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Intellectual disabilities (ID) and autism spectrum disorders (ASD) have a variety of etiologies, including environmental and genetic factors. Our study reports a psychiatric clinical investigation and a molecular analysis using whole exome sequencing (WES) of two siblings with ID and ASD from a consanguineous family. Bioinformatic prediction and molecular docking analysis were also carried out. The two patients were diagnosed with profound intellectual disability, brain malformations such as cortical atrophy, acquired microcephaly, and autism level III. The neurological and neuropsychiatric examination revealed that P2 was more severely affected than P1, as he was unable to walk, presented with dysmorphic feature and exhibited self and hetero aggressive behaviors. The molecular investigations revealed a novel TRAPPC9 biallelic nonsense mutation (c.2920 C > T, p.R974X) in the two siblings. The more severely affected patient (P2) presented, along with the TRAPPC9 variant, a new missense mutation c.166 C > T (p.R56C) in the MID2 gene at hemizygous state, while his sister P1 was merely a carrier. The 3D modelling and molecular docking analysis revealed that c.166 C > T variant could affect the ability of MID2 binding to Astrin, leading to dysregulation of microtubule dynamics and causing morphological abnormalities in the brain. As our knowledge, the MID2 mutation (p.R56C) is the first one to be detected in Tunisia and causing phenotypic variability between the siblings. We extend the genetic and clinical spectrum of TRAPPC9 and MID2 mutations and highlights the possible concomitant presence of X-linked as well as autosomal recessive inheritance to causing ID, microcephaly, and autism.
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Discapacidad Intelectual , Simulación del Acoplamiento Molecular , Trastornos del Neurodesarrollo , Fenotipo , Niño , Preescolar , Femenino , Humanos , Masculino , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Secuenciación del Exoma , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Péptidos y Proteínas de Señalización Intercelular , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/química , Modelos Moleculares , Mutación , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Linaje , HermanosRESUMEN
Metachromatic leukodystrophy (MLD) is a severe metabolic disorder caused by the deficient activity of arylsulfatase A due to ARSA gene mutations. According to the age of onset, MLD is classified into three forms: infantile, juvenile, and adult. In our study, we aimed to perform a genetic analysis for two siblings with juvenile MLD for a better characterization of the molecular mechanisms behind the disease. A consanguineous family including two MLD patients (PII.1 and PII.2) was enrolled in our study. The diagnosis was made based on the clinical and neuroimaging investigations. The sequencing of ARSA gene was performed followed by in silico analysis. Besides, the cis/trans distribution of the variants was verified through a PCR-RFLP. The ARSA gene sequencing revealed three known variants, two exonic c.1055A > G and c.1178C > G and an intronic one (c.1524 + 95A > G) in the 3'UTR region. All variants were present at heterozygous state in the two siblings and their mother. The assessment of the cis/trans distribution showed the presence of these variants in cis within the mother, while PII.2 and PII.2 present the c.1055A > G/c.1524 + 95A > G and the c.1178C > G in trans. Additionally, PII.1 harbored a de novo novel missense variant c.1119G > T, whose pathogenicity was supported by our predictive results. Our genetic findings, supported by a clinical examination, confirmed the affection of the mother by the adult MLD. Our results proved the implication of the variable distribution of the found variants in the age of MLD onset. Besides, we described a variable severity between the two siblings due to the de novo pathogenic variant. In conclusion, we identified a complex genotype of ARSA variants within two MLD siblings with a variable severity due to a de novo variant present in one of them. Our results allowed the establishment of an adult MLD diagnosis and highlighted the importance of an assessment of the trans/cis distribution in the cases of complex genotypes.
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Leucodistrofia Metacromática , Adulto , Femenino , Humanos , Leucodistrofia Metacromática/diagnóstico por imagen , Leucodistrofia Metacromática/genética , Mutación/genética , Cerebrósido Sulfatasa/genética , Cerebrósido Sulfatasa/metabolismo , Genotipo , FenotipoRESUMEN
Intellectual disabilities (ID) and autism spectrum disorders (ASD) are characterized by extreme genetic and phenotypic heterogeneity. However, understanding this heterogeneity is difficult due to the intricate interplay among multiple interconnected genes, epigenetic factors, oxidative stress, and environmental factors. Employing next-generation sequencing (NGS), we revealed the genetic cause of ID and autistic traits in two patients from a consanguineous family followed by segregation analysis. Furthermore, in silico prediction methods and 3D modeling were conducted to predict the effect of the variants. To establish genotype-phenotype correlation, X-chromosome inactivation using Methylation-specific PCR and oxidative stress markers were also investigated. By analyzing the NGS data of the two patients, we identified a novel frameshift mutation c.2174_2177del (p.Thr725MetfsTer2) in the MAP7D3 gene inherited from their mother along with the functional BDNF Val66Met polymorphism inherited from their father. The 3D modeling demonstrated that the p.Thr725MetfsTer2 variant led to the loss of the C-terminal tail of the MAP7D3 protein. This change could destabilize its structure and impact kinesin-1's binding to microtubules via an allosteric effect. Moreover, the analysis of oxidative stress biomarkers revealed an elevated oxidative stress in the two patients compared to the controls. To the best of our knowledge, this is the first report describing severe ID and autistic traits in familial cases with novel frameshift mutation c.2174_2177del in the MAP7D3 gene co-occurring with the functional polymorphism Val66M in the BDNF gene. Besides, our study underlines the importance of investigating combined genetic variations, X-chromosome inactivation (XCI) patterns, and oxidative stress markers for a better understanding of ID and autism etiology.
