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To evaluate the electro-clinical manifestations and outcomes of children with absence epilepsy at a tertiary center in Saudi Arabia.This retrospective study reviewed the medical and EEG records of patients who were diagnosed to have CAE as per the International League Against Epilepsy (ILAE) definition for CAE. The study was conducted in the pediatric neurology clinic of King Khalid University Hospital, King Saud University Medical City, Riyadh, Saudi Arabia, between January 2000 and December 2019. Patients who did not meet (ILAE) criteria, lost follow-up, and those who did not receive treatment at KKUH were excluded. Data regarding the patient's disease, electro-clinical manifestations, anti-seizure medication response, and outcomes were collected.A total of 35 patients, with an average age at diagnosis of 7 ± 2.1 y, were included in the study; among them, 51.4% were female and approximately 48.6% presented with a family history of epilepsy. Regarding clinical features, all patients experienced staring and altered awareness, 94.2% had less than 20 spells per day at the time of diagnosis, and 65.7% were provoked by the hyperventilation test. Regarding EEG findings, all patients had bilateral, symmetrical, and synchronous discharges in the form of regular 3 Hz spike-and-wave complexes, and 94.3% had a generalized initial ictal discharge. Also, 22.8% had eye fluttering with electrographic seizures. Ethosuximide (ESM) was used as the drug of choice in 45.7% of the patients. Regarding clinical outcomes, 94.3% had their disease clinically controlled, and 80% had a normalized EEG after few months of starting anti-seizure medication. Finally, 37.2% experienced complete remission of epilepsy after 3-5 y; however, one patient developed juvenile myoclonic epilepsy.This study described the electro-clinical manifestations of patients with childhood absence epilepsy and outcomes. Furthermore, early diagnosis and prompt treatment of childhood absence epilepsy improve treatment outcomes.

To investigate seizure characteristics, types, and define the etiology of epilepsy in children aged ≤2 years using the 2017 ILAE classification.A retrospective chart review was conducted at King Khalid University Hospital, King Saud University Medical City, Riyadh, Kingdom of Saudi Arabia for children below 2 years of age diagnosed with epilepsy, and on anti-seizure medications from January 2017 - December 2018. The collected data involved detailed information on the patients' seizure, electroclinical, neuroimaging, laboratory evaluations, and underlying etiology.One- hundred and fifty patients were included in the study and classified according to etiology into: genetic (43, 28.7%), structural (41, 27.3%), metabolic (10, 6.7%), infectious (8, 5.3%), immune-mediated (1, 0.7%) and unknown (47, 31.3%) groups. The most common seizure types were generalized epilepsy, among which generalized tonic-clonic seizures occurred in 56 (37%) patients, followed by tonic seizures in 31 (21%), infantile spasm in 19 (13%), myoclonic seizures in 4 (2.7%), atonic seizures in 6 (4%), and focal seizures in 33 (22%) patients. Global developmental delay and abnormalities in both neurologic exam and neuroimaging were more common in the structural and genetic groups. Electroencephalography was abnormal in 82 (55%) patients, including the majority of the structural group (26, 63.4%).The etiology of epilepsy in this cohort remains undetermined (unknown) in a large proportion of cases, followed by genetic and structural causes. This result added to the published international data about epilepsy in the first 2-years of life.

Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a rare recently recognised clinical syndrome with common presentations that include tics, Tourette’s-like syndrome or obsessive-compulsive disorder. It is associated with various behavioural and psychiatric manifestations in children, such as separation anxiety disorder, body dysmorphic disorder, and attention deficit hyperactivity disorder. Steroid responsive encephalopathy with autoimmune thyroiditis (SREAT) is a rare disorder in children associated also with various movement disorders and neuropsychiatric manifestations. The present report describes a previously healthy 10-year-old girl who presented with motor tics, visual hallucination, separation anxiety, and emotional liability. Her workup showed an evidence of Hashimoto’s thyroiditis on laboratory results, in addition to the elevation of antistreptolysin O titre (ASO). Based on this, a diagnosis of SREAT was made, and she was given courses of methylprednisolone with inadequate response. Then, the possibility of PANDAS was considered, and she responded to multiple courses of antibiotics with abate of symptoms after a course of intravenous immunoglobulin combined with monthly benzathine penicillin injections. To the best of our knowledge, this is the first reported case of PANDAS associated with autoimmune thyroiditis causing such diagnostic dilemma.

