Prenatal Diagnosis of c.437-1G>A Mutation in the MAN2B1 Gene in a Family With Alpha-Mannosidosis: Unraveling Clinical Presentation and Treatment Outcomes in a Novel Prenatal Case.

Alpha-mannosidosis is a rare lysosomal storage disorder with progressive impairments in motor functions, skeletal deformities, and immunodeficiency. Enzyme replacement therapy (ERT) should be initiated early to achieve optimal outcomes. This report describes how alpha-mannosidosis diagnosis in a seven-year-old girl led to a successful prenatal diagnosis in the subsequent pregnancy and pre-symptomatic treatment at the early disease stage. The index patient was a seven-year-old girl who was referred with a confirmed diagnosis of alpha-mannosidosis based on the presence of homozygous c.437-1G>A mutation in the MAN2B1 gene. A prenatal diagnosis was made in the subsequent pregnancy through molecular analysis, which revealed the same homozygous variant. The patient was treated at the fifth week of age and showed mild skeletal involvement and normal development at ERT initiation. At 11 months of age, the ERT level increased to 15.8 µmol/l/h. The motor assessment showed that the patient was developmentally normal and was able to maintain her sitting and walking for a few steps only. Prenatal molecular screening in affected families can allow for the early identification and implementation of appropriate management strategies for alpha-mannosidosis.

Cystic Lung Changes, Bronchiectasis, and a Heterozygous-Primary Ciliary Dyskinesia-Associated Variant in the DNAH5 Gene: A Diagnostic Challenge.

BACKGROUND Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disease that can present at different ages with different phenotypes. Missed and delayed diagnoses are fairly common. Many variants in the DNAH5 gene have been described that confirm the diagnosis of PCD. Advances in medicine, especially in molecular genetics, have led to increasingly early discoveries of such cases, especially in those with nonclassical presentations. CASE REPORT This report describes a patient with bronchiectasis, lung cysts, finger clubbing, and failure to thrive who was misdiagnosed for several years as having asthma. Many differentials were suspected and worked up, including a suspicion of PCD. Genetic tests with whole-exome sequencing (WES) and whole-genome sequencing (WGS) detected a heterozygous, likely pathogenic, variant in the DNAH5 gene associated with PCD. CONCLUSIONS Despite a thorough workup done for this case, including a genetic workup, a PCD diagnosis was not established. We plan to reanalyze the WGS in the future, and with advent of technology and better coverage of genes, a genetic answer for this challenging case may resolve this diagnostic quandary in the future.

A Niemann-Pick Disease Type C2 with Severe Pulmonary Involvement and Limited Therapeutic Options: A Case Report.

Niemann-Pick disease type C (NPC) is an autosomal recessive lipid storage disorder. There are two types, NPC1, which is the predominant form (95%), and the rare NPC2, which represents less than 5% of the reported cases. Niemann-Pick disease type C2 usually presents with respiratory symptoms, cholestasis, neurological impairment, and hepatosplenomegaly. Case report: Here, we report a 3-year-old boy who presented to our hospital with exacerbation of chronic lung disease requiring invasive ventilatory support. He was previously diagnosed with interstitial lung disease. His parents used to instill olive oil in his nose (a few drops in each nostril daily for several months) to treat frequent nasal bleeding. A detailed history revealed prolonged neonatal jaundice for four months, with hepatosplenomegaly. In his second year, generalized hypotonia and delayed psychomotor development were observed. Upon presentation to our institute, chest CT showed evidence of intraparenchymal fat; therefore, lipoid pneumonia and lipid storage disease were suspected. The bronchoalveolar lavage results suggested pulmonary alveolar proteinosis (PAP). Whole-exome sequencing (WES) revealed a class one homozygous pathogenic variant in the NPC2 gene. Our patient faced a range of difficulties, including prolonged mechanical ventilation and diagnostic and therapeutic challenges. Conclusion: Niemann-Pick disease type C2 is a progressive and lethal condition that requires a high index of suspicion to pinpoint the diagnosis. Gene study remains the method of choice to confirm the diagnosis. There are limited choices of therapeutic interventions; therefore, genetic counseling and the prevention of recurrence should be the ultimate goal for affected families.