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Trastorno del Espectro Autista , Trastorno Autístico , Discapacidad Intelectual , Humanos , Discapacidad Intelectual/genética , Hermanos , Trastorno Autístico/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Inactivación del Cromosoma X , Trastorno del Espectro Autista/genética , Mutación , Gravedad del PacienteRESUMEN
OBJECTIVE: To develop a high throughput sequencing panel for the diagnosis of developmental and epileptic encephalopathy in Tunisia and to clarify the frequency of disease-causing genes in this region. METHODS: We developed a custom panel for next generation sequencing of the coding sequences of 116 genes in individuals with developmental and epileptic encephalopathy from the Tunisian population. Segregation analyses as well as in silico studies have been conducted to assess the identified variants' pathogenicity. RESULTS: We report 12 pathogenic variants in SCN1A, CHD2, CDKL5, SZT2, KCNT1, GNAO1, PCDH19, MECP2, GRIN2A, and SYNGAP1 in patients with developmental and epileptic encephalopathy. Five of these variants are novel: "c.149delA, p.(Asn50MetfsTer26)" in CDKL5; "c.3616C>T, p.(Arg1206Ter)" in SZT2; "c.111_113del, p.(Leu39del)" in GNAO1; "c.1435G>C , p.(Asp479His)" in PCDH19; as well as "c.2143delC, p. (Arg716GlyfsTer10)"in SYNGAP1. Additionally, for four of our patients, the genetic result facilitated the choice of the appropriate treatment. SIGNIFICANCE: This is the first report of a custom gene panel to identify genetic variants implicated in developmental and epileptic encephalopathy in the Tunisian population as well as the North African region (Tunisia, Egypt, Libya, Algeria, Morocco) with a diagnostic rate of 30%. This high-throughput sequencing panel has considerably improved the rate of positive diagnosis of developmental and epileptic encephalopathy in the Tunisian population, which was less than 15% using Sanger sequencing. The benefit of genetic testing in these patients was approved by both physicians and parents.
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ABSTRACT: We report a 5-year-old boy who presented with progressive weakness in 4 limbs and gait disorders over 7 months. No skin rash was observed on admission. A symmetrical proximodistal weakness was found. The creatine kinase level was normal with a slightly elevated lactate dehydrogenase level. Biopsy specimens showed infiltration of mononuclear cells, few necrotic fibers, and perifascicular atrophy. Screening for myositis-specific antibodies was positive for the antinuclear matrix protein 2 antibody, which is mainly associated with dermatomyositis. Symptoms improved on receiving corticosteroids. Our findings suggest that in cases where inflammatory muscle disease is suspected, antinuclear matrix protein 2 antibody analyses should be considered for precise diagnosis, even with the absence of dermatological symptoms. The case suggests consideration of juvenile dermatomyositis in children with no associated skin manifestations or elevated creatine kinase levels and highlights the importance of screening for myositis-specific antibodies in helping with the diagnosis, given the possible heterogeneity of its clinical presentations.
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Dermatomiositis , Miositis , Masculino , Niño , Humanos , Preescolar , Dermatomiositis/diagnóstico , Anticuerpos Antinucleares , Atrofia , Creatina QuinasaRESUMEN
Pathogenic germline variants in the PIGT gene are associated with the "multiple congenital anomalies-hypotonia-seizures syndrome 3" (MCAHS3) phenotype. So far, fifty patients have been reported, most of whom suffer from intractable epilepsy. Recently, a comprehensive analysis of a cohort of 26 patients with PIGT variants has broadened the phenotypical spectrum and indicated that both p.Asn527Ser and p.Val528Met are associated with a milder epilepsy phenotype and less severe outcomes. Since all reported patients are of Caucasian/Polish origin and most harbor the same variant (p.Val528Met), the ability to draw definitive conclusions regarding the genotype-phenotype correlation remains limited. We report a new case with a homozygous variant p.Arg507Trp in the PIGT gene, detected on clinical exome sequencing. The North African patient in question displays a predominantly neurological phenotype with global developmental delay, hypotonia, brain abnormalities, and well-controlled epileptic seizures. Homozygous and heterozygous variants in codon 507 have been reported to cause PIGT deficiency without biochemical confirmation. In this study, FACS analysis of knockout HEK293 cells that had been transfected with wild-type or mutant cDNA constructs demonstrated that the p.Arg507Trp variant leads to mildly reduced activity. Our result confirm the pathogenicity of this variant and strengthen recently reported evidence on the genotype-phenotype correlation of the PIGT variant.
