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Acid ceramidase deficiency is an orphan lysosomal disorder caused by ASAH1 pathogenic variants and presenting with either Farber disease or spinal muscle atrophy with progressive myoclonic epilepsy (SMA-PME). Phenotypic and genotypic features are rarely explored beyond the scope of case reports. Furthermore, the new biomarker C26-Ceramide requires validation in a clinical setting. We evaluated the clinical, biomarker and genetic spectrum of 15 Egyptian children from 14 unrelated families with biallelic pathogenic variants in ASAH1 (12 Farber and 3 SMA-PME). Recruited children were nine females/six males ranging in age at diagnosis from 13 to 118 months. We detected ASAH1 pathogenic variants in all 30 alleles including three novel variants (c.1126A>G (p.Thr376Ala), c.1205G>A (p.Arg402Gln), exon-5-deletion). Both total C26-Ceramide and its trans- isomer showed 100% sensitivity for the detection of ASAH1-related disorders in tested patients. A 10-year-old girl with the novel variant c.1205G>A (p.Arg402Gln) presented with a new peculiar phenotype of PME without muscle atrophy. We expanded the phenotypic spectrum of ASAH1-related disorders and validated the biomarker C26-Ceramide for supporting diagnosis in symptomatic patients.
Asunto(s)
Ceramidasa Ácida/genética , Miopatías Distales/genética , Lipogranulomatosis de Farber/complicaciones , Epilepsias Mioclónicas Progresivas/genética , Mioclonía/congénito , Preescolar , Miopatías Distales/complicaciones , Miopatías Distales/patología , Exones/genética , Lipogranulomatosis de Farber/genética , Lipogranulomatosis de Farber/patología , Femenino , Humanos , Lactante , Masculino , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patología , Mutación/genética , Epilepsias Mioclónicas Progresivas/complicaciones , Epilepsias Mioclónicas Progresivas/patología , Mioclonía/complicaciones , Mioclonía/genética , Mioclonía/patología , FenotipoRESUMEN
Introduction Guillain-Barré syndrome (GBS) is an autoimmune peripheral neuropathy characterized by demyelination and axonal damage. Biallelic functional polymorphisms in the immunoglobulin G Fc receptors (FcγR)-FcγRIIA: H131/R131, FcγRIIIA: V158/F158, and FcγRIIIB: NA1/NA2 affect the affinity of the IgG-FcγR interaction, therefore, diseases such as GBS in which this interaction plays a critical role might be influenced by the polymorphisms. Methods We evaluated the role of FcγR polymorphisms in susceptibility to GBS in Egyptian pediatric patients and the association of the variant alleles with neurophysiological types, severity, and outcome of the disease. A total of 50 patients with GBS and 50 controls were examined for FcγR polymorphisms by allele-specific polymerase chain reaction. Results FcγRIIA H131 allele (p = < 0.0001; odds ratio [OR] = 4.78; 95% confidence interval [CI], 2.62-8.70) and FcγRIIA H/H131 genotype (p = < 0.0001 ; OR = 10.56; 95% CI, 3.59-31.06) were significantly increased in GBS patients while FcγRIIIA and FcγRIIIB allelic distributions were similar among patients and controls. The FcγR genotypes showed no association with neurophysiological types of GBS, severity or outcome of the disease. Conclusions These findings reflect that FcγRIIA H131 allele may represent a risk marker for susceptibility to GBS.
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Síndrome de Guillain-Barré/genética , Receptores de IgG/genética , Alelos , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Proteínas Ligadas a GPI/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lactante , Masculino , Reacción en Cadena de la Polimerasa , Polimorfismo GenéticoRESUMEN
BACKGROUND: The presented evidence-based clinical practice guideline (CPG) is proposed as a National CPG where we adapted the international recommendations for the emergency management of seizures in children beyond the neonatal period to suit the health care in Egypt. The quality of evidence and the strength of recommendations are indicated. This study aimed to standardize the treatment of acute epileptic seizures and to provide an easy-to-apply acute treatment protocol that will allow immediate and appropriate seizure control. METHODS: This is part of a larger program by the Egyptian Pediatric Clinical Practice Guidelines Committee (EPG) in collaboration with the staff of pediatric departments of 15 Egyptian universities and the National Research Centre. EPG was affiliated later to the Supreme Council of the Egyptian University Hospitals aiming to define the topics of, assign authors to, and assist in the adaptation of pediatric evidence-based CPGs according to a national strategic plan (http://epg.edu.eg). The committee is guided by a formal CPG adaptation methodology: the "Adapted ADAPTE." RESULTS: The Egyptian Childhood Seizure Group (ECSG) reviewed the results of the Appraisal of Guidelines for Research and Evaluation II assessment and decided to adapt the recommendations of three source CPGs: American Epilepsy Society, Italian League Against Epilepsy, Neurocritical Care Society, and Neurologic & Psychiatric Society of Zambia. Eight implementation tools were included. A comprehensive set of multifaceted CPG implementation strategies was provided for the clinicians, patients, nurses, and other relevant stakeholders contextualized to the national settings. CONCLUSIONS: Our experience with this adaptation methodology provides useful insight into its national utilization in Egypt.