A Biallelic Variant in FRA10AC1 Is Associated With Neurodevelopmental Disorder and Growth Retardation.

Objectives: Our objective was to identify the genetic cause in a family with a remarkable history of neurodevelopmental disease and growth retardation. Methods: A neurologic evaluation was performed, and DNA samples were obtained from the affected siblings and parents to perform whole-exome sequencing (WES). Results: Both siblings presented with dysmorphic features, failure to thrive, global developmental delay, generalized hypotonia, feeding problems, and congenital heart disease. WES revealed a homozygous nonsense variant in the FRA10AC1 gene in both siblings. Discussion: A recent study has reported the first association of biallelic variants in the spliceosomal C complex gene, FRA10AC1, with syndromic neurodevelopmental disease and growth retardation in 5 patients from 3 consanguineous families complex. In this study, we provide the first confirmation of the reported FRA10AC1-related neurologic syndrome in an additional family.

Further clinical and genetic evidence of ASC-1 complex dysfunction in congenital neuromuscular disease.

Transcriptional coregulators modulate the efficiency of transcription factors. Bi-allelic variants in TRIP4 and ASCC1, two genes that encode members of the tetrameric coregulator ASC-1, have recently been associated with congenital bone fractures, hypotonia, and muscular dystrophy in a total of 22 unrelated families. Upon exome sequencing and data repository mining, we identified six new patients with pathogenic homozygous variants in either TRIP4 (n = 4, two novel variants) or ASCC1 (n = 2, one novel variant). The associated clinical findings confirm and extend previous descriptions. Considering all patients reported to date, we provide supporting evidence suggesting that ASCC1-related disease has a more severe phenotype compared to TRIP4-related disorder regarding higher incidence of perinatal bone fractures and shorter survival.

A novel variant of RBCK1 gene causes mild polyglucosan myopathy.

Homozygous or compound heterozygous pathogenic variants of the RBCK1 gene can result in a systemic disorder characterized by the accumulation of complex carbohydrate molecules, namely polyglucosan bodies in the muscular tissues. The role of this gene in the pathophysiology of the disorder at the molecular level remains unclear. Being a very rare disorder, the medical knowledge is based on just a few reported cases. Here we report a 7-year-old girl who presented with exercise intolerance and hepatosplenomegaly. Her liver profile was constantly raised. The genetic investigation has revealed a variant of the RBCK1 gene of unknown significance, which has later been confirmed as pathogenic via a variety of clinical, genetic, and histopathological approaches. More importantly, it is evident that the availability of sophisticated genetic testing, such as whole-exome sequencing, has significantly improved the knowledge of and diagnosis of many rare metabolic disorders.

The first Saudi baby with classic homocystinuria diagnosed by universal newborn screening.

Classic homocystinuria (CH) is an inborn error of metabolism caused by cystathionine beta-synthase enzyme deficiency. Affected patients present with intellectual disability and other comorbidities. If diagnosed early in infancy and started treatment, inevitable complications can be prevented. Newborn screening (NBS) uses tandem mass-spectroscopy (MSMS) to measure the amino acid levels. In CH, the first-tier screening test is the measurement of methionine by MSMS. If methionine remained elevated in the recall sample, plasma level for homocysteine is performed. A newborn infant underwent routine NBS in our institute that showed elevated methionine in the first and the recall sample. Thereafter, total serum homocysteine was found to be elevated, consistent with the diagnosis of CH. An early medical and dietary management was commenced for this first Saudi baby diagnosed with homocystinuria by universal NBS. This report demonstrates that NBS for CH is feasible and effective in preventing the disease burden.

Screening for Fabry disease among 619 hemodialysis patients in Saudi Arabia.