Objectives: To assess the neurodevelopmental and epilepsy outcomes in children with infantile spasms (IS). Methods: A retrospective chart review of all patients with infantile spasms admitted to King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia between January 2000 and December 2017. Infants who were diagnosed to have IS as per the International League Against Epilepsy (ILAE) definition were included in this study. Patients who lost follow-up and those who did not receive treatment at KKUH were excluded. Results: Total of 53 patients were included and categorized into unknown, cryptogenic and symptomatic type of IS. The majority had symptomatic etiology (71.7%). Type of etiology and delay in initiation of treatment were significant predictors of motor and cognitive outcomes, but not seizure control. Patients with unknown IS, who were diagnosed earlier (0.72-month), had better neurodevelopmental outcomes. Vigabatrin in combination with either Adrenocorticotropic hormone (ACTH) or Prednisolone showed better seizure control in comparison to monotherapy and other combination modalities. Conclusion: Neurodevelopmental outcomes of IS are strongly associated with the underlying etiology. Early initiation of treatments had a favorable cognitive and motor outcome. Early response to combination therapy with resolution of spasms and hypsarrhythmia had better seizure outcomes. However, motor and cognitive outcomes were not affected by the response to the combination therapy.

Background: Acute necrotizing encephalopathy of childhood (ANEC) is a rapidly progressing encephalopathy characterized by fever, depressed level of consciousness, and seizures. Diagnosis depends on clinical presentation and characteristic neuroimaging findings of abnormal signal intensity involving the thalami as well as the supra and infra-tentorial areas. Treatment modalities are not well-established; empirical treatment with antibiotics and antiviral agents is the initial step, followed by steroids and immunoglobulin, as well as supportive care. Patients with ANEC have a variable prognosis, but mortality is very high. Methods: A retrospective chart review of patients diagnosed with ANEC in five tertiary centers from January 2015 to October 2018 was performed. Clinical and radiological findings, as well as the therapeutic approach and outcomes, were described. Results: Twelve children were included ranging in age from 10 months to 6 years. All patients presented with preceding febrile illness, altered level of consciousness, and seizure. Radiological features showed abnormal signals in the thalami, and five patients (41.7%) had brainstem involvement. All patients received empirical treatment with antibiotics and antiviral agents. Ten patients (83.3%) received intravenous immunoglobulin (IVIG) and IV Methylprednisolone therapy. Outcomes were variable ranging from good outcomes with minimal neurological deficits to poor outcomes and death in 25% of cases. Conclusion: ANEC is a rare fulminant disease in children. The treatment is challenging. Early interventions with the use of IVIG and IV Methylprednisolone may change the outcome; however, further studies are needed to establish a consensus guideline for the management.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a recently identified auto-immune disorder characterised by severe memory deficit, a decreased level of consciousness, seizures, autonomic dysfunction and movement disorders. Three girls with the disorder are reported; they were aged 4 years, 5 years and 10 months. The 10-month-old infant who is one of the youngest patients reported with anti-NMDAR encephalitis worldwide, had MRI features suggestive of herpes simplex encephalitis (known to trigger anti-NMDAR encephalitis), but CSF PCR for herpes simplex was negative. All the patients presented with seizures, behavioural change, regression of speech, dystonia and choreo-athetosis. Anti-NMDAR antibodies were detected in all patients' sera and cerebrospinal fluid (CSF). Intravenous immunoglobulin, corticosteroids and rituximab were administered at different intervals. Cases 1 and 2 made a full recovery, but case 3 has mild motor and speech delay. Patients who present with encephalopathy, seizures and movement disorders should be tested for anti-NMDAR antibodies in serum and CSF in addition to being screened for herpes simplex encephalitis.

Defects in the peroxisomes biogenesis and/or function result in peroxisomal disorders. In this study, we describe the largest Arab cohort to date (72 families) of clinically, biochemically and molecularly characterized patients with peroxisomal disorders. At the molecular level, we identified 43 disease-causing variants, half of which are novel. The founder nature of many of the variants allowed us to calculate the minimum disease burden for these disorders in our population ~1:30 000, which is much higher than previous estimates in other populations. Clinically, we found an interesting trend toward genotype/phenotype correlation in terms of long-term survival. Nearly half (40/75) of our peroxisomal disorders patients had documented survival beyond 1 year of age. Most unusual among the long-term survivors was a multiplex family in which the affected members presented as adults with non-specific intellectual disability and epilepsy. Other unusual presentations included the very recently described peroxisomal fatty acyl-CoA reductase 1 disorder as well as CRD, spastic paraparesis, white matter (CRSPW) syndrome. We conclude that peroxisomal disorders are highly heterogeneous in their clinical presentation. Our data also confirm the demonstration that milder forms of Zellweger spectrum disorders cannot be ruled out by the "gold standard" very long chain fatty acids assay, which highlights the value of a genomics-first approach in these cases.

