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3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMG-CoA lyase) is a rare inborn error of leucine degradation and ketone body synthesis, caused by homozygous or compound heterozygous disease-causing variants in HMGCL. To understand the natural history of this disease, we reviewed the biochemical, clinical, and molecular data of 62 patients from 54 different families with confirmed HMG-CoA lyase deficiency (HMGCLD) diagnosis from Saudi Arabia. The majority of the affected individuals were symptomatic. At initial diagnosis, 38 patients (61.29%) presented with hypoglycemia and 49 patients (79.03%) developed metabolic acidosis. In 27 patients (43.54%), the disorder manifested in the neonatal period, mostly within the first days of life, while 35 (56.45%) patients were diagnosed within the first year of life or beyond. All the patients were alive and developed long-term neurological complications during data collection, which may significantly influence their quality of life. Common neurological findings include seizures 17/62 (27.41%), hypotonic 3/62 (4.83%), speech delay 7/62 (11.29%), hyperactivity 4/62 (4.83%), developmental delay 6/62 (9.677%), learning disability 15/62 (24.14%), and ataxic gate 1/62 (1.612%). An MRI of the brain exhibited nonspecific periventricular and deep white matter hyperintense signal changes in 16 patients (25.80%) and cerebral atrophy was found in one (1/62; 1.612%) patient. We identified a founder variant [c.122G>A; p.(Arg41Gln)] in 48 affected individuals (77.41%) in the HMGCL gene. This is the largest cohort of HMGCLD patients reported from Saudi Arabia, signifying this disorder as a likely life-threatening disease, with a high prevalence in the region. Our findings suggest that diagnosis at an early stage with careful dietary management may avoid metabolic crises. [ABSTRACT FROM AUTHOR]

Objective: The startup phase of a clinical trial (CT) plays a vital role in the execution of new drug development. Hence, the aim of this study is to identify the factors responsible for delaying the CT startup phase. Further, it focuses on streamlining and reducing the cycle time of the startup phase of newly sponsored CTs.Methods: Thirteen sponsored CTs conducted between 2016 and 2017 at the Clinical Research Department of King Fahad Medical City, Riyadh, Saudi Arabia, were considered for this study. Eight trials were analyzed to identify the data specific to startup metrics using the FOCUS-PDCA cycle (Find an improvement area-Organize a team-Clarify current practices-Understand the source of variation/problem-Select a Strategy-Plan-Do-Check-Act). Six measures incorporated in the metrics were (1) date of initial contact with site to the signing of confidentiality agreement, (2) date of receiving questionnaire from sponsor to date of its completion, (4) time taken to review protocol and approve investigational drug service form, and (5) time taken to study protocol and approve pharmacy and pathology and clinical laboratory medicine form and date of receipt of institutional review board (IRB) submission package to final IRB approval. Fishbone analysis was used to understand the potential causes of process variation. Mean (SD) time was calculated for each metric before and after implementation of the intervention protocol to analyze and compare percentage reduction in the mean cycle time of CTs. Data were represented as mean (SD), and the P value was calculated for each metric. The significance level was set at P < 0.05.Results: Of the various potential factors of delay identified through fishbone analysis, the two major ones were lack of a well-defined timeline for approval and review of the study protocol and inconsistent IRB meetings. After introduction of the new intervention protocol, the entire CT life cycle was reduced by 45.6% (mean [SD], 24.8 [8.2] weeks vs. 13.5 [11.6] weeks before and after the intervention, respectively).Conclusion: Various factors are responsible for the delay of the startup phase of CTs, and understanding the impact of each element allows for optimization and faster execution of the startup phase of CTs. [ABSTRACT FROM AUTHOR]