OBJECTIVES: To determine the prevalence of Fabry disease (FD) among Saudi patients on hemodialysis. METHODS: This prospective study was conducted in 3 major hospitals in the Kingdom of Saudi Arabia (KSA). All adult patients (greater than 18 years old) attending the dialysis unit who have end-stage renal disease (ESRD) and on hemodialysis were included. Known patients with FD and those who refused to participate in the study were excluded. All eligible patients were screened for FD using dry blood spot (DBS) for alpha-galactosidase A (α-Gal A). A positive DBS (enzyme activity less than 40%) was followed by another con rmatory enzyme assay. When the second DBS sample was also positive (enzyme activity less than 40%), a Sanger sequencing of the GLA gene was performed. RESULTS: A total of 619 patients with ESRD and on hemodialysis were screened for FD using DBS for α-Gal A enzyme level. Enzymatic activity was below 40% in 11 samples. On retesting, 3 females had less than 20% enzymatic activity suggesting FD. Sanger sequencing of these 3 females showed the variant c.1055C greater than G (p.Ala352Gly) confirming the diagnosis of FD. Family screening of one of these 3 patients revealed one asymptomatic female carrying the same variant. CONCLUSION: The prevalence of FD in this cohort was 4.8 per 1000 patients. Screening of Fabry patients with ESRD seems to be a cost-effective strategy. Furthermore, relatives of the patients identified by screening enhances this screening strategy.

Comment on: Prediction of retinopathy of prematurity using the screening algorithm WINROP in a Saudi cohort of preterm infants.

[No Abstract Available].

Comment on: Sensitivity and specificity of cerebrospinal fluid glucose measurement by an amperometric glucometer.

[No Abstract Available].

Incidence of newborn screening disorders among 56632 infants in Central Saudi Arabia. A 6-year study.

OBJECTIVES: To determine the incidence of newborn screening (NBS) disorders and to study the key performance indicators of the program. METHODS: This retrospective single-center study enrolled all infants who underwent NBS from January 2012 to December 2017 at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. We screened 17 NBS disorders. Blood samples were collected 24 hours after birth. If the initial result was positive, a second sample was collected. True positive cases were immediately referred for medical management. Data were extracted from laboratory computerized and non-computerized records using case report forms. RESULTS: During the study period, 56632 infants underwent NBS with a coverage rate of 100%. Thirty-eight cases were confirmed. The incidence of congenital hypothyroidism was 1:3775. The positive predictive value for the detection of congenital hypothyroidism was 11.8%. Propionic aciduria was the most common metabolic disorder, with an incidence of 1:14158. Very long-chain acyl CoA dehydrogenase deficiency and glutaric aciduria type 1 had an incidence of 1:18877 each. Phenylketonuria, biotinidase deficiency, maple syrup urine disease, and citrullinemia had an incidence of 1:28316 each. However, galactosemia and 3-methyl crotonyl carboxylase deficiency had the lowest incidence of 1:56632. CONCLUSION: The NBS coverage rate at our facility was 100%. Congenital hypothyroidism was the most frequently detected disorder with an incidence that matches worldwide figures. The incidence of other inherited disorders was consistent with regional figures.

Molecular and clinical characteristics of very-long-chain acyl-CoA dehydrogenase deficiency: A single-center experience in Saudi Arabia.

OBJECTIVES: To describe the clinical and molecular characteristics of patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.   Methods: A retrospective observational cross-sectional analysis was conducted on all patients with VLCAD deficiency at  (Genetic/Metabolic Section), Prince Sultan Military Medical City (PSMMC), Riyadh, Saudi Arabia from 2000 to 2019. Demographic, clinical, and laboratory data were abstracted from the electronic hospital records using a case report form. Results: A total of 14 children were analyzed. Six presented with hypoglycemia, 4 with cardiomyopathy, and 10 had rhabdomyolysis. Five patients had early onset severe phenotype, while 9 had mild form. The molecular study revealed homozygous mutations in ACADVL in all 14 patients. Three variants were not reported before. All patients were treated with medium-chain triglyceride and carnitine. Ten patients are alive and have normal development, while 4 died. Conclusion: Most of the patients in this cohort presented in the neonatal period either by newborn screening or clinically with hypoglycemia, cardiomyopathy, and rhabdomyolysis. The new molecular variants detected in this study broaden the genetic spectrum of VLCAD deficiency in Saudi Arabia.

