Exome Sequencing Reveals Novel TTN Variants in Saudi Patients with Congenital Titinopathies.

Aim: Our goal was to determine the genetic basis of early-onset myopathy in patients from two unrelated families. Materials and Methods: Whole-exome sequencing, autozygosity mapping, and confirmatory targeted Sanger sequencing were performed using genomic DNA extracted from blood samples from three myopathic patients of two unrelated families. Variant filtering and pathogenicity analyses were evaluated according to standard protocols and up-to-date pipelines applied at the King Faisal Specialist Hospital and Research Center. Results: A novel homozygous variant was detected in TTN gene within the first three M-line-encoding exons in a 9-year-old female in the first family who had delayed motor development and proximal weakness. Her 4-year-old affected brother, with the same homozygous variant, could not yet walk without help. This pathogenic nonsense variant is predicted to cause a premature stop during translation. In the second family we identified two novel variants as compound heterozygosites (a deletion and a variant affecting a canonical splice site) in an affected 9-year-old female with weakness that developed at age 3, in the second family. SpliceAI predicted the variants being splice-altering with high probability. These variants were fully segregated in the family. The deletion was found to be on the paternal allele, whereas the splicing variant was on the maternal allele. The patient's echocardiography revealed mitral valve prolapse with mild mitral regurgitation. Muscle histology showed minicores that were also confirmed by electron microscopy. Conclusion: Our study identified novel pathogenic variants in the TTN gene that are likely responsible for the phenotype of early-onset myopathy; hence, expanding genotype-phenotype relationship of titinopathies.

Case Report: Neonatal Multi-System Inflammatory Syndrome Associated With SARS-CoV-2 Exposure in Two Cases From Saudi Arabia.

Background: Vertical transmission of SARS-CoV-2 is under investigation. A few reports suggest the possibility of SARS-CoV-2 transmission from mothers to their neonates. Most neonates have mild symptoms, but some develop multisystem involvement and shock. Case Presentation: We report two cases of possible SARS-CoV-2 vertical transmission from mothers to their neonates. The first case shows maternal infection with SARS-CoV-2 in the second trimester followed by recurrent infection in the third trimester right before the delivery. The infant demonstrated respiratory distress soon after delivery along with myocardial dysfunction and multi-organ system involvement. The second case shows maternal infection with SARS-COV-2 at the time of delivery with preterm labor secondary to placental abruption, with that delivery resulting in the preterm neonate requiring non-invasive ventilation with multisystem involvement in the context of persistently positive SARS-COV-2 PCR in the neonate. Both neonates were treated with IVIG along with steroids. Both neonates recovered fully and were discharged and allowed to go home. Conclusion: In neonates, COVID-19 usually presents as an asymptomatic or mild illness; some may develop a more severe course. Our two cases, however, demonstrate that multisystem involvement, although rare, is possible. This report also supports the current evidence of possible vertical transmission from mothers to their neonates. This multisystem involvement might be underreported and should be considered in neonates with respiratory distress when born to mothers suffering of COVID-19. Clinical Trial Registration: [KSUMC], identifier [No#98763298].

Tyrosinemia type 1: a rare and forgotten cause of reversible hypertrophic cardiomyopathy in infancy.

BACKGROUND: Tyrosinemia type 1 (TT1) is an autosomal recessive disorder caused by deficiency of the enzyme fumarylacetoacetate hydrolase (FAH). TT1 usually presents in infancy with features suggestive of liver disease or with sepsis-like symptoms. CASE PRESENTATION: We report two Saudi siblings with TT1. Case 1 was a male infant who presented at 2 months old with fever, vomiting and refusal of feeding. Examination revealed a sick-looking infant with signs of severe dehydration and hypovolemic shock. He was jaundiced, and had hepatomegaly and elevated liver enzymes. Echocardiography was performed in light of a lack of response to inotropes, and revealed biventricular and interventricular septal hypertrophies. The ventricular ejection fraction was 65%. Urine organic acid analysis showed elevated succinylacetone, consistent with a diagnosis of TT1. An FAH gene study identified a c.1 A > G homozygous mutation. This patient responded well to intensive cardiorespiratory therapy, tyrosine-free formula, and oral 2-nitro-4- trifluoromethylbenzyl 1, 3 cyclohexanedione (NTBC). Echocardiographic findings reverted to normal after 4 weeks. Case 2 was the younger brother of Case 1, and was born 6 months after his brother had been confirmed with tyrosinemia. Pregnancy and delivery were uneventful. Serum amino acid and organic acid analyses 4 days after birth confirmed tyrosinemia. DNA analysis identified a c.1 A > G homozygous mutation, as in his brother. Echocardiography was normal. Special formula and NTBC were commenced on day 7 of life. The infant remained asymptomatic after 9 months of follow-up. CONCLUSIONS: These cases highlight TT1 as a treatable cause of cardiomyopathy in children. It also supports the idea that early diagnosis and treatment may prevent the development of cardiomyopathy associated with tyrosinemia.

