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BACKGROUND: Lysosomal storage diseases (LSDs), a group of inborn errors of metabolism, include various subtypes, for example, mucopolysaccharidosis (MPS) and Gaucher disease (GD). Besides the physical/mental disabilities, they suffer from several oral deteriorations. AIM: To evaluate the oral health status of Egyptian children with LSD. DESIGN: Thirty LSD children and thirty non-LSD children were enrolled for this study according to the inclusion and exclusion criteria. Dental indices were used to assess caries prevalence and periodontal status. Saliva samples were collected from all enrolled children to estimate interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and protein levels as well as Streptococcus mutans and Lactobacilli colony counts. RESULTS: Children with MPS and GD showed non-significant differences in decayed, missing, or filled teeth (DMFT) scores (p = .115). Scores of dmft showed a significant increase in MPS, but not in GD children (p = .020, p = .127). Children with LSD showed significantly increased Modified Gingival Index (MGI), Plaque Index (PI), Oral Hygiene Index (OHI-s) scores (p < .001) and salivary IL-6 and TNF-α (p = .007, p = .001, p < .0001, p = .002, respectively) and salivary total proteins (p = .001) levels. Unexpectedly, non-significant differences were observed in salivary Streptococcus mutans or Lactobacilli counts in children with MPS and GD (p = .058, p = .420, p = .502, p = .053, respectively). CONCLUSION: To our knowledge, this is the first article that evaluates Egyptian children with LSD. We demonstrated high caries prevalence in primary teeth, not permanent teeth, in children with MPS and poor gingival/hygiene status in children with MPS and GD, which triggered a state of inflammation. The daily supplement intake prevented oral bacterial growth. The most probable cause of oral alterations is decreased salivary flow rate, as deduced from a significantly increased salivary protein.
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Gaucher disease (GD) is the most common lysosomal storage disorder, the aim of the current study was to investigate hyperimmunoglobulinemia and abnormalities of serum immunoglobulin G (IgG) subclasses in children with GD and the relation of those findings to the GD phenotype and genotype, duration of enzyme replacement therapy (ERT), and infection frequency. The study included 20 Egyptian children with GD receiving ERT and 20 age-matched and sex-matched healthy children as controls. Serum Ig and serum IgG subclass levels were measured in the children with GD. Serum IgG subclass levels were measured in the control subjects. Hyperimmunoglobulinemia was present in 15 of the 20 (75%) children with GD. In addition, it is found significantly lower IgG2 levels and significantly higher IgG3 levels in the GD group than in the control group (P<0.001 and <0.006, respectively). Patients with 12 infections per year had significantly higher IgG3 levels compared with patients with 6 infections per year (P=0.022). In conclusion, hyperimmunoglobulinemia and IgG subclass abnormalities occur in children with GD who are on ERT and may be related to recurrent infections.
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Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/inmunología , Hipergammaglobulinemia/inmunología , Inmunoglobulina G/inmunología , Adolescente , Niño , Preescolar , Historia del Siglo XV , Humanos , Lactante , MasculinoRESUMEN
Anophthalmia or microphthalmia (A/M), characterized by absent or small eye, can be unilateral or bilateral and represent developmental anomalies due to the mutations in several genes. Recently, mutations in aldehyde dehydrogenase family 1, member A3 (ALDH1A3) also known as retinaldehyde dehydrogenase 3, have been reported to cause A/M. Here, we screened a cohort of 75 patients with A/M and showed that mutations in ALDH1A3 occurred in six families. Based on this series, we estimate that mutations in ALDH1A3 represent a major cause of A/M in consanguineous families, and may be responsible for approximately 10% of the cases. Screening of this gene should be performed in a first line of investigation, together with SOX2.