Introduction: Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare autosomal recessive inborn errors of metabolism characterized by hyperammonemia due to N-acetylglutamate synthase (NAGS) dysfunction. Carglumic acid (Carbaglu®; Orphan Europe Ltd.) is approved by the US Food and Drug Administration (USFDA) for the treatment of hyperammonemia due hepatic NAGS deficiency. Here we report the rationale and design of a phase IIIb trial that is aimed at determining the long-term efficacy and safety of carglumic acid in the management of PA and MMA.Methods: This prospective, multicenter, open-label, randomized, parallel group phase IIIb study will be conducted in Saudi Arabia. Patients with PA or MMA (≤15 years of age) will be randomized 1:1 to receive twice daily carglumic acid (50 mg/kg/day) plus standard therapy (protein-restricted diet, L-carnitine, and metronidazole) or standard therapy alone for a 2-year treatment period. The primary efficacy outcome is the number of emergency room visits due to hyperammonemia. Safety will be assessed throughout the study and during the 1 month follow-up period after the study.Discussion: Current guidelines recommend conservative medical treatment as the main strategy for the management of PA and MMA. Although retrospective studies have suggested that long-term carglumic acid may be beneficial in the management of PA and MMA, current literature lacks evidence for this indication. This clinical trial will determine the long-term safety and efficacy of carglumic acid in the management of PA and MMA.Trial Registration: King Abdullah International Medical Research Center ( KAIMRC ): (RC13/116) 09/1/2014. Saudi Food and Drug Authority (SFDA) (33066) 08/14/2014. ClinicalTrials.gov (identifier: NCT02426775) 04/22/2015. [ABSTRACT FROM AUTHOR]

Aim: To address the implementation of the National Newborn Screening Program (NBS) in Saudi Arabia and stratify the incidence of the screened disorders.Methods: A retrospective study conducted between 1 August 2005 and 31 December 2012, total of 775 000 newborns were screened from 139 hospitals distributed among all regions of Saudi Arabia. The NBS Program screens for 16 disorders from a selective list of inborn errors of metabolism (IEM) and endocrine disorders. Heel prick dry blood spot samples were obtained from all newborns for biochemical and immunoassay testing. Recall screening testing was performed for Initial positive results and confirmed by specific biochemical assays.Results: A total of 743 cases were identified giving an overall incidence of 1:1043. Frequently detected disorders nationwide were congenital hypothyroidism and congenital adrenal hyperplasia with an incidence of 1:7175 and 1:7908 correspondingly. The highest incidence among the IEM was propionic acidaemia with an incidence rate of 1:14 000.Conclusion: The article highlights the experience of the NBS Program in Saudi Arabia and providing data on specific regional incidences of all the screened disorders included in the programme; and showed that the incidence of these disorders is one of the highest reported so far world-wide. [ABSTRACT FROM AUTHOR]

Background: Aicardi-Goutières syndrome is a rare genetic neurological disorder with variable clinical manifestations. Molecular detection of specific mutations is required to confirm the diagnosis. The aim of this study was to review the clinical and molecular diagnostic findings in 24 individuals with Aicardi-Goutières syndrome who presented during childhood in an Arab population.Materials and Methods: We reviewed the records of 24 patients from six tertiary hospitals in different Arab countries. All included patients had a molecular diagnosis of Aicardi-Goutières syndrome.Results: Six individuals with Aicardi-Goutières syndrome (25%) had a neonatal presentation, whereas the remaining patients presented during the first year of life. Patients presented with developmental delay (24 cases, 100%); spasticity (24 cases, 100%); speech delay (23 cases, 95.8%); profound intellectual disability (21 cases, 87.5%); truncal hypotonia (21 cases, 87.5%); seizures (eighteen cases, 75%); and epileptic encephalopathy (15 cases, 62.5%). Neuroimaging showed white matter abnormalities (22 cases, 91.7%), cerebral atrophy (75%), and small, multifocal calcifications in the lentiform nuclei and deep cerebral white matter (54.2%). Homozygous mutations were identified in RNASEH2B (54.2%), RNASEH2A (20.8%), RNASEH2C (8.3%), SAMHD1 (8.3%), TREX1 (4.2%), and heterozygous mutations in IFIH1 (4.2%), with c.356A>G (p.Asp119Gly) in RNASEH2B being the most frequent mutation. Three novel mutations c.987delT and c.625 + 1G>A in SAMHD1 gene and c.961G>T in the IFIHI1 gene were identified.Conclusions: This is the largest molecularly confirmed Aicardi-Goutières syndrome cohort from Arabia. By presenting these clinical and molecular findings, we hope to raise awareness of Aicardi-Goutières syndrome and to demonstrate the importance of specialist referral and molecular diagnosis. [ABSTRACT FROM AUTHOR]