Mutation of IGFBP7 causes upregulation of BRAF/MEK/ERK pathway and familial retinal arterial macroaneurysms.

Insulin-like growth factor binding proteins (IGFBPs) play important physiological functions through the modulation of IGF signaling as well as IGF-independent mechanisms. Despite the established role of IGFs in development, a similar role for the seven known IGFBPs has not been established in humans. Here, we show that an autosomal-recessive syndrome that consists of progressive retinal arterial macroaneurysms and supravalvular pulmonic stenosis is caused by mutation of IGFBP7. Consistent with the recently established inhibitory role of IGFBP7 on BRAF signaling, the BRAF/MEK/ERK pathway is upregulated in these patients, which may explain why the cardiac phenotype overlaps with other disorders characterized by germline mutations in this pathway. The retinal phenotype appears to be mediated by a role in vascular endothelium, where IGFBP7 is highly expressed.

Efficient identification of novel mutations in patients with limb girdle muscular dystrophy.

Limb girdle muscular dystrophy type 2 (LGMD2) is a genetically heterogeneous autosomal recessive disorder caused by mutations in 15 known genes. DNA sequencing of all candidate genes can be expensive and laborious, whereas a selective sequencing approach often fails to provide a molecular diagnosis. We aimed to efficiently identify pathogenic mutations via homozygosity mapping in a population in which the genetics of LGMD2 has not been well characterized. Thirteen consanguineous families containing a proband with LGMD2 were recruited from Saudi Arabia, and for 11 of these families, selected individuals were genotyped at 10,204 single nucleotide polymorphisms. Linkage analysis excluded all but one or two known genes in ten of 11 genotyped families, and haplotype comparisons between families allowed further reduction in the number of candidate genes that were screened. Mutations were identified by DNA sequencing in all 13 families, including five novel mutations in four genes, by sequencing at most two genes per family. One family was reclassified as having a different myopathy based on genetic and clinical data after linkage analysis excluded all known LGMD2 genes. LGMD2 subtypes A and B were notably absent from our sample of patients, indicating that the distribution of LGMD2 mutations in Saudi Arabian families may be different than in other populations. Our data demonstrate that homozygosity mapping in consanguineous pedigrees offers a more efficient means of discovering mutations that cause heterogeneous disorders than comprehensive sequencing of known candidate genes.

Down's syndrome and the pattern of congenital heart disease in a community with high parental consanguinity.

BACKGROUND: It is speculated that parents' consanguinity status effects the pattern of congenital heart defects (CHDs). In this study the CHD pattern in children with Down's syndrome (DS) was determined in a Saudi population with a high consanguineous marriage rate and compared with historical cohorts from populations with low prevalence of parental consanguinity. MATERIAL/METHODS: The prospective study was conducted in an open-access pediatric echocardiography clinic in Riyadh, Saudi Arabia. The subjects were all children with DS proven by clinical and cytogenetic study and referred to the pediatric cardiology service from 2001-2004. Parents' consanguinity was documented and 2D echocardiography and Doppler studies were performed after physical examination, ECG, and chest X-ray for each patient. RESULTS: CHDs were detected in 54/110 (49%) children. These included ventricular septal defect (VSD: 23/54), patent ductus arteriosus (PDA: 4/54), secundum atrial septal defect (ASD: 14/54), atrioventricular septal defect (AVSD: 8/54), tetralogy of Fallot (2/54), bicuspid aortic valve (1/54), supra-pulmonary stenosis (1/54), and double outlet right ventricle (1/54). Consanguinity was found in 25% of all parents. Aortic stenosis, coarctation of the aorta, transposition of great arteries, and complex heart diseases were not detected. CONCLUSIONS: A slightly higher frequency of CHD was documented in DS children from this population with a high consanguineous marriage rate. The frequencies of specific lesions were similar to those reported locally and internationally; VSD was the most frequently detected in this study. Interesting was the predominance of left-right shunt lesions and the relative rarity of cyanotic and complex CHD in this DS population.

Arrhythmogenic right ventricular cardiomyopathy in an 11-year-old girl and typical echocardiographic features.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare entity that affects children as well as adults. This is a genetic disorder that can be inherited and whose hallmark is fibrofatty replacement of ventricular muscle, especially of the right side, with ventricular arrhythmias and progressive heart failure. We describe a case of an 11-year-old Saudi girl with ARVC and the echocardiographic characteristics that had been highlighted by the Taskforce for ARVC, and we suggest that a concurrent criterion be added to aid further echo identification in children.

Cardiac diseases as a risk factor for stroke in Saudi children.