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Aldehído Oxidorreductasas/genética , Anoftalmos/genética , Consanguinidad , Microftalmía/genética , Mutación , Secuencia de Aminoácidos , Anoftalmos/enzimología , Anoftalmos/patología , Secuencia de Bases , Ojo/enzimología , Ojo/patología , Femenino , Genotipo , Humanos , Masculino , Microftalmía/enzimología , Microftalmía/patología , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Fenotipo , Alineación de SecuenciaRESUMEN
Waardenburg anophthalmia syndrome, also known as microphthalmia with limb anomalies, ophthalmoacromelic syndrome, and anophthalmia-syndactyly, is a rare autosomal-recessive developmental disorder that has been mapped to 10p11.23. Here we show that this disease is heterogeneous by reporting on a consanguineous family, not linked to the 10p11.23 locus, whose two affected children have a homozygous mutation in SMOC1. Knockdown experiments of the zebrafish smoc1 revealed that smoc1 is important in eye development and that it is expressed in many organs, including brain and somites.
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Mutación , Osteonectina/genética , Adulto , Secuencia de Bases , Niño , Consanguinidad , Ojo/crecimiento & desarrollo , Femenino , Dedos/diagnóstico por imagen , Dedos/crecimiento & desarrollo , Genes Recesivos , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Radiografía , Síndrome de Waardenburg/genéticaRESUMEN
PURPOSE: To report the clinical and genetic study of two families of Egyptian origin with clinical anophthalmia. To further determine the role of the retina and anterior neural fold homeobox gene (RAX) in anophthalmia and associated cerebral malformations. METHODS: Three patients with clinical anophthalmia and first-degree relatives from two consanguineous families of Egyptian origin underwent full ophthalmologic, general and neurologic examination, and blood tests. Cerebral magnetic resonance imaging (MRI) was performed in the index cases of both families. Genomic DNA was prepared from venous leukocytes, and direct sequencing of all the exons and intron-exon junctions of RAX was performed after PCR amplification. RESULTS: Clinical bilateral anophthalmia was observed in all three patients. General and neurologic examinations were normal; obesity and delay in psychomotor development were observed in the isolated case. Orbital MRI showed a hypoplastic orbit with present but rudimentary extraocular muscles and normal lacrimal glands. Cerebral MRI showed agenesis of the optic nerves, optic tracts, and optic chiasma. In the index case of family A, the absence of the frontal and sphenoidal sinuses was also noted. In the index case of family B, only the sphenoidal sinus was absent, and there was significant cortical atrophy. The three patients carried a novel homozygous c.543+3A>G mutation (IVS2+3A>G) in RAX. Parents were healthy heterozygous carriers. No mutations were detected in orthodenticle homeobox 2 (OTX2), ventral anterior homeobox 1 (VAX1), or sex determining region Y-box 2 (SOX2). CONCLUSIONS: This is the first report of a homozygous splicing RAX mutation associated with autosomal recessive bilateral anophthalmia. To our knowledge, only two isolated cases of anophthalmia, three null and one missense case affecting nuclear localization or the DNA-binding homeodomain, have been found to be caused by compound heterozygote RAX mutations. A novel missense RAX mutation was identified in three patients with bilateral anophthalmia and a distinct systemic and neurologic phenotype. The mutation potentially affects splicing of the last exon and is thought to result in a protein that has an aberrant homeodomain and no paired-tail domain. Functional consequences of this change still need to be characterized.