Background: Neuronal ceroid lipofuscinoses (NCLs) represent a heterogeneous group of inherited metabolic lysosomal disorders characterized by neurodegeneration. This study sought to describe the clinical and molecular characteristics of NCLs in Saudi Arabia and determine the most common types in that population., Methods: A retrospective review of electronic medical records was conducted for 63 patients with NCL (55 families) from six tertiary and referral centers in Saudi Arabia between 2008 and 2022. Clinical, radiological, and neurophysiological data as well as genetic diagnoses were reviewed., Results: CLN6 was the predominant type, accounting for 45% of cases in 25 families. The most common initial symptoms were speech delay (53%), cognitive decline (50%) and/or gait abnormalities (48%), and seizure (40%). Behavioral symptomatology was observed in 20%, whereas visual impairment was less frequently (9.3%) encountered. Diffuse cerebral and cerebellar atrophy was the predominant finding on brain magnetic resonance imaging. Electroencephalography generally revealed background slowing in all patients with generalized epileptiform discharges in 60%. The most common genotype detected was the p.Ser265del variant found in 36% (20 of 55 families). The most rapidly progressive subtypes were CLN2 and CLN6. Two patients with each died at age five years. The earliest age at which a patient was nonambulatory was two years in a patient with CLN14., Conclusions: This is the largest molecularly confirmed NCL cohort study from Saudi Arabia. Characterizing the natural history of specific NLC types can increase understanding of the underlying pathophysiology and distinctive genotype-phenotype characteristics, facilitating early diagnosis and treatment initiation as well as genetic counseling for families., Competing Interests: Declaration of competing interest The authors declare the following competing interests: Mohammed M. Saleh, Abdulrahim M. Hamhom, Ali AlOtaibi, Malak AlGhamdi, Yousef Housawi, Yaser I. Aljadhai, Seham Alameer, Mohammed Almannai, Lamyaa Ali Jad, Ali H. AlWadie, Sadia Tabassum, Abdulaziz Alsaman, Ali AlAsmari, Fuad Al Mutairi, Hamad Althiyab, Fahad A. Bashiri, Suzan AlHumaidi, Majid Alfadhel, and Aqeela AlHashim have no conflicts of interest to declare. Jonathan W. Mink is in receipt of research funding from Theranexus, Inc, Neurogene Inc, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; is a consultant for the Beyond Batten Disease Foundation, Amicus, Inc, Polaryx, Inc, and TEVA, Inc; is a member of Data and Safety Monitoring Board for PTC Therapeutics and Passage Bio; and is a Trial Steering Committee for Applied Therapeutics. Eissa A. Faqeih is in receipt of a research grant from the Intramural Research Fund for an extended project to study common genetic diseases in Saudi Arabia (Demography of Recessive Diseases in KSA; Grant #019-052)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pycnodysostosis is characterized by short stature, osteosclerosis, acro-osteolysis, increased tendency of fractures, and distinctive dysmorphic features. It is a rare autosomal recessive disease caused by biallelic CTSK mutations. The clinical details of 18 patients from Saudi Arabia were reviewed. Short stature, osteopetrosis, acro-osteolysis, and distinctive facial dysmorphism were documented in all cases. Our results highlight the significant complications associated with this disease. The large anterior fontanelle is one of the cardinal signs of this disease; however, half of our patients had small fontanelles and a quarter had craniosynostosis, which caused optic nerve compression. Sleep apnea was of the major complications in three patients. Bone fracture can be a presenting symptom, and in our patients it mainly occurred after the age of 3 years. Bone marrow suppression was seen in a single patient of our cohort who was misdiagnosed initially with malignant osteopetrosis. In this study, we also describe two novel (c.5G > A [p.Trp2Ter], c.538G > A [p.Gly180Ser]) and two reported (c.244-29 A > G, c.830C > T [p.Ala277Val]) CTSK mutations. Our results indicate that the recurrent intronic variant, c.244-29 A > G is likely to be a founder mutation, as it was found in 78% (14/18 patients) of our cohort belonging to the same tribe., (© 2021 Wiley Periodicals LLC.)