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Convulsiones , Humanos , Convulsiones/terapia , Convulsiones/diagnóstico , Egipto , Guías de Práctica Clínica como Asunto/normas , Niño , Medicina Basada en la Evidencia/normas , Servicios Médicos de Urgencia/normasRESUMEN
BACKGROUND/OBJECTIVES: Ataxia telangiectasia (A-T) is a multiorgan disorder with increased vulnerability to cancer. Despite this increased cancer risk, there are no widely accepted guidelines for cancer surveillance in people affected by A-T. We aimed to understand the current international practice regarding cancer surveillance in A-T and agreed-upon approaches to develop cancer surveillance in A-T. DESIGN/METHODS: We used a consensus development method, the e-Delphi technique, comprising three rounds. Round 1 consisted of a Delphi questionnaire and a survey that collected the details of respondents' professional background, experience, and current practice of cancer surveillance in A-T. Rounds 2 and 3 were designed based on previous rounds and modified according to the comments made by the panellists. The pre-specified consensus threshold was ≥75% agreement. RESULTS: Thirty-five expert panellists from 13 countries completed the study. The survey indicated that the current practice of cancer surveillance varies widely between experts and centres'. Consensus was reached that evidence-based guidelines are needed for cancer surveillance in people with A-T, with separate recommendations for adults and children. Statements relating to the tests that should be included, the age for starting and stopping cancer surveillance and the optimal surveillance interval were also agreed upon, although in some areas, the consensus was that further research is needed. CONCLUSION: The international expert consensus statement confirms the need for evidence-based cancer surveillance guidelines in A-T, highlights key features that the guidelines should include, and identifies areas of uncertainty in the expert community. This elucidates current knowledge gaps and will inform the design of future clinical trials.
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Ataxia Telangiectasia , Neoplasias , Adulto , Niño , Humanos , Ataxia Telangiectasia/complicaciones , Ataxia Telangiectasia/diagnóstico , Consenso , Técnica Delphi , Encuestas y CuestionariosRESUMEN
Metachromatic leukodystrophy (MLD) is a neurodegenerative disorder characterized by progressive demyelination due to deficiency of the enzyme arylsulfatase A (ARSA) in leukocytes, and consequently leads to impaired degradation and accumulation of cerebroside-3-sulfate (sulfatide). This study aimed to sequence the ARSA gene in a total of 43 patients with metachromatic leukodystrophy descendant from 40 Egyptian families. In addition, four carrier parents from two families with children who had died from MLD came to the clinic for genetic analysis. Prenatal diagnosis was performed for four families with molecularly diagnosed MLD sibs. Different mutations were characterized in our cohort, including missense, nonsense, splice, and deletion. Overall, 21 different mutations in the ARSA gene were detected, with 12 novel mutations, i.e. p.Arg60Pro, p.Tyr65*, p.Val112Asp, p.Arg116*, p.Gly124Asp, p.Pro193Ser, p.Gln238*, p.Gln456*, p.Thr276Lys, and p.Gly311Arg, in addition to two new acceptor splice-site mutations 685-1G > A and c.954_956 delCTT. The amniotic fluid samples revealed two carrier fetuses with heterozygous monoallelic mutations, and two affected fetuses had the homozygous biallelic mutations. In conclusion, the current study sheds light on the underlying ARSA gene defect, with an expansion of the mutation spectrum. To our knowledge, this is the first molecular study of MLD among the Egyptian population.