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Anoftalmos/genética , Corteza Cerebral/metabolismo , Proteínas del Ojo/genética , Proteínas de Homeodominio/genética , Mutación Missense , Órbita/metabolismo , Retina/metabolismo , Factores de Transcripción/genética , Anoftalmos/metabolismo , Anoftalmos/patología , Secuencia de Bases , Corteza Cerebral/patología , Niño , Consanguinidad , Egipto , Exones , Proteínas del Ojo/metabolismo , Femenino , Genes Recesivos , Proteínas de Homeodominio/metabolismo , Homocigoto , Humanos , Intrones , Masculino , Datos de Secuencia Molecular , Órbita/patología , Factores de Transcripción Otx/genética , Linaje , Retina/patología , Factores de Transcripción SOXB1/genética , Factores de Transcripción/metabolismoRESUMEN
PURPOSE: In patients diagnosed with diabetes mellitus (DM) before the age of 12 months, there is an increasing recognition of diabetes caused by single-gene mutations, also known as monogenic diabetes of infancy or neonatal DM (NDM). This study aimed to classify patients at Alexandria University Children's Hospital (AUCH) diagnosed with infantile-onset DM into type 1 DM (T1DM) or NDM and to detect differences in molecular characteristics of NDM patients at our center in comparison to other countries. METHODS: This retrospective/prospective observational study was conducted on 39 patients diagnosed with infantile-onset DM (age of onset ≤1 year) at AUCH from January 2003 to November 2020. The patients were divided into 2 groups according to age at the onset of DM: ≤6 months and >6-12 months. Molecular testing was done in patients diagnosed with DM at ≤6 months and those with negative autoantibodies. RESULTS: Twelve patients were diagnosed with DM at age ≤6 months and 27 patients were diagnosed between 6-12 months. Seventeen patients (43.6%) had T1DM, whereas 9 patients (23.1%) had genetically confirmed NDM, including 3 harboring novel mutations. The most common genetic causes of NDM were EIF2AK3 mutations (n=3), followed by KCNJ11 (n=2) and ABCC8 (n=2). Other mutations included SLC19A2 (n=1) and INS (n=1). Three patients with potassium ATP channel mutations were transferred from insulin to sulfonylurea treatment. CONCLUSION: It is essential to identify patients with NDM clinically and confirm the diagnosis by molecular testing to distinguish them from T1DM as it helps in refining their management, predicting prognosis, and guiding genetic counseling.
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To present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Within this cohort, the highest diagnostic yield was obtained for patients from Asia (57.5%, mainly from Pakistan). Overall, 701 pathogenic/likely pathogenic unique SNVs and 40 CNVs were identified. In 620 patients, the result of the biochemical tests guided variant classification and reporting. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We show that integrated genetic and biochemical testing facilitated the decision on clinical relevance of the variants and led to a high diagnostic yield (37%), which is comparable to exome/genome sequencing. More importantly, up to 43% of these patients (n = 610) could benefit from medical treatments (e.g., enzyme replacement therapy). This multiomic approach constitutes a unique and highly effective tool for the genetic diagnosis of IMDs.
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Variaciones en el Número de Copia de ADN , Enfermedades Metabólicas , Exoma , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Enfermedades Metabólicas/diagnóstico , Enfermedades Metabólicas/genética , Pakistán , Secuenciación del ExomaRESUMEN
Gaucher disease is the most prevalent inherited lysosomal storage disorder caused by deficiency of beta-glucocerebrosidase enzyme. Clinically, 3 forms of Gaucher disease are recognized, of which type 1 is the mild to moderately severe, slowly progressive, nonneuropathic form. Bleeding disorders in Gaucher disease are believed to be due to thrombocytopenia but there may be additional factors that influence coagulation and fibrinolysis in Gaucher disease patients. The aim of the present work was to study some coagulation parameters in the Egyptian children with type 1 Gaucher disease. Five newly diagnosed patients and another 5 patients on enzyme replacement therapy (ERT) were enrolled in the study. Their coagulation profile, including coagulation factors, was evaluated. The results showed that in newly diagnosed cases factors II and VII were deficient in 40%, factor V was deficient in 20%, and all the cases had low levels of serum fibrinogen. In patients on ERT, factors VII and VIII were deficient in 60%, factor XI was deficient in 40% and factors V, X, and XII were deficient in 20% of cases. In conclusion, Egyptian patients with type 1 Gaucher disease, whether newly diagnosed or receiving enzyme replacement therapy, experience coagulation factor abnormalities regardless the clinical expression of bleeding diathesis. This should be taken into consideration before these patients are subjected to surgery for, e.g., splenectomy, which is common in these patients.