Purpose: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD., Methods: We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia., Results: The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively., Conclusion: Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.

We report two consanguineous families with probands that exhibit intellectual disability, developmental delay, short stature, aphasia, and hypotonia in which homozygous non-synonymous variants were identified in IQSEC1 (GenBank: NM&#95;001134382.3). In a Pakistani family, the IQSEC1 segregating variant is c.1028C>T (p.Thr343Met), while in a Saudi Arabian family the variant is c.962G>A (p.Arg321Gln). IQSEC1-3 encode guanine nucleotide exchange factors for the small GTPase ARF6 and their loss affects a variety of actin-dependent cellular processes, including AMPA receptor trafficking at synapses. The ortholog of IQSECs in the fly is schizo and its loss affects growth cone guidance at the midline in the CNS, also an actin-dependent process. Overexpression of the reference IQSEC1 cDNA in wild-type flies is lethal, but overexpression of the two variant IQSEC1 cDNAs did not affect viability. Loss of schizo caused embryonic lethality that could be rescued to 2 nd instar larvae by moderate expression of the human reference cDNA. However, the p.Arg321Gln and p.Thr343Met variants failed to rescue embryonic lethality. These data indicate that the variants behave as loss-of-function mutations. We also show that schizo in photoreceptors is required for phototransduction. Finally, mice with a conditional Iqsec1 deletion in cortical neurons exhibited an increased density of dendritic spines with an immature morphology. The phenotypic similarity of the affecteds and the functional experiments in flies and mice indicate that IQSEC1 variants are the cause of a recessive disease with intellectual disability, developmental delay, and short stature, and that axonal guidance and dendritic projection defects as well as dendritic spine dysgenesis may underlie disease pathogenesis., (Copyright © 2019. Published by Elsevier Inc.)

Jeune asphyxiating thoracic dystrophy (JATD) is a skeletal dysplasia characterized by a small thoracic cage and a range of skeletal and extra-skeletal anomalies. JATD is genetically heterogeneous with at least nine genes identified, all encoding ciliary proteins, hence the classification of JATD as a skeletal ciliopathy. Consistent with the observation that the heterogeneous molecular basis of JATD has not been fully determined yet, we have identified two consanguineous Saudi families segregating JATD who share a single identical ancestral homozygous haplotype among the affected members. Whole-exome sequencing revealed a single novel variant within the disease haplotype in CEP120, which encodes a core centriolar protein. Subsequent targeted sequencing of CEP120 in Saudi and European JATD cohorts identified two additional families with the same missense mutation. Combining the four families in linkage analysis confirmed a significant genome-wide linkage signal at the CEP120 locus. This missense change alters a highly conserved amino acid within CEP120 (p.Ala199Pro). In addition, we show marked reduction of cilia and abnormal number of centrioles in fibroblasts from one affected individual. Inhibition of the CEP120 ortholog in zebrafish produced pleiotropic phenotypes characteristic of cilia defects including abnormal body curvature, hydrocephalus, otolith defects and abnormal renal, head and craniofacial development. We also demonstrate that in CEP120 morphants, cilia are shortened in the neural tube and disorganized in the pronephros. These results are consistent with aberrant CEP120 being implicated in the pathogenesis of JATD and expand the role of centriolar proteins in skeletal ciliopathies., (© The Author 2014. Published by Oxford University Press.)

