who underwent CMR were reviewed. The volumes of the RVOT and of the remainder of the RV were measured separately. Echocardiographic RV strain measurements based on ultrasound speckle tracking were collected. RESULTS After excluding the akinetic RVOT, RVEF was statistically higher (47.1 vs. 45.0%, P< 0.0001) but the average increase in EF was small. The correlations of fractional area change and global longitudinal strain, both by echocardiography, with global RVEF were moderate (r= 0.59, P= 0.0001 and r= 0.56, P= 0.0004, respectively). The correlation between RVEF and predicted maximal oxygen consumption (VO(2)max-predicted) was weak, regardless of whether the akinetic RVOT was included or not (r= 0.33, P= 0.049 and r= 0.36, P= 0.03, respectively). Of all imaging parameters, echocardiographic RV longitudinal strain correlated best with VO(2)max-predicted (r= 0.66, P= 0.0001). CONCLUSIONS In patients following TOF repair, echocardiographic and CMR descriptors of global RV systolic function are, at best, weak predictors of exercise tolerance. Longitudinal function of the RV, measured remotely from the RVOT, may be a more important determinant of exercise performance than global RVEF in patients with aneurismal RVOTs.

A randomized, double blind pilot study to assess the effects of losartan vs. atenolol on the biophysical properties of the aorta in patients with Marfan and Loeys–Dietz syndromes

BACKGROUND Patients with Marfan (MFS) and Loeys-Dietz (LDS) syndromes have been shown to have abnormal aortic biophysical properties. The purpose of this study was to compare the effects of 12-months of therapy with atenolol or losartan on vascular function in young patients with MFS and LDS. METHODS Seventeen patients with MFS or LDS were recruited and randomized to treatment with atenolol, 25-50mg, or losartan, 25mg daily. Prior to treatment and following therapy, echocardiography for left ventricular size, function and aortic root size was performed. Pulse wave velocity (PWV), input (Zi, ZiF) and characteristic (Zc, ZcF) impedances, arterial stiffness (Ep and β-index), total arterial compliance (TAC), mean (Wm) and total (Wt) hydraulic power, efficiency, power cost per unit of forward flow (Wt/CI) and brachial artery flow-mediated dilation (FMD) were measured. RESULTS The atenolol group consisted of 9 females (17.6years) and the losartan group 7 males and 1 female (17.0years). Their height, weight, BSA, BMI, systolic and diastolic blood pressures were similar. Baseline to 12-month changes for atenolol and losartan were PWV (20% vs -14%), Zi (-2% vs -27%), Zc (-20% vs -27%), Ep (1%, vs -13%), β-index (10% vs 14%), FMD (11% vs 20%), TAC (3% vs 42%), Wm (-24% vs 15%), Wt (-24% vs 17%), and Wt/CI (3% vs 21%). There was a trend for losartan to decrease PWV and stiffness indexes while atenolol decreased power and power/unit flow. CONCLUSION This pilot study suggests that atenolol and losartan may have different mechanisms of action on vascular function. A larger clinical trial is needed to confirm these effects.Clinical trials registration NCT00593710 (ClinicalTrials.gov).

Randot stereoacuity norms in a population of Saudi Arabian children.

Background: The onset and development of stereoacuity in children have been investigated by several authors. In addition to the study of those aspects of stereopsis, it is also important to collect normative data, which can be applied in the clinical setting. The purpose of this study was to establish Randot stereoacuity norms using a Saudi Arabian children population.

Positional mapping of PRKD1 , NRP1 and PRDM1 as novel candidate disease genes in truncus arteriosus

Background Truncus arteriosus (TA) is characterised by failure of septation of the outflow tract into aortic and pulmonary trunks and is associated with high morbidity and mortality. Although ranked among the least common congenital heart defects, TA provides an excellent model for the role of individual genes in cardiac morphogenesis as exemplified by TBX1 deficiency caused by point mutations or, more commonly, hemizygosity as part of the 22q11.2 deletion syndrome. The latter genetic lesion, however, is only observed in a proportion of patients with TA, which suggests the presence of additional disease genes. Objective To identify novel genes that cause Mendelian forms of TA. Methods and results We exploited the occurrence of monogenic forms of TA in the Saudi population, which is characterised by high consanguinity, a feature conducive to the occurrence of Mendelian phenocopies of complex phenotypes as we and others have shown. Indeed, we demonstrate in two multiplex consanguineous families that we are able to map TA to regions of autozygosity in which whole-exome sequencing revealed homozygous truncating mutations in PRKD1 (encoding a kinase derepressor of MAF2) and NRP1 (encoding a coreceptor of vascular endothelial growth factor (VEGFA)). Previous work has demonstrated that Prkd1−/− is embryonic lethal and that its tissue-specific deletion results in abnormal heart remodelling, whereas Nrp1−/− develops TA. Surprisingly, molecular karyotyping to exclude 22q11.2 deletion syndrome in the replication cohort of 17 simplex TA cases revealed a de novo hemizygous deletion that encompasses PRDM1, deficiency of which also results in TA phenotype in mouse. Conclusions Our results expand the repertoire of molecular lesions in chromatin remodelling and transcription factors that are implicated in the pathogenesis of congenital heart disease in humans and attest to the power of monogenic forms of congenital heart diseases as a complementary approach to dissect the genetics of these complex phenotypes.