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Trastornos de la Coagulación Sanguínea/etiología , Enfermedad de Gaucher/complicaciones , Trastornos de la Coagulación Sanguínea/sangre , Factores de Coagulación Sanguínea/análisis , Niño , Preescolar , Trastornos de las Proteínas de Coagulación , Egipto , Enfermedad de Gaucher/sangre , Glucosilceramidasa/deficiencia , Glucosilceramidasa/uso terapéutico , Hemorragia/etiología , Hemostasis , HumanosRESUMEN
Abstract Gaucher disease (GD) is an autosomal recessive lipid storage disorder, caused by deficient activity of the lysosomal enzyme b-glucocerebrosidase, resulting in accumulation of glucocerebroside in tissue macrophages. HGT-GCB-068 was an open-label study designed to explore the efficacy and safety of velaglucerase alfa in children and adolescents with type 3 GD, a neuronopathic form of the disease. Six treatment-naive patients received infusions of velaglucerase alfa every other week at 60 U/kg over 12 months. Velaglucerase alfa demonstrated a favorable tolerability profile, and 1 infusion-related reaction (headache) was the only drug-related adverse event reported. Numerical increases from baseline in hematological parameters and decreases in visceral parameters were seen at 12 months. http://ClinicalTrials.gov identifier NCT01685216.
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The aim of the study is to characterize markers of apoptosis in children with acute lymphoblastic leukemia (ALL) in relation to treatment outcome of the disease. The study was performed on 34 children with ALL and 39 healthy children as a control group. Apoptosis was assessed by cell morphology; DNA fragmentation; ELISA and RT-PCR for CD95, CD95L, BcL-2 and nuclear factor-kappa B (NF-kappaB); and flow cytometry for CD95, CD40, CD49d and CD11a. Apoptosis was significantly lower in patients than controls. Apoptosis detected by CD95 ligand was significantly lower in cases with no remission after treatment than those who achieved remission. Anti-apoptotic factors: CD40, BcL-2, and NF-kappaB were all found to be higher in cases than controls and in cases with no remission than those achieved remission. CD49d was significantly lower in cases than controls, and significantly lower in cases with who did not achieve remission. CD11a levels were similar in the various groups. Delayed apoptosis of ALL cells is genetically controlled either directly or indirectly by a network of oncogenes and tumor suppressor genes. CD40 appeared to stimulate both T and B lineage and is considered the most potent influencer and predictor of resistance to therapy. Inhibitors for the activity of CD40, Bcl-2 and NF-kappaB as well as stimulants to CD95 could have a potential therapeutic benefit.
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Apoptosis/genética , Proliferación Celular , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Valor Predictivo de las Pruebas , Biomarcadores/análisis , Antígenos CD40 , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Genes Supresores de Tumor , Humanos , Lactante , Masculino , Oncogenes , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , PronósticoRESUMEN
Thalassaemia is a group of inherited haemoglobin disorders characterized by reduced synthesis of one or more of the globin chains leading to imbalanced a /non-a globin synthesis which is the major factor in determining the severity of the disease in the thalassaemia syndromes. In Egypt, beta-thalassemia is the commonest cause of chronic haemolytic anaemia and it represents a major genetic disease and a public health problem. This study included 50 transfusion dependent beta-thalassaemic cases. They were subjected to detailed history taking, physical examination to assess the size of liver and spleen and laboratory investigations including complete haemogram, bone marrow (BM) aspiration, haemoglobin electrophoresis and serum ferritin. Genetic analysis for detection of point mutations was done by PCR amplification refractory mutation system (ARMS) which is a PCR method based on allele specific priming. Using this technology, it was possible to characterize mutations in 73% of beta-thalassaemia cases, while 27% remained uncharacterized. The five common mutations used were: IVS-1-110 (G-->A), IVS-1-6 (T-->C) IVS-I-1 (G-->T), IVS-II-1 (G-->A) and codon 39 (C-->T). The commonest was IVS-I-110 (62%) followed by IVS-1-6 (7%), then IVS-I-1 (4%). On the other hand mutations such as IVS-II-1 and Cd- 39 were not found in any of our patients. No significant difference was found between different genotypes regarding the frequency of blood transfusion needed, degree of anaemia and microcytosis, HbF% or serum ferritin levels. This may be due to the small sample size of some of the genotypes (IVS-I-110/IVS-I-1 & IVS-I-110/IVS-I-6) or due to repeated blood transfusions which mask the patient original CBC and Hb electrophoresis pattern or due to co-inheritance of other genetic modifying factors that alter the typical phenotype.