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1.
Clin Genet ; 95(2): 310-319, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30561787

RESUMO

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.

2.
Genet Med ; 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30237576

RESUMO

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.

4.
Paediatr Int Child Health ; 37(3): 222-226, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27329512

RESUMO

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.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Encefalite Antirreceptor de N-Metil-D-Aspartato/patologia , Autoanticorpos/sangue , Encéfalo/diagnóstico por imagem , Receptores de N-Metil-D-Aspartato/imunologia , Corticosteroides/uso terapêutico , Encefalite Antirreceptor de N-Metil-D-Aspartato/tratamento farmacológico , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lactente , Imagem por Ressonância Magnética , Rituximab/uso terapêutico , Resultado do Tratamento
5.
Sudan J Paediatr ; 16(2): 86-92, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28096564

RESUMO

Sturge-Weber Syndrome (SWS) is a rare, sporadic neurocutaneous disorder. It is typically characterized by unilateral, posterior leptomeningeal angiomas that calcify, glaucoma, and facial portwine tains. Klippel-Trenaunay syndrome (KTS) is a rare congenital syndrome characterized by ipsilateral cutaneous capillary malformations, venous varicosities, and bony or soft tissue overgrowth of the affected limbs. The clinical, neuroradiological features as well as the outcome of a Saudi boy who was referred to the Division of Pediatric Neurology, King Saud University Medical City, Riyadh, Saudi Arabia, with intractable focal seizure and left-sided hemiparesis who was eventually diagnosed with combined SWS and KTS is described here. The rare coexistence of SWS and KTS should be suspected in a child presenting with neurological manifestation such as epilepsy, mental sub normality, or hemiparesis, with port-wine staining or capillary hemangioma and enlarged limbs. Awareness may help in improving the quality of life and survival of these patients.

6.
J Med Genet ; 52(6): 400-4, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25748484

RESUMO

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.


Assuntos
Facies , Síndrome de Klippel-Feil/diagnóstico , Síndrome de Klippel-Feil/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Mutação , Miosinas/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Criança , Mapeamento Cromossômico , Consanguinidade , Análise Mutacional de DNA , Feminino , Homozigoto , Humanos , Masculino , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Linhagem , Fenótipo , Coluna Vertebral/patologia , Síndrome
7.
Cell Rep ; 10(2): 148-61, 2015 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-25558065

RESUMO

Our 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.


Assuntos
Doenças do Sistema Nervoso Central/genética , Estudos de Associação Genética , Doenças do Sistema Nervoso Central/patologia , Mapeamento Cromossômico , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
8.
Genet Med ; 17(9): 719-25, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25503496

RESUMO

PURPOSE: 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. METHODS: We have reviewed the data of 584 patients with neurocognitive phenotypes (mainly referred from pediatric neurology clinics), all evaluated by a single clinical geneticist. RESULTS: 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. CONCLUSION: Our study confirms the clinical utility of molecular karyotyping even in highly consanguineous populations.


Assuntos
Transtornos Cromossômicos/genética , Consanguinidade , Transtornos Neurocognitivos/genética , Adolescente , Adulto , Criança , Aberrações Cromossômicas , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/epidemiologia , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/genética , Cariotipagem/métodos , Masculino , Transtornos Neurocognitivos/diagnóstico , Transtornos Neurocognitivos/epidemiologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Arábia Saudita/epidemiologia , Adulto Jovem
9.
J Med Genet ; 51(4): 224-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24399846

RESUMO

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.


Assuntos
Subunidades alfa do Complexo de Proteínas Adaptadoras/genética , Proteínas de Membrana/genética , Mutação/genética , Espasmos Infantis/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Análise Mutacional de DNA , Família , Evolução Fatal , Feminino , Loci Gênicos/genética , Homozigoto , Humanos , Lactente , Masculino , Camundongos , Linhagem
10.
Sudan J Paediatr ; 14(2): 61-70, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-27493406

RESUMO

The term hypomelanosis of Ito (HI) is applied to individuals with skin hypopigmentation along the lines of Blaschko. Although it was originally described as a purely cutaneous disease, subsequent studies describing HI reported a 33% to 94% association with multiple extracutaneous manifestations, mostly of the central nervous and musculoskeletal systems. This leads to characterization of HI as a neurocutaneous disorder. We report a 10-year-old boy who presented with constellation of multiple congenital anomalies including facial dysmorphism, skin hypopigmentation, musculoskeletal, and nervous system abnormalities. The latter manifested as hypotonia, generalized seizures, and mild mental retardation. Cranial magnetic resonance imaging revealed normal finding initially, however; follow-up diffusion weighted images were suggestive of a possible iron accumulation. The facial phenotype coupled with the bilateral globus pallidi lesions were never been reported in association with HI. Thus, our patient represents a possible novel example of HI.

11.
PLoS One ; 8(10): e76831, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24130795

RESUMO

Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.