Purpose Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases. Methods Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines. Results We highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders. Conclusions Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.

Çalışmada 47 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır. Purpose: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. Methods: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. Results: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1. Conclusion: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect. King Salman Center for Disability Research Saudi Human Genome Program Howard Hughes Medical Institute National Institute of Neurological Disorders and Stroke Manton Center for Orphan Disease Research, Boston Children's Hospital King Abdullah University of Science and Technology King Abdulaziz City for Science and Technology Deanship of Scientific Research, King Saud University

Myopathies are heterogeneous disorders characterized clinically by weakness and hypotonia, usually in the absence of gross dystrophic changes. Mitochondrial dysfunction is a frequent cause of myopathy. We report a simplex case born to consanguineous parents who presented with muscle weakness, lactic acidosis, and muscle changes suggestive of mitochondrial dysfunction. Combined autozygome and exome analysis revealed a missense variant in the SLC25A42 gene, which encodes an inner mitochondrial membrane protein that imports co-enzyme A into the mitochondrial matrix. Zebrafish slc25a42 knockdown morphants display severe muscle disorganization and weakness. Importantly, these features are rescued by normal human SLC25A42 RNA, but not by RNA harboring the patient’s variant. Our data support a potentially causal link between SLC25A42 mutation and mitochondrial myopathy in humans.

Objective: To increase the use of evidence-based approaches in the diagnosis, investigations and treatment of Convulsive Status Epilepticus (CSE) in children in relevant care settings. Method: A Clinical Practice Guideline (CPG) adaptation group was formulated at a university hospital in Riyadh. The group utilized 2 CPG validated tools including the ADAPTE method and the AGREE II instrument. Results: The group adapted 3 main categories of recommendations from one Source CPG. The recommendations cover; (i)first-line treatment of CSE in the community; (ii)treatment of CSE in the hospital; and (iii)refractory CSE. Implementation tools were built to enhance knowledge translation of these recommendations including a clinical algorithm, audit criteria, and a computerized provider order entry. Conclusion: A clinical practice guideline for the Saudi healthcare context was formulated using a guideline adaptation process to support relevant clinicians managing CSE in children.

Dominant SCN1B mutations are known to cause several epilepsy syndromes in humans. Only 2 epilepsy patients to date have been reported to have recessive mutations in SCN1B as the likely cause of their phenotype. Here, we confirm the recessive inheritance of 2 novel SCN1B mutations in 5 children from 3 families with developmental epileptic encephalopathy. The recessive inheritance and early death in these patients is consistent with the Dravet-like phenotype observed in Scn1b-/- mice. The 'negative' clinical exome in one of these families highlights the need to consider recessive mutations in the interpretation of variants in typically dominant genes.

Background Epileptic encephalopathy is a broad clinical category that is highly heterogeneous genetically. Objective To describe a multiplex extended consanguineous family that defines a molecularly novel subtype of early infantile epileptic encephalopathy. Methods Autozygosity mapping and exome sequencing for the identification of the causal mutation. This was followed by expression analysis of the candidate gene. Results In an extended multigenerational family with six affected individuals, a single novel disease locus was identified on chromosome 12p13.31-p13.2. Within that locus, the only deleterious novel exomic variant was a homozygous truncating mutation in NECAP1 , encoding a clathrin-accessory protein. The mutation was confirmed to trigger nonsense-mediated decay. Consistent with previous reports, we show that NECAP1 is highly enriched in the central nervous system. Conclusions NECAP1 is known to regulate clathrin-mediated endocytosis in synapses. The mutation we report here links for the first time this trafficking pathway in early infantile epileptic encephalopathy.