Lethal congenital contracture syndrome (LCCS) is a lethal autosomal recessive form of arthrogryposis multiplex congenita (AMC). LCCS is genetically heterogeneous with mutations in five genes identified to date, all with a role in the innervation or contractile apparatus of skeletal muscles. In a consanguineous Saudi family with multiple stillbirths presenting with LCCS, we excluded linkage to all known LCCS loci and combined autozygome analysis and whole-exome sequencing to identify a novel homozygous variant in ZBTB42, which had been shown to be enriched in skeletal muscles, especially at the neuromuscular junction. Knockdown experiments of zbtb42 in zebrafish consistently resulted in grossly abnormal skeletal muscle development and myofibrillar disorganization at the microscopic level. This severe muscular phenotype is successfully rescued with overexpression of the human wild-type ZBTB42 gene, but not with the mutant form of ZBTB42 that models the human missense change. Our data assign a novel muscular developmental phenotype to ZBTB42 in vertebrates and establish a new LCCS6 type caused by ZBTB42 mutation., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Nephrotic syndrome (NS) is a renal disease characterized by heavy proteinuria, hypoalbuminemia, edema and hyperlipidemia. Its presentation within the first 3 months of life or in multiple family members suggests an underlying inherited cause. To determine the frequency of inherited NS, 62 cases (representing 49 families with NS) from Saudi Arabia were screened for mutations in NPHS1, NPHS2, LAMB2, PLCE1, CD2AP, MYO1E, WT1, PTPRO and Nei endonuclease VIII-like 1 (NEIL1). We detected likely causative mutations in 25 out of 49 families studied (51%). We found that the most common genetic cause of NS in our cohort was a homozygous mutation in the NPHS2 gene, found in 11 of the 49 families (22%). Mutations in the NPHS1 and PLCE1 genes allowed a molecular genetic diagnosis in 12% and 8% of families, respectively. We detected novel MYO1E mutations in three families (6%). No mutations were found in WT1, PTPRO or NEIL1. The pathogenicity of novel variants was analyzed by in silico tests and by genetic screening of ethnically matched control populations. This is the first report describing the molecular genetics of NS in the Arabian Peninsula.

Bruck syndrome (BS) is an autosomal recessive syndromic form of osteogenesis imperfecta (OI) that is characterized by the additional presence of pterygium formation. We have recently shown that FKBP10 previously reported as a novel autosomal recessive OI gene also defines a novel Bruck syndrome locus (BKS3). In this manuscript, we extend our analysis to describe a mutation previously described in isolated OI patients and show that it results in BS phenotype in a Saudi family. More interestingly, we describe a novel FKBP10 mutation that results in isolated OI as well as BS phenotype in the same family. These results, combined with recently published work, confirm that FKBP10 is a bonafide BS locus and lay the foundation for future research into modifiers that underlie the phenotypic heterogeneity of FKBP10 mutations., (Copyright © 2011 Wiley-Liss, Inc.)

Mutated PSAP gene resulting in sphingolipid activator protein B deficiency is known to cause metachromatic leukodystrophy variant in which arylsulfatase A is normal. Of 16 patients with metachromatic leukodystrophy that were evaluated in our center, 7 patients were diagnosed with arylsulfatase A-deficient metachromatic leukodystrophy, whereas 9 children from 4 unrelated Saudi families were found to have sphingolipid activator protein B deficiency. PSAP analysis found that the 4 families segregate the same homozygous mutation that was a g.722G>C transversion resulting in C241S change, which was previously reported in an Arab patient. Our work, which reports the largest series of patients with sphingolipid activator protein B deficiency, suggests that this variant is likely to be more common than arylsulfatase A-deficient metachromatic leukodystrophy in Arabs, a notion that has potential diagnostic and preventive implications.