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Cerebrósido Sulfatasa/genética , Leucodistrofia Metacromática/genética , Fenotipo , Niño , Preescolar , Humanos , Lactante , Leucodistrofia Metacromática/metabolismo , Leucodistrofia Metacromática/patología , MutaciónRESUMEN
Galactose is a hexose essential for production of energy, which has a prebiotic role and is essential for galactosylation of endogenous and exogenous proteins, ceramides, myelin sheath metabolism and others. The inability to metabolize galactose results in galactosemia. Galactosemia is an autosomal recessive disorder that affects newborns who are born asymptomatic, apparently well and healthy, then develop serious morbidity and mortality upon consuming milk that contains galactose. Those with galactosemia have a deficiency of an enzyme: classic galactosemia (type 1) results from severe deficiency of galactose-1-uridylyltransferase, while galactosemia type II results from galactokinase deficiency and type III results from galactose epimerase deficiency. Many countries include neonatal screening for galactosemia in their national newborn screening program; however, others do not, as the condition is rather rare, with an incidence of 1:30,000-1:100,000, and screening may be seen as not cost-effective and logistically demanding. Early detection and intervention by restricting galactose is not curative but is very rewarding, as it prevents deaths, mental retardation, liver cell failure, renal tubular acidosis and neurological sequelae, and may lead to resolution of cataract formation. Hence, national newborn screening for galactosemia prevents serious potential life-long suffering, morbidity and mortality. Recent advances in communication and biotechnology promise facilitation of logistics of neonatal screening, including improved cost-effectiveness.
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Classic galactosemia is caused by deficiency of galactose-1-phosphate uridylyltransferase (GALT). It causes serious morbidity and mortality if left untreated. Screening for galactosemia is not included in Egyptian neonatal screening program. The study aimed to define clinical presentation and complications of galactosemia at Pediatric Hepatology Clinic, Cairo University, Egypt. Thus, the clinical presentation, course and outcome of 37 children with documented galactosemia was studied. Jaundice was the main presentation (67.6%). Other presentations included; convulsions (29.7%), motor retardation (24.3%), mental retardation (5.4%), microcephaly (5.4%), failure to thrive (16.2%), hepatomegaly (62.2%), splenomegaly (35.1%), vomiting (16.2%), diarrhea (8.1%), liver cell failure (10.8%), renal tubular acidosis (5.4%), cataract (5.4%), autoimmune hepatitis (2.7%), self-mutilation (2.7%), combined immune deficiency (2.7%) and kernicterus (2.7%). There was no correlation of residual enzyme activity to severity, clinical presentation, liver function tests, liver biopsy findings or outcome apart from highly significant correlation with repeated chest infections (Pâ¯=â¯0.001). Duration to diagnosis and exposure to galactose in diet correlated with liver pathology severity i.e. hepatocyte necrosis (Pâ¯=â¯0.003) and cytoskeleton damage (Pâ¯=â¯0.003), but not to outcome. Galactosemia should be suspected in any child with liver, neurologic disease and/or immunodeficiency. Its complications are potentially preventable. Early detection is mandatory to prevent serious morbidity and mortality. Initiation of neonatal screening for galactosemia in Egypt is recommended.
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Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding αN-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The αN-catenin paralog, αE-catenin, acts as a switch regulating the balance between ß-catenin and Arp2/3 actin filament activities1. Loss of αN-catenin did not affect ß-catenin signaling, but recombinant αN-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of αN-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons.
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Complejo 2-3 Proteico Relacionado con la Actina/genética , Movimiento Celular/genética , Corteza Cerebral/fisiología , Neuronas/patología , alfa Catenina/genética , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Animales , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Embrión de Mamíferos , Genoma Humano , Humanos , Ratones , Ratones Endogámicos C57BL , Mutación , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Linaje , alfa Catenina/metabolismoRESUMEN
BACKGROUND: Rett syndrome (RTT) is an X-linked dominant neurodegenerative disorder with various MECP2 mutations. RTT is one of the most common causes of severe intellectual and complex disability in girls. Therefore, the aims of the study were as follows: to highlight the clinical manifestations of RTT; to present the genotype-phenotype relationship; and to assess the possible relation between severity score, clinical manifestations, and MECP2 gene mutations. PATIENTS AND METHODS: The present cross-sectional study included 15 girls with typical RTT, diagnosed according to the international criteria of RTT. All included patients were followed up at the pediatric neurology clinic, Cairo University Specialized Pediatric Hospital. They were subjected to screening of the entire coding region of the MECP2 gene (MECP2A and MECP2B) using denaturing high-performance liquid chromatography. The clinical severity was assessed among RTT cases using the International Scoring System. RESULTS: Stereotypic hand movements were present in all cases, acquired microcephaly was present in 73.3% of cases, autistic features in 66.7% of cases, recurrent seizures in 53.3% of cases, delayed language development in 46.6% of cases, deterioration of speech in 53.3% of cases, and growth retardation and peripheral vasomotor changes in 46.6% of cases. Positive mutations were detected in 10 cases (66.66%): heterozygous for p.R270X mutation (three cases), heterozygous for p.R255X mutation (three cases), and heterozygous for p.R168X nonsense mutation (four cases). Microcephaly, seizures, growth retardation, and autistic features were more frequent in patients with a mutated gene; it was also observed that walking ability was more frequent in patients without a mutation.; thus, genotype-phenotype relationship was confirmed. The relationship between severity score and MECP2 mutation was detected in three cases with severe RTT, but there was no relationship between the severity score and specific MECP2 mutation. There was a relationship between the severity score and the clinical manifestations of RTT. CONCLUSION: Mutations of MECP2 analysis were detected in 66.7% of RTT cases. There were relationships between the severity score, clinical manifestations, and MECP2 gene mutations. However, there was no relationship between the severity score and specific MECP2 gene mutation.