Fructose-1,6-bisphosphatase deficiency with confirmed molecular diagnosis. An important cause of hypoglycemia in children.

OBJECTIVES: To draw attention towards fructose-1,6-bisphosphatase (FBPase) deficiency as an important cause of hypoglycemia and lactic acidosis and to implement preventive strategies. Methods: This observational, cross-sectional study was conducted on 7 Saudi patients with genetically confirmed FBPase deficiency from 2008 to 2018 at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. Results: Participants ranged in age from 1-10 years, and all presented with recurrent hypoglycemia. All but one had associated severe metabolic acidosis, and 3 patients (42.9%) presented with hypoglycemia and severe acidosis since birth. The mean duration from presentation to diagnosis was 39.4 months, as other diagnoses, like glycogen storage diseases and mitochondrial diseases needed to be ruled out. Development was normal apart from speech delay in one patient with a novel variant of the FBP1 gene. All patients have homozygous variants in the FBP1 gene.  Conclusion: Fructose-1,6-bisphosphatase is an important cause of hypoglycemia and acidosis; therefore, it is important to offer early molecular diagnostics in any child presenting with these symptoms. Molecular diagnostics should always be undertaken to confirm the diagnosis and for further preventive strategies.

Peripheral venous route for administration of ammonul infusion for treatment of acute hyperammonemia. An experience from a tertiary center in Saudi Arabia.

OBJECTIVES: To determine the local effects of peripheral Ammonul infusion on the skin and the subcutaneous tissues.  Methods: This retrospective study was conducted at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. All children less than 16 years of age admitted between December 2015 and October 2018 with hyperammonemia and received Ammonul infusion for treatment were recruited. Results: Twenty-one patients received the Ammonul infusion. They were admitted 58 times with acute hyperammonemia during the study period, with an average of 2.8 admissions per patient. The mean age of the included patients was 49.5 months. The most frequent underlying diagnoses were propionic acidemia (n=9), urea cycle disorders (n=5), and intrinsic liver disease (n=3). All participants received Ammonul through peripheral lines except 3 who received it through central lines. No extravasation, burns, or other local side effects were observed in this cohort. CONCLUSION: This data indicate that the use of Ammonul through a peripheral venous route appears to be safe and not associated with infusion-related local adverse effects.

Oxandrolone for growth hormone-treated girls aged up to 18 years with Turner syndrome.