Intellectual disability (ID) is a measurable phenotypic consequence of genetic and environmental factors. In this study, we prospectively assessed the diagnostic yield of genomic tools (molecular karyotyping, multi-gene panel and exome sequencing) in a cohort of 337 ID subjects as a first-tier test and compared it with a standard clinical evaluation performed in parallel. Standard clinical evaluation suggested a diagnosis in 16% of cases (54/337) but only 70% of these (38/54) were subsequently confirmed. On the other hand, the genomic approach revealed a likely diagnosis in 58% (n=196). These included copy number variants in 14% (n=54, 15% are novel), and point mutations revealed by multi-gene panel and exome sequencing in the remaining 43% (1% were found to have Fragile-X). The identified point mutations were mostly recessive (n=117, 81%), consistent with the high consanguinity of the study cohort, but also X-linked (n=8, 6%) and de novo dominant (n=19, 13%). When applied directly on all cases with negative molecular karyotyping, the diagnostic yield of exome sequencing was 60% (77/129). Exome sequencing also identified likely pathogenic variants in three novel candidate genes (DENND5A, NEMF and DNHD1) each of which harbored independent homozygous mutations in patients with overlapping phenotypes. In addition, exome sequencing revealed de novo and recessive variants in 32 genes (MAMDC2, TUBAL3, CPNE6, KLHL24, USP2, PIP5K1A, UBE4A, TP53TG5, ATOH1, C16ORF90, SLC39A14, TRERF1, RGL1, CDH11, SYDE2, HIRA, FEZF2, PROCA1, PIANP, PLK2, QRFPR, AP3B2, NUDT2, UFC1, BTN3A2, TADA1, ARFGEF3, FAM160B1, ZMYM5, SLC45A1, ARHGAP33 and CAPS2), which we highlight as potential candidates on the basis of several lines of evidence, and one of these genes (SLC39A14) was biallelically inactivated in a potentially treatable form of hypermanganesemia and neurodegeneration. Finally, likely causal variants in previously published candidate genes were identified (ASTN1, HELZ, THOC6, WDR45B, ADRA2B and CLIP1), thus supporting their involvement in ID pathogenesis. Our results expand the morbid genome of ID and support the adoption of genomics as a first-tier test for individuals with ID.

Objective To investigate the utility of autozygome analysis and exome sequencing in a cohort of patients with suspected or confirmed mitochondrial encephalomyopathy. Methods Autozygome was used to highlight candidate genes for direct sequencing in 10 probands, all born to consanguineous parents. Autozygome was also used to filter the variants from exome sequencing of four probands. Results In addition to revealing mutations in known mitochondrial genes, the analysis revealed the identification of two novel candidate disease genes: MFF and FARS2 , encoding the mitochondrial fission factor and phenylalanyl-tRNA synthetase, respectively. Interpretation These findings expand the repertoire of genes that are mutated in patients with mitochondrial disorders and highlight the value of integrating genomic approaches in the evaluation of these patients.

Ehlers–Danlos syndrome (EDS) describes a group of clinical entities in which the connective tissue, primarily that of the skin, joint and vessels, is abnormal, although the resulting clinical manifestations can vary widely between the different historical subtypes. Many cases of hereditary disorders of connective tissue that do not seem to fit these historical subtypes exist. The aim of this study is to describe a large series of patients with inherited connective tissue disorders evaluated by our clinical genetics service and for whom a likely causal variant was identified. In addition to clinical phenotyping, patients underwent various genetic tests including molecular karyotyping, candidate gene analysis, autozygome analysis, and whole-exome and whole-genome sequencing as appropriate. We describe a cohort of 69 individuals representing 40 families, all referred because of suspicion of an inherited connective tissue disorder by their primary physician. Molecular lesions included variants in the previously published disease genes B3GALT6, GORAB, ZNF469, B3GAT3, ALDH18A1, FKBP14, PYCR1, CHST14 and SPARC with interesting variations on the published clinical phenotypes. We also describe the first recessive EDS-like condition to be caused by a recessive COL1A1 variant. In addition, exome capture in a familial case identified a homozygous truncating variant in a novel and compelling candidate gene, AEBP1. Finally, we also describe a distinct novel clinical syndrome of cutis laxa and marked facial features and propose ATP6V1E1 and ATP6V0D2 (two subunits of vacuolar ATPase) as likely candidate genes based on whole-genome and whole-exome sequencing of the two families with this new clinical entity. Our study expands the clinical spectrum of hereditary disorders of connective tissue and adds three novel candidate genes including two that are associated with a highly distinct syndrome.