Assuntos
Fosfolipases A2 do Grupo VI/genética , Mutação , Fenótipo , Adolescente , Adulto , Árabes , Criança , Pré-Escolar , Consanguinidade , Eletroencefalografia , Potenciais Evocados Visuais/genética , Feminino , Seguimentos , Genótipo , Humanos , Lactente , Masculino , Músculos/patologia , Músculos/fisiopatologia , Condução Nervosa/genética , Distrofias Neuroaxonais/etnologia , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/patologia , Distrofias Neuroaxonais/fisiopatologia , Neuroimagem , Linhagem , Adulto Jovem
12.
Ophthalmic Genet ; 34(4): 249-53, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23406309

RESUMO

BACKGROUND: To carefully assess the phenotype and genotype of a patient with partial mosaic trisomy 8 with particular attention to ophthalmologic features. METHODS: Ophthalmologic and neuro-ophthalmologic examination; neuroimaging; conventional karyotyping; and array comparative genomic hybridization (CGH). RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Agenesia do Corpo Caloso/diagnóstico , Esotropia/diagnóstico , Mosaicismo , Trissomia/diagnóstico , Agenesia do Corpo Caloso/genética , Cromossomos Humanos Par 8/genética , Hibridização Genômica Comparativa , Esotropia/genética , Feminino , Genótipo , Humanos , Lactente , Cariotipagem , Imagem por Ressonância Magnética , Linhagem , Fenótipo , Trissomia/genética
13.
Saudi Med J ; 27 Suppl 1: S12-20, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16532126

RESUMO

OBJECTIVES: 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. METHODS: 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. RESULTS: 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%). CONCLUSION: 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.


Assuntos
Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Arábia Saudita/epidemiologia , Acidente Vascular Cerebral/etiologia
14.
Saudi Med J ; 27 Suppl 1: S21-34, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16532128

RESUMO

OBJECTIVE: To explore the hematologic risk factors for stroke in a cohort of Saudi children. METHODS: 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. RESULTS: 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. CONCLUSIONS: The study strongly highlights the importance of prothrombotic disorders and the severe phenotype of SCD as risk factors for stroke in Saudi children.


Assuntos
Doenças Hematológicas/complicações , Acidente Vascular Cerebral/etiologia , Criança , Pré-Escolar , Feminino , Doenças Hematológicas/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Arábia Saudita/epidemiologia , Acidente Vascular Cerebral/epidemiologia
15.
Saudi Med J ; 27 Suppl 1: S35-40, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16532129

RESUMO

OBJECTIVES: To describe the clinical features and presentations of perinatal stroke in a prospective and retrospective cohort of Saudi children and ascertain the risk factors. METHODS: Patients with perinatal stroke were identified from within a cohort of 104 Saudi children who were evaluated 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). Neuroimaging for suspected cases of stroke consisted of cranial CT, MRI, or both. RESULTS: During the study period, 23 (22%) of 104 children (aged one month to 12 years) were diagnosed to have had perinatal stroke. The male:female ratio was 1.6:1. Ten (67%) of the 15 children who had unilateral ischemic involvement had their lesion in the left hemisphere. The presentation of the ischemic result was within 24-72 hours of life in 13 (57%) patients, and in 6 children (26%), motor impairment was recognized at or after the age of 4 months. Nine children (39%) had seizures at presentation. Pregnancy, labour, and delivery risk factors were ascertained in 18 (78%) cases. The most common of these included emergency cesarean section in 5 cases, and instrumental delivery in another 5. Screening for prothrombotic risk factors detected abnormalities in 6 (26%) patients on at least one test carried out between 2 months and 9 years of age. Four children (17%) had low protein C, which was associated with low protein S and raised anticardiolipin antibodies (ACA) in one patient, and low antithrombin III in another. Low protein S was detected in a 42-month-old boy. The abnormality in the sixth child was confined to raised ACA. CONCLUSIONS: The present study highlights the non-specific features by which stroke presents during the neonatal period. The data are in keeping with the potential role for inherited and acquired thrombophilia as being the underlying cause. However, the high prevalence of additional acquired antenatal and perinatal risk factors support a multifactorial disorder.


Assuntos
Complicações na Gravidez/diagnóstico , Complicações na Gravidez/etiologia , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Arábia Saudita
16.
Saudi Med J ; 27 Suppl 1: S41-52, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16532131

RESUMO

OBJECTIVE: To report on the role of infectious and inflammatory disorders as risk factors for stroke in a prospective and retrospective cohort of Saudi children. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Acidente Vascular Cerebral/etiologia , Infecções Bacterianas/complicações , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Lúpus Eritematoso Sistêmico/complicações , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Síndrome da Rubéola Congênita/complicações , Arábia Saudita , Toxoplasmose Congênita/complicações
17.
Saudi Med J ; 27 Suppl 1: S53-60, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16532132

RESUMO

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Anormalidades Congênitas/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Arábia Saudita/epidemiologia , Acidente Vascular Cerebral/etiologia
18.
Saudi Med J ; 27 Suppl 1: S61-8, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16532133

RESUMO

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


Assuntos
Cardiomiopatia Restritiva/complicações , Cardiopatias Congênitas/complicações , Acidente Vascular Cerebral/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Arábia Saudita
19.
Saudi Med J ; 27 Suppl 1: S69-80, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16532134

RESUMO

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Doença de Moyamoya/complicações , Acidente Vascular Cerebral/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Arábia Saudita
20.
Saudi Med J ; 27 Suppl 1: S91-6, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16532136

RESUMO

OBJECTIVE: To report on the prognosis, neurologic outcome, and recurrences of stroke in Saudi children. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Deficiências do Desenvolvimento/fisiopatologia , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Arábia Saudita/epidemiologia , Acidente Vascular Cerebral/mortalidade
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