BACKGROUND: The final adult height of untreated girls aged up to 18 years with Turner syndrome (TS) is approximately 20 cm shorter compared with healthy females. Treatment with growth hormone (GH) increases the adult height of people with TS. The effects of adding the androgen, oxandrolone, in addition to GH are unclear. Therefore, we conducted this systematic review to investigate the benefits and harms of oxandrolone as an adjuvant therapy for people with TS treated with GH. OBJECTIVES: To assess the effects of oxandrolone on growth hormone-treated girls aged up to 18 years with Turner syndrome. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, the ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was October 2018. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled clinical trials (RCTs) that enrolled girls aged up to 18 years with TS who were treated with GH and oxandrolone compared with GH only treatment. DATA COLLECTION AND ANALYSIS: Three review authors independently screened titles and abstracts for relevance, selected trials, extracted data and assessed risk of bias. We resolved disagreements by consensus, or by consultation with a fourth review author. We assessed trials for overall certainty of the evidence using the GRADE instrument. MAIN RESULTS: We included six trials with 498 participants with TS, 267 participants were randomised to oxandrolone plus GH treatment and 231 participants were randomised to GH only treatment. The individual trial sample size ranged between 22 and 133 participants. The included trials were conducted in 65 different paediatric endocrinology healthcare facilities including clinics, centres, hospitals and academia in the USA and Europe. The duration of interventions ranged between 3 and 7.6 years. The mean age of participants at start of therapy ranged from 9 to 12 years. Overall, we judged only one trial at low risk of bias in all domains and another trial at high risk of bias in most domains. We downgraded the level of evidence mainly because of imprecision (low number of trials, low number of participants or both). Comparing oxandrolone plus GH with GH only for final adult height showed a mean difference (MD) of 2.7 cm in favour of oxandrolone plus GH treatment (95% confidence interval (CI) 1.3 to 4.1; P < 0.001; 5 trials, 270 participants; moderate-quality evidence). The 95% prediction interval ranged between 0.3 cm and 5.1 cm. For adverse events, we based our main analysis on reliable date from two trials with overall low risk of bias. There was no evidence of a difference between oxandrolone plus GH and GH for adverse events (RR 1.81, 95% CI 0.83 to 3.96; P = 0.14; 2 trials, 170 participants; low-quality evidence). Six out of 86 (18.6%) participants receiving oxandrolone plus GH compared with 8/84 (9.5%) participants receiving GH only reported adverse events, mainly signs of virilisation (e.g. deepening of the voice). One trial each investigated the effects of treatments on speech (voice frequency; 88 participants), cognition (51 participants) and psychological status (106 participants). The overall results for these comparisons were inconclusive (very low-quality evidence). No trial reported on health-related quality of life or all-cause mortality. AUTHORS' CONCLUSIONS: Addition of oxandrolone to the GH therapy led to a modest increase in the final adult height of girls aged up to 18 years with TS. Adverse effects identified included virilising effects such as deepening of the voice, but reporting was inadequate in some trials.

6-Pyruvoyltetrahydropterin Synthase Deficiency: Review and Report of 28 Arab Subjects.

BACKGROUND: Tetrahydrobiopterin is an essential cofactor for the hydroxylation of aromatic amino acids phenylalanine, tyrosine, and tryptophan. Therefore, tetrahydrobiopterin deficiency results in hyperphenylalaninemia as well as dopamine and serotonin depletion in the central nervous system. The enzyme 6-pyruvoyltetrahydropterin synthase catalyzes the second step of de novo synthesis of tetrahydrobiopterin, and its deficiency is the most frequent cause of tetrahydrobiopterin metabolism disorders. METHOD: We conducted a retrospective chart review of 28 subjects from 24 families with molecularly confirmed 6-pyruvoyltetrahydropterin synthase deficiency from six centers in three Arab countries. We reviewed clinical, biochemical, and molecular data. We also reviewed previously published cohorts of subjects with 6-pyruvoyltetrahydropterin synthase deficiency. RESULTS: Similar to previous observations, we show that early treatment (less than two months) is associated with better outcome. We identify eight PTS variants in 24 independent families. The most common variant is (c.238A>G; p.M80V) with an allele count of 33%. We also identify one novel variant (c.2T>G; p.?). CONCLUSION: The deficiency of 6-pyruvoyltetrahydropterin synthase is relatively common in the Arab population and should be considered in individuals with hyperphenylalaninemia. More natural history studies with comprehensive biochemical and molecular genetics data are needed for a robust base for the development of future therapy.

Methionyl-tRNA synthetase novel mutation causes pulmonary alveolar proteinosis.

The  methionyl-tRNA  synthetase  (MARS)  mutation is  a  very  rare  cause  of  congenital  pulmonary  alveolar proteinosis.We report a 6-month-old boy born with symmetrical intrauterine growth retardation presented with unexplained persistent tachypnea and hypoxemia associated with severe failure to thrive, anemia, hypoalbuminemia and hepatomegaly. Detailed pulmonary investigations including computed tomography chest scan, bronchoscopy and bronchoalveolar lavage revealed pulmonary alveolar proteinosis. Whole exome sequencing identified a homozygous novel variant in the MARS gene, c.854T>C p.(Ile285Thr).

Perception, attitude, and satisfaction of paediatric physicians and nurses towards clinical practice guidelines at a university teaching hospital.