Genes disrupted in human microcephaly (meaning "small brain") define key regulators of neural progenitor proliferation and cell-fate specification. In comparison, genes mutated in human lissencephaly (lissos means smooth and cephalos means brain) highlight critical regulators of neuronal migration. Here, we report two families with extreme microcephaly and grossly simplified cortical gyral structure, a condition referred to as microlissencephaly, and show that they carry homozygous frameshift mutations in NDE1, which encodes a multidomain protein that localizes to the centrosome and mitotic spindle poles. Both human mutations in NDE1 truncate the C-terminal NDE1domains, which are essential for interactions with cytoplasmic dynein and thus for regulation of cytoskeletal dynamics in mitosis and for cell-cycle-dependent phosphorylation of NDE1 by Cdk1. We show that the patient NDE1 proteins are unstable, cannot bind cytoplasmic dynein, and do not localize properly to the centrosome. Additionally, we show that CDK1 phosphorylation at T246, which is within the C-terminal region disrupted by the mutations, is required for cell-cycle progression from the G2 to the M phase. The role of NDE1 in cell-cycle progression probably contributes to the profound neuronal proliferation defects evident in Nde1-null mice and patients with NDE1 mutations, demonstrating the essential role of NDE1 in human cerebral cortical neurogenesis.

Background Klippel-Feil anomaly (KFA) can be seen in a number of syndromes. We describe an apparently novel syndromic association with KFA. Methods Clinical phenotyping of two consanguineous families followed by combined autozygome/exome analysis. Results Two patients from two apparently unrelated families shared a strikingly similar phenotype characterised by KFA, myopathy, mild short stature, microcephaly, and distinctive facies. They shared a single founder autozygous interval in which whole exome sequencing revealed a truncating mutation in MYO18B. There was virtually complete loss of the transcript in peripheral blood, indicative of nonsense-mediated decay. Electron microscopy of muscle confirms abnormal myosin filaments with accompanying myopathic changes. Conclusions Deficiency of MYO18B is linked to a novel developmental disorder which combines KFA with myopathy. This suggests a widespread developmental role for this gene in humans, as observed for its murine ortholog.

SummaryOur knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function.

Molecular karyotyping has rapidly become the test of choice in patients with neurocognitive phenotypes, but studies of its clinical utility have largely been limited to outbred populations. In consanguineous populations, single-gene recessive causes of neurocognitive phenotypes are expected to account for a relatively high percentage of cases, thus diminishing the yield of molecular karyotyping. The aim of this study was to test the clinical yield of molecular karyotyping in the highly consanguineous population of Saudi Arabia. We have reviewed the data of 584 patients with neurocognitive phenotypes (mainly referred from pediatric neurology clinics), all evaluated by a single clinical geneticist. At least 21% of tested cases had chromosomal aberrations that are likely disease-causing. These changes include both known and novel deletion syndromes. The higher yield of molecular karyotyping in this study as compared with the commonly cited 11% can be explained by our ability to efficiently identify single-gene disorders, thus enriching the samples that underwent molecular karyotyping for de novo chromosomal aberrations. We show that we were able to identify a causal mutation in 37% of cases on a clinical basis with the help of autozygome analysis, thus bypassing the need for molecular karyotyping. Our study confirms the clinical utility of molecular karyotyping even in highly consanguineous populations. Genet Med 17 9, 719–725.

Background Intellectual disability (ID) is one of the most common forms of disability worldwide, displaying a wide range of aetiologies and affecting nearly 2% of the global population. Objective To describe a novel autosomal recessive form of ID with strabismus and its underlying aetiology. Materials and methods Autozygosity mapping, linkage analysis and exome sequencing were performed in a large multiplex consanguineous family that segregates ID and strabismus. Exome sequencing was independently performed in three other consanguineous families segregating the same disease. Direct sequencing of the resulting candidate gene was performed in four additional families with the same phenotype. Results A single missense mutation was identified in ADAT3 in all studied families on an ancient ancestral haplotype. This gene encodes one of two eukaryotic proteins that are necessary for the deamination of adenosine at position 34 to inosine in t-RNA. Our results show the first human mutation in the t-RNA editing machinery and expand the landscape of pathways involved in the pathogenesis of ID.

To carefully assess the phenotype and genotype of a patient with partial mosaic trisomy 8 with particular attention to ophthalmologic features.Ophthalmologic and neuro-ophthalmologic examination; neuroimaging; conventional karyotyping; and array comparative genomic hybridization (CGH).The proband was the only affected child of a non-consanguineous family. At birth she was noted to have facial dysmorphism including telecanthus, low set ears, prominent nares, and an everted lower lip. She had an accommodative esotropia with otherwise normal globes, optic nerves, retinae, and orbits. She also had delayed motor milestones and mild mental retardation associated with agenesis of the corpus callosum. Both karyotyping and array CGH documented mosaic partial trisomy of chromosome 8 that included all of the "q" arm and part of the proximal "p" arm.This girl had a number of the classic features of mosaic trisomy 8, including an accommodative esotropia with none of the other ocular and orbital anomalies described in patients with mosaic trisomy 8. This report constitutes an initial effort to create a virtual database of patients with mosaic chromosome 8 in which careful phenotype-genotype correlation employing high resolution array CGH may help identify clues regarding the genetic etiology of ophthalmologic features of this syndrome.