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Proteína 2 de Unión a Metil-CpG/genética , Mutación/genética , Síndrome de Rett/genética , Preescolar , Cromatografía Líquida de Alta Presión , Estudios Transversales , Cartilla de ADN , Egipto , Femenino , Genotipo , Hospitales Pediátricos , Humanos , Lactante , Fenotipo , Reacción en Cadena de la Polimerasa , Síndrome de Rett/sangre , Síndrome de Rett/complicaciones , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy of childhood. It leads to progressive deterioration in cardiac and skeletal muscles. Corticosteroids are considered an effective therapy. OBJECTIVE: This study aimed to evaluate the role of short-term prednisone therapy in improving left ventricular (LV) systolic function, LV mass (LVM), and motor power in cases of muscular dystrophies. PATIENTS AND METHODS: Twenty-five cases of muscular dystrophy including 17 cases of DMD, 3 cases of Becker muscular dystrophies, and 5 cases of female patients with DMD-like phenotype were included in the study. The diagnosis of 12 patients was confirmed by muscle biopsy with immunohistochemistry; the patients were subjected to motor assessment, measurement of creatine kinase level, and echocardiographic examination before and after prednisone therapy. Transthoracic echocardiographic assessment of the LV systolic function (fractional shortening) was done. Myocardial performance index and LVM were calculated. Intermittent dosage of prednisone was administered 5 mg/kg per day on 2 consecutive days weekly for 3 months. RESULTS: Fractional shortening improved on prednisone therapy (P = 0.009) and LVM increased (P = 0.012); improvement in walking was detected in 77% of the patients, climbing stairs improved in 88.9%, Gower sign improved in 70%, and rising from chair improved in 60%. Prednisone had no effect on the patients with marked motor impairment (on wheelchair). The creatine kinase level was significantly lower after steroid therapy (P = 0.04). CONCLUSIONS: Three months of intermittent prednisone therapy could improve cardiac and skeletal muscle function in congenital muscular dystrophy.
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Glucocorticoides/administración & dosificación , Músculo Esquelético/fisiología , Distrofias Musculares/tratamiento farmacológico , Prednisona/administración & dosificación , Función Ventricular Izquierda/fisiología , Caminata/fisiología , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/efectos de los fármacos , Distrofias Musculares/fisiopatología , Miocardio , Estudios Prospectivos , Factores de Tiempo , Resultado del Tratamiento , Ultrasonografía , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.
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Exoma/genética , Estudios de Asociación Genética , Enfermedad de la Neurona Motora/genética , Neuronas/metabolismo , Tractos Piramidales/metabolismo , Paraplejía Espástica Hereditaria/genética , Animales , Axones/fisiología , Transporte Biológico/genética , Estudios de Cohortes , Redes Reguladoras de Genes , Humanos , Mutación , Nucleótidos/genética , Nucleótidos/metabolismo , Análisis de Secuencia de ADN , Sinapsis/fisiología , Transcriptoma , Pez CebraRESUMEN
The translation of "next-generation" sequencing directly to the clinic is still being assessed but has the potential for genetic diseases to reduce costs, advance accuracy, and point to unsuspected yet treatable conditions. To study its capability in the clinic, we performed whole-exome sequencing in 118 probands with a diagnosis of a pediatric-onset neurodevelopmental disease in which most known causes had been excluded. Twenty-two genes not previously identified as disease-causing were identified in this study (19% of cohort), further establishing exome sequencing as a useful tool for gene discovery. New genes identified included EXOC8 in Joubert syndrome and GFM2 in a patient with microcephaly, simplified gyral pattern, and insulin-dependent diabetes. Exome sequencing uncovered 10 probands (8% of cohort) with mutations in genes known to cause a disease different from the initial diagnosis. Upon further medical evaluation, these mutations were found to account for each proband's disease, leading to a change in diagnosis, some of which led to changes in patient management. Our data provide proof of principle that genomic strategies are useful in clarifying diagnosis in a proportion of patients with neurodevelopmental disorders.