OBJECTIVE: To ascertain the role of cardiac diseases as a risk factor for stroke in a cohort of Saudi children who were evaluated in a retrospective and prospective study. METHODS: Children with cardiac diseases were identified from within a cohort of 104 Saudi children who presented with stroke. They were seen as inpatients in the Pediatric Wards or evaluated at the Outpatient Clinics of the Division of Pediatric Neurology (DPN), and the Division of Pediatric Cardiology at King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia during the periods July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). A comprehensive form for clinical, neuroimaging, neurophysiological and laboratory data retrieval was designed and completed for each patient. Cardiac evaluation included 12-lead ECG and serial echocardiograms. Cardiac catheterization and 24-hour ambulatory ECG (Holter) were conducted on clinical discretion. RESULTS: Cardiac diseases were the underlying risk factor for stroke in 6 (5.8%) of the 104 children (aged one month to 12 years). The patients (4 males and 2 females) were evaluated at the DPN at a mean age of 5.3 years (range = 1-8 years; median 6.5 years). Onset of stroke was at a mean age of 34 months (range = 4 months-8 years; median = 30 months). Five patients had stroke in association with congenital heart disease (CHD), whereas the sixth had restrictive cardiomyopathy. The identified CHD consisted of membranous ventricular septal defect in a 5-year-old boy who had moyamoya syndrome and sickle cell beta(0)-thalassemia, asymptomatic patent ductus arteriosus (PDA) in a 17-month-old girl, atrioventricular canal defect and PDA in an 8-year-old boy who also had Down syndrome, partial anomalous pulmonary venous drainage in a one-year-old boy, and Tetralogy of Fallot in an 8-year-old boy. The latter patient developed hemiparesis secondary to a septic embolus, which evolved into brain abscess involving the right fronto-parietal region. This was successfully managed surgically. The sixth patient was an 8 1/2-year-old girl who had hemiparesis and complex partial seizure in association with restrictive cardiomyopathy. Serial echocardiograms depicted resolution of the cardiac abnormalities within 5 years and subsequent normal findings. CONCLUSIONS: Cardiac diseases, as a group, constitute a significant risk factor for stroke in Saudi children. Early diagnosis of these diseases is important to prevent further recurrences of stroke, and because some of them are potentially curable.

Rare but fatal complication of umbilical venous catheterization.

Umbilical venous catheterization in neonates is an intravascular infusion route for resuscitation and maintenance fluids, blood and blood products, parenteral nutrition, and hypertonic solutions that can be used as an alternative when peripheral venous access is not possible. When used, special precautions should be taken and guidelines followed to prevent rare but often fatal complications.

Endocarditis prophylaxis in children with congenital heart disease. A parent's awareness.

OBJECTIVE: The aim of this study is to determine the parental knowledge of bacterial endocarditis prophylaxis (BEP). METHODS: Parents of 205 patients attending the Pediatric Cardiology Clinics at King Khalid University Hospital, Riyadh, King Fahad University Hospital, Al-Khobar and Prince Sultan Cardiac Center, Riyadh, Kingdom of Saudi Arabia from July 1999 to June 2000, were interviewed by a standard questionnaire pertaining to their knowledge of their child's cardiac disease, medications, and BEP. The patients' cardiac lesions and current medications were verified by a review of medical records. Each patient's need for BEP was determined according to American Heart Association recommendations. RESULTS: All parents answered the interview questions. The patients' mean age was 5 years and 8 months with a range of one month to 15 years. One hundred and two (50%) parents were high school graduates. Fifty-two (25%) parents correctly defined endocarditis. Two hundred and one (98%) parents knew the correct name of their child's cardiac condition, and 46/50 (92%) of those on medication knew the names of their child's current medications. Only 113/176 (64%) parents with at risk children were aware of measures to prevent endocarditis. CONCLUSION: While most parents know the name of their child's heart lesion and current medications, parental knowledge of endocarditis and BEP was limited. Intensified education and awareness programs are needed in order to prevent potential major morbidity and mortality for pediatric patients with congenital heart disease.

Perception of Canadian training programs by Saudi resident trainees.

BACKGROUND: The aim of the study was to determine how Saudi medical trainees in Canada perceive their training programs with regards to educational, ethnic and socio-cultural issues, and if different factors such as the chosen field of training, place or level of training make any difference to this perception. SUBJECTS AND METHODS: All Saudi residents in training programs in Canada in the 1996/1997 academic year were surveyed using a written anonymous self-administered questionnaire, evaluating educational, ethnic and socio-cultural aspects of various training programs. RESULTS: The response rate was 72.5% (185/255). Most of the respondents were in the fourth year of training. Overall, the level of stress was rated as tolerable in 154 (83%), and 179 respondents (96.8%) described the educational aspects of their program positively. Furthermore, 154 (83%) of the respondents agreed that they were treated fairly in the distribution of job functions with regards to Canadian residents, and 133 (72%) did not face any major difficulty in practicing their religion. The sites of training, type of specialty and the level of training made significant impact on the perceived educational, social, religious and administrative aspects of training. CONCLUSION: The majority of Saudi medical trainees in Canada perceived the educational aspects of their training as a positive experience. Major problems faced were mainly related to administrative matters and to some extent, social adjustment. Issues that affect the training process need to be tackled by the concerned authorities to ensure the success of the training programs.