There were errors in the Funding section. The correct funding information is as follows: MAS and co-authors are thankful to the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia, for supporting the work through the research group project number RGP-VPP-301. RC was supported by the Gebert Ruf Foundation (grant number GRS-046/09). GS was supported by the French National Agency for Research(ANR), Association Contre les Syndromes Cerebelleux, France, The Verum Foundation, the European Union (Omics call, "Neuromics"), The Fondation Roger de Spoelberch and the program "Investissements d'avenir" ANR-10-IAIHU-06 (to the Brain and Spine Institute). HA was supported by Association Francaise contre les Myopathies (AFM), France. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PLoS one 8(10), e76831 (2013). doi:10.1371/journal.pone.0076831, Published by PLoS [u.a.], Lawrence, Kan.

To explore the hematologic risk factors for stroke in a cohort of Saudi children.We evaluated children at the Division of Pediatric Neurology at King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, during the periods July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). Investigations for suspected cases included neuroimaging, transcranial Doppler (TCD) for cases of sickle cell disease (SCD), and Duplex scan. Hemostatic assays included coagulation screening tests, tests of thrombin generation and fibrinolysis, coagulation inhibitors, and activated protein C resistance.During the study period, 104 Saudi children (aged one month to 12 years) with stroke were seen. The mean age of the cohort was 27.1 months (SD = 39.3 months) and median was 6 months. Ischemic strokes accounted for the majority of cases (76%). A major risk factor was identified in 93 of 104 cases of stroke (89.4%). Hematologic disorders were the most common (46.2%), followed by prothrombic disorders (31.7%); microcytic hypochromic anemia (26%); sickle cell disease (SCD), or SCbeta(0)-thalassemia, (11.5%), and factor IX deficiency (2.9%). Raised anticardiolipin antibodies (13/49, 26.5%) was the most frequent abnormality. Deficiencies of the natural anticoagulants (protein S, protein C and antithrombin III) were as follows: protein S (15/70, 21.4%); protein C (15/70, 21.4%) and combined deficiency of 2 or more inhibitors (9/70, 12.9%). Activated protein C resistance has not been detected. Contrary to the findings of previous studies from Saudi Arabia, SCD is a common risk factor and is severe, as it resulted in multiple strokes. Moyamoya syndrome was diagnosed in 2 patients with SCD, one of whom had revascularization surgery (encephaloduroarteriosynangiosis). Assessment of children with SCD at risk of stroke was helped by the introduction of TCD followed by neuroimaging, using MRI and magnetic resonance angiography.The study strongly highlights the importance of prothrombotic disorders and the severe phenotype of SCD as risk factors for stroke in Saudi children.

To report on the role of infectious and inflammatory disorders as risk factors for stroke in a prospective and retrospective cohort of Saudi children.Children, who presented with stroke, were evaluated at the Division of Pediatric Neurology or admitted to King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia during the periods July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). Investigations for suspected cases included hemostatic assays, microbiological and serological tests. Neuroimaging included cranial CT, MRI, magnetic resonance angiography (MRA), magnetic resonance venography (MRV) and single photon emission computed tomography (SPECT) brain scan.Of the 104 Saudi children with stroke, seen during the combined study periods of 10 years and 7 months, infectious and inflammatory disorders of the circulatory system were the identified risk factor in 18 (17.3%). Five children had stroke following acute bacterial meningitis at ages ranging between 5-21 months. The causative organism was identified in 3 of them and consisted of Haemophilus influenzae (in a 5-month-old girl), Streptococcus pneumoniae (in a 21-month-old girl complicated by subdural empyema and sinovenous thrombosis), and Staphylococcus aureus in a 6-month-old boy who had an underlying chronic granulomatous disease. Unspecified meningitis/meningoencephalitis affected 4 patients, whereas 3 children had an underlying congenital infection as a cause for their stroke. Two of the latter 3 children were diagnosed to have congenital toxoplasmosis, and the third had congenital rubella syndrome. Two girls had stroke following septicemia at ages of one and 2 months. Neurobrucellosis caused stroke in 2 boys at the ages of 4 1/2 and 4 years. In both patients, neuroimaging revealed lacunar and other infarcts involving mainly the deep cerebral nuclei, secondary to occlusion of small penetrating end arteries. Two patients presented with cerebrovascular disease following systemic lupus erythematosus. These were a 12-year-old girl and a 5-year-old boy.Several of the infectious diseases that caused stroke in this cohort of Saudi children are potentially preventable through childhood immunization programs or other maternity health programs. In particular, immunogenic conjugate vaccines against the 3 most common organisms causing acute bacterial meningitis (Haemophilus influenzae type b, Neisseria meningitidis and defined serotypes of Streptococcus pneumoniae) are needed to protect the young (2 years) who are mostly affected.