A substitution mutation in cardiac ubiquitin ligase, FBXO32, is associated with an autosomal recessive form of dilated cardiomyopathy

BackgroundFamilial dilated cardiomyopathy (DCM) is genetically heterogeneous. Mutations in more than 40 genes have been identified in familial cases, mostly inherited in an autosomal dominant pattern. DCM due to recessive mutations is rarely observed. In consanguineous families, homozygosity mapping and whole exome sequencing (WES) can be utilized to identify the genetic defects in recessively inherited DCM.MethodsIn a consanguineous family with four affected siblings with severe DCM, we combined homozygosity mapping, linkage analysis and WES, to uncover the genetic defect.ResultsA region of homozygosity (ROH) on chromosome 8q24.13–24.23 was found to be shared by all of the four affected siblings. WES detected ~47,000 variants that were filtered to a homozygous mutation (p.Gly243Arg) in the FBXO32 gene, located within the identified ROH. The mutation segregated with the phenotype, replaced a highly-conserved amino acid, and was not detected in 1986 ethnically-matched chromosomes. FBXO32, which encodes a muscle-specific ubiquitin ligase, has been implicated in the pathogenesis of cardiomyopathy through the ubiquitin proteasome system (UPS). In addition, FBXO32-knockout mice manifest with cardiomyopathy. Screening the index patient for all of the WES variants in 48 genes known to be implicated in hypertrophic and dilated cardiomyopathy was negative.ConclusionsOur data suggest that FBXO32 is a candidate gene for recessive DCM. Acting as a cardiac ubiquitin ligase, mutated FBXO32 could perturb the degradation of target proteins in the UPS, the impairment of which has been observed in cardiomyopathy. Our work proposes that genes encoding other ubiquitin ligases could also be implicated in familial cardiomyopathy.

Postgraduate specialties interest, career choices and qualifications earned by male dentists graduated from King Saud University

OBJECTIVES To study the career development of male graduates of King Saud University (KSU), College of Dentistry in terms of pursuit of postgraduate dental education, higher degrees or Board Certification, choice of universities and countries of study, and place of work after qualification. METHODS A questionnaire survey was carried out through face to face or telephone interview among 666 KSU graduates of 1982-2004. RESULTS 80% (532 graduates) response rate. (77%) finished postgraduate dental education. 17% specialized in Prosthodontics, 16% in Saudi Board Advanced Restorative Dentistry, 14% in Advanced General Dentistry, 10.5% in Orthodontics, 10% in Oral and Maxillofacial Surgery, 8.3% in Pediatric Dentistry, 7.7% in Endodontics, 6% in Periodontics, 5.5% in Operative Dentistry, 5% in other Specialties. 61% had a Masters degree and 16% had a Doctorate degree. 23% had Board Certificates and 8% had a Fellowship Certificate. (78%) are working in the government, 15% at the university and 6% in private, and 19% in administrative positions. CONCLUSION Most of the dental graduates were motivated and eager to continue their postgraduate education to get either clinical specialty or academic degrees from nationally and internationally well recognized and known Universities and programs.

Cor triatriatum dexter: A rare cause of cyanosis during neonatal period

Cor-triatriatum dexter is an extremely rare congenital heart defect in which there is complete persistence of the right valve of embryonic sinus venosus that results in partitioning of the right atrium into a smooth and trabeculated portion. The smooth portion receives venous blood from inferior vena cava, superior vena cava, and coronary sinus while the trabeculated portion contains the right atrial appendage and the opening of tricuspid valve. We report a 1-week-old child who presented with intermittent episodes of central cyanosis. Echocardiography, established, and bubble contrast study confirmed the diagnosis of an isolated cor-triatriatum dexter. The baby initially underwent an intervention by cardiac catheterization, which was unsuccessful in disrupting the membrane and re-direct the systemic venous flow to the right heart chambers. She subsequently had the cor-triatriatum dexter membrane resected via an uncomplicated open-heart surgery.

Do We Need More Than a Transthoracic Echocardiography When Evaluating Children with Congenital Heart Disease before Cardiac Surgery

AIM To determine if a transthoracic echocardiography (TTE) can be used as the sole diagnostic imaging modality to evaluate children with congenital heart disease (CHD) undergoing cardiac surgery. METHODS A retrospective study was carried out at the King Abdulaziz Cardiac Center. We reviewed all pediatric patients who underwent cardiac surgery during the period January 2011 to December 2011. RESULTS Three hundred ninety-two pediatric patients with CHD fulfilled the inclusion criteria. Of these patients, 287 (73%) underwent surgical interventions based on a TTE alone, while 105 (27%) required additional diagnostic imaging modalities, including a cardiac catheterization (68/105; 65%), cardiac computed tomography angiography (36/105; 34%), or cardiac magnetic resonance imaging (1/105; 1%). A TTE was not enough for all the patients who underwent a cardiac catheterization to find out additional anatomical information (22%), either to directly measure pulmonary artery pressures (62%) or to study vascular reactivity in patients with pulmonary hypertension (16%). Of 36 patients who underwent a cardiac computed tomography angiography, five (14%) had additional information to be added to TTE findings. Of all the patients, 81% had enough information using only the TTE compared to 19% in whom the TTE was not enough to provide all needed information. Only (7/392; 1.8%) patients had additional minor intraoperative findings that did not affect the surgical decision. CONCLUSION Despite the emergence of other imaging modalities, a TTE can be used as the sole diagnostic imaging modality for a preoperative assessment in the majority of children with CHD. Other imaging modalities can be employed with limited indications.