RATIONALE, AIMS, AND OBJECTIVES: To explore perception, attitude, and satisfaction of paediatric clinicians, trainees, and nurses at King Khalid University Hospital towards clinical practice guidelines (CPGs) including the locally adapted diabetic ketoacidosis CPG (DKA-CPG). METHODS: A cross-sectional survey was distributed to 260 doctors and nurses working in the paediatrics department. RESULTS: The response rate was 95.4%. The respondents had a positive perception and attitude towards general CPGs and specifically for the DKA-CPG; 98.7% thought CPGs were useful sources of advice, improved safety, and decreased risk, and reduced variation in practice. A total of 99.2% thought CPGs were good clinical tools, 98.3% satisfied with, had confidence in well-developed CPGs, and would recommend them to their colleagues to use, and 94.6% agreed they were cost-effective. The preferred format for CPGs was paper (46.6%) and electronic (42.9%). The DKA-CPG helped in managing patients and respondents were all satisfied and had confidence with it (100%). The rationale and objectives of the DKA-CPG were clear for 99.25%; 98.5% thought the layout was clear and well organized and user-friendly (96.2%). Compared with nurses, physicians had a higher perception towards CPGs in general (P < .05) and the DKA-CPG (P < .05). CONCLUSIONS: The paediatric doctors, and nurses have a great perception and satisfaction and positive attitude towards CPGs in general, towards the paediatric diabetic ketoacidosis CPG in particular, which in turn had a positive impact on the acceptability and implementation of the CPGs. These findings could help in sustaining a safe and high-quality health care environment through implementation of evidence-based CPGs.

Assessment of professionalism among medical students at a regional university in Saudi Arabia.

Professionalism is the relationship that is built on trust between the medical profession and their community. We aim to assess the understanding and the perception of professionalism by the medical students at University of Bisha (UB) in Saudi Arabia. This was an observational, descriptive, and cross-sectional study conducted among the medical students at UB. A validated questionnaire containing nine questions was distributed to all medical students. The questionnaire addresses the knowledge, attitudes, and perception toward professionalism. Out of the all 122 students studying at the university, 97 responded by filling the questionnaire giving a response rate of 79.5%. Most of the responders gave a positive attitude and perception when asked about presumed scenarios addressing professionalism. The majority of the participants (83.5%) mentioned that it is necessary for the medical student to wear lab coat in the hospital, 67.0% disagreed on medical student to wear accessories during work, and 67.0% disagreed to request your friend to sign on behalf of you when you are absent. Only 15.5% accepted to report on an incidence during daily activities or exam, and 72.2% did not accept to discuss patients issues in public. Most of the medical students enrolled in this study seems to have positive attitude and perception regarding professionalism.

Clinical characteristics and aetiology of early childhood epilepsy: a single centre experience in Saudi Arabia.

Seizures in children and neonatal period have variety of causes; however, most of childhood seizures are idiopathic. The aim of this study was to review the causes of epilepsy in children presenting in the first 2 years of life using the International League Against Epilepsy classification released in 2010. This was a retrospective chart review study that was conducted at a tertiary center in Saudi Arabia. Two hundred and twenty-one patients were included in the study, 31 with conditions mimic epilepsy were excluded. The remaining 190 patients were classified into: Group A, structural/metabolic, 82 (43%); Group B, genetic, 24 (13%) and Group C, unknown, 84 (44%). The commonest seizures' type was tonic-clonic in 106 (56%), followed by clonic 29 (15.3%), myoclonic 22 (11.6%) and a tonic 16 (8.4%). Pyramidal signs, global developmental delay, hypotonia, micro/macrocephaly and abnormal computed tomography and/or magnetic resonance imaging brain were more common in the structural/metabolic group (p < 0.05). Electroencephalography was abnormal in 136 (72%) patients, mostly in the structural/metabolic group (p = 0.011). In conclusion, the aetiology of epilepsy in this cohort was mainly unknown or secondary to structural/metabolic causes.