To explore the role of and report on congenital and genetic cerebrovascular anomalies as risk factors for stroke in a prospective and retrospective cohort of Saudi children.Children with stroke were evaluated at the Division of Pediatric Neurology (DPN), or were seen as inpatients in the Pediatric Wards at King Khalid University Hospital (KKUH), Riyadh, Kingdom of Saudi Arabia during the periods July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). Stroke work-up for each suspected case included hemostatic assays, serological, biochemical and neurophysiological tests. Neuroimaging modalities included routine skull x-rays, CT, MRI, magnetic resonance angiography (MRA) and conventional cerebral angiography.Of 104 children with stroke, congenital and genetic cerebrovascular anomalies were the underlying risk factor in 7 (6.7%). The patients were evaluated at the DPN at a mean age of 66 months (range = 8 months to 11 years, median = 6 years); and they had stroke at a mean age of 48 months (range = 2 months to 10 years, median = 8 months). Four patients had stroke in association with neurocutaneous syndromes. Two had Sturge-Weber syndrome (SWS), one had Klippel-Trenaunay syndrome associated with SWS, and the fourth had neurofibromatosis type 1. Two patients had intracranial hemorrhage secondary to ruptured aneurysm. A girl (aged 9 years and 4 months) had left posterior cerebral artery aneurysm. She was diagnosed to have autosomal dominant polycystic kidney disease following renal ultrasonography. She died 5 months later despite surgical intervention (clipping of aneurysm). The second child was an 8-month-old boy who presented with subarachnoid and intraventricular hemorrhage (IVH) following ruptured anterior communicating artery aneurysm. He recovered with no residual symptoms following successful clipping of the aneurysm. Arteriovenous malformation (AVM) caused IVH in a 7-year-old boy who reported to hospital 5 hours after onset of headache, vomiting, drowsiness, and dizziness. Following drainage of the IVH and stabilization of the patient, the AVM was successfully embolized 6 weeks later.As a group, congenital and genetic cerebrovascular anomalies constitute a significant risk factor for stroke in Saudi children. Recognition of these diseases is important since some are treatable and because other family members may be at risk.

To describe the epidemiology and clinical features of stroke in a prospective and retrospective cohort of Saudi children and ascertain the causes, pathogenesis, and risk factors.The Retrospective Study Group (RSG) included children with stroke who were evaluated at the Division of Pediatric Neurology, or admitted to King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia during the period July 1992 to February 2001. The Prospective Study Group (PSG) included those seen between February 2001 and March 2003.During the combined study periods of 10 years and 7 months, 117 children (61 males and 56 females, aged one month-12 years) were evaluated; the majority (89%) of these were Saudis. The calculated annual hospital frequency rate of stroke was 27.1/100,000 of the pediatric (1 month-12 years) population. The mean age at onset of the initial stroke in the 104 Saudi children was 27.1 months (SD = 39.3 months) and median was 6 months. Ischemic strokes accounted for the majority of cases (76%). Large-vessel infarcts (LVI, 51.9%) were more common than small-vessel lacunar lesions (SVLL, 19.2%). Five patients (4.8%) had combined LVI and SVLL. Intracranial hemorrhage was less common (18.2%), whereas sinovenous thrombosis was diagnosed in 6 (5.8%) patients. A major risk factor was identified in 94 of 104 (89.4%) Saudi children. Significantly more hematologic disorders and coagulopathies were identified in the PSG compared to the RSG (p=0.001), reflecting a better yield following introduction of more comprehensive hematologic and coagulation laboratory tests during the prospective study period. Hematologic disorders were the most common risk factor (46.2%), presumed perinatal ischemic cerebral injury was a risk factor in 23 children (22.1%) and infectious and inflammatory disorders of the circulatory system in 18 (17.3%). Congenital and genetic cerebrovascular anomalies were the underlying cause in 7 patients (6.7%) and cardiac diseases in 6 (5.8%). Six patients (5.8%) had moyamoya syndrome, which was associated with another disease in all of them. Inherited metabolic disorders (3.8%) included 3 children with Leigh syndrome and a 29-month-old girl with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Systemic vascular disease was a risk factor in 3 children (2.9%) including 2 who had hypernatremic dehydration; and post-traumatic arterial dissection was causative in 3 cases (2.9%). Several patients had multiple risk factors, whereas no risk factor could be identified in 11 (10.6%).Due to the high prevalence and importance of multiple risk factors, a comprehensive investigation, including hematologic, neuroimaging and metabolic studies should be considered in every child with stroke.

To report on the prognosis, neurologic outcome, and recurrences of stroke in Saudi children.We evaluated a cohort of 104 Saudi children with stroke at the Division of Pediatric Neurology at King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia from July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). We analyzed the salient clinical, neuroimaging, neurophysiological, neuropsychological and laboratory data following retrieval from a specialty designed comprehensive protocol.Of the 104 children in the cohort (aged one month to 12 years), 5 (4.8%) died during the study period and 9 (8.7%) were lost to follow-up. The mean duration of follow-up for the remaining 90 children was 40 months (median 33 months). Recovery was judged complete in 6 (6.7%) of these 90 children. We detected residual hemiparesis (irrespective of its effect on daily functions) in 73 (81%) and this was combined with other motor deficits in 45 children (50%). Forty-one children (46%) had residual dysphasia or language deficits, whereas 45 (50%) were judged to have had cognitive deficit. Psychometry revealed an abnormal intelligence quotient test (70) in 19 of 26 (73%) children. Other neurologic sequelae included epilepsy in 52 (58%), recurrent headaches in 13 (14%) and hydrocephalus in 4 (4.4%) patients. Six of the 95 (6.3%) children, who were ascertained to have died or kept their follow-up, had one or more recurrences, one month to 5 years after the initial stroke (median 23 months). Patients who had recurrent strokes were significantly more likely to be the product of consanguineous marriages (p=0.04). Regarding the group of 23 children with perinatal stroke, neither deaths nor recurrences occurred during the follow-up period. However, 20 (87%) of them had significant delays in their developmental milestones.The toll of stroke in Saudi children is demanding, with most children demonstrating persistent neurologic or cognitive deficits. Primary prevention for recurrences is feasible through informed genetic counseling.

To report on moyamoya syndrome (MMS) as a risk factor for stroke in a prospective and retrospective cohort of Saudi children. The usual and novel associations of MMS in this cohort will also be described.Children with stroke were evaluated at the Division of Pediatric Neurology at King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia during the periods July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). Investigations for suspected cases included hemostatic assays, biochemical, and serological tests. Neuroimaging included CT, MRI, magnetic resonance angiography (MRA), single photon computerized tomography (SPECT) brain scan and conventional cerebral angiography.Moyamoya syndrome was the underlying risk factor for stroke in 6 (5.8%) of the 104 children (aged one month to 12 years). They were 4 females and 2 males. Their first cerebral ischemic event occurred at a mean age of 45 months (median = 44 months, range 17-66 months). In all 6 cases, MMS was associated with an underlying hematologic abnormality or other diseases. Protein C deficiency was identified in one girl and protein S deficiency in another. Two patients had respectively, sickle cell disease (SCD) and sickle cell-beta-thalassemia (S beta-thalassemia), which had been associated in the latter with membranous ventricular septal defect. Adams-Oliver syndrome (AOS, OMIM 100300) was associated with MMS in an 18-month-old girl. A 4-year-old boy had wrinkly skin syndrome (WSS, OMIM 278250) phenotype. The association of MMS and protein C deficiency was first reported in this cohort of patients, whereas the association of the syndrome with WWS and AOS has not, hitherto, been described. The 3 patients who had MMS associated with protein C deficiency, SCD, and AOS underwent successful revascularization surgery in the form of encephaloduroarteriosynangiosis.Moyamoya syndrome constitutes an important risk factor of stroke in Saudi children. Comprehensive clinical evaluation and investigations, including screening for thrombophilia and neuroimaging studies, are required for the primary diagnosis of the disease and for unraveling other diseases associated with MMS. This will help in managing these patients and in guiding genetic counseling for their families.