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FoxG1 encoded by FOXG1 gene is a transcriptional factor interacting with the DNA of targeted genes as well as with several proteins to regulate the forebrain development. Mutations in the FOXG1 gene have been shown to cause a wide spectrum of brain disorders, including the congenital variant of Rett syndrome. In this study, the direct sequencing of FOXG1 gene revealed a novel c.645C > A (F215L) variant in the patient P1 and a de novo known one c.755G > A (G252D) in the patient P2. To investigate the putative impact of FOXG1 missense variants, a computational pipeline by the application of in silico prediction methods, molecular dynamic simulation, and molecular docking approaches was used. Bioinformatics analysis and molecular dynamics simulation have demonstrated that F215L and G252D variants found in the DNA binding domain are highly deleterious mutations that may cause the protein structure destabilization. On the other hand, molecular docking revealed that F215L mutant is likely to have a great impact on destabilizing the protein structure and the disruption of the Bmi-1 binding site quite significantly. Regarding G252D mutation, it seems to abolish the ability of FoxG1 to bind DNA target, affecting the transcriptional regulation of targeted genes. Our study highlights the usefulness of combined computational approaches, molecular dynamic simulation, and molecular docking for a better understanding of the dysfunctional effects of FOXG1 missense mutations and their role in the etiopathogenesis as well as in the genotype-phenotype correlation.
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Simulación de Dinámica Molecular , Mutación Missense , ADN , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Simulación del Acoplamiento Molecular , Mutación , Proteínas del Tejido Nervioso/metabolismoRESUMEN
Intellectual disability (ID) often co-occurs with other neurologic phenotypes making molecular diagnosis more challenging particularly in consanguineous populations with the co-segregation of more than one ID-related gene in some cases. In this study, we investigated the phenotype of three patients from a large Tunisian family with significant ID phenotypic variability and microcephaly and performed a clinical exome sequencing in two cases. We identified, within the first branch, a homozygous variant in the TRAPPC9 gene (p.Arg472Ter) in two cases presenting severe ID, absent speech, congenital/secondary microcephaly in addition to autistic features, supporting the implication of TRAPPC9 in the "secondary" autism spectrum disorders and congenital microcephaly. In the second branch, we identified a homozygous variant (p.Lys189ArgfsTer15) in the CDK5RAP2 gene associated with an heterozygous TRAPPC9 variant (p.Arg472Ter) in one case harbouring primary hereditary microcephaly (MCPH) associated with an inter-hypothalamic adhesion, mixed hearing loss, selective thinning in the retinal nerve fiber layer and parafoveal ganglion cell complex, and short stature. Our findings expand the spectrum of the recently reported neurosensorial abnormalities and revealed the variable phenotype expressivity of CDK5RAP2 defect. Our study highlights the complexity of the genetic background of microcephaly/ID and the efficiency of the exome sequencing to provide an accurate diagnosis and to improve the management and follow-up of such patients.
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Proteínas de Ciclo Celular/genética , Discapacidad Intelectual/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Microcefalia/genética , Proteínas del Tejido Nervioso/genética , Niño , Consanguinidad , Femenino , Variación Genética/genética , Homocigoto , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Malformaciones del Sistema Nervioso/genética , Linaje , Fenotipo , Trastornos del Habla/genética , TúnezRESUMEN
INTRODUCTION: Epilepsy is one of the most stigmatizing disorders. Stigma and negative attitudes associated with epilepsy are due to poor public awareness and knowledge. This study evaluated knowledge, awareness, and attitude toward epilepsy among Tunisian general population. METHODS: This was a cross-sectional study conducted between 2017 and 2019. On national epilepsy day on February and during awareness campaigns at Sfax Tunisia, we asked people who visited the epilepsy stand to anonymously answer a 31-item questionnaire on epilepsy. RESULTS: Five hundred and four participants have been included. About 43.6% of participants had personal or familial history of epilepsy. More than seventy percent of subjects thought that epilepsy is a neurological disease and 34.1% believed it is psychiatric. Majority (92.1%) of our population believed that epilepsy is non-contagious but 37.7% thought it is hereditary and 55.8% thought it causes intellectual deficiency. EEG was the most reported diagnostic method (61.7%). The two most popular therapeutic modalities reported in our population were drug treatment alone (85.3%) and associated with Quran (35.3%). Most (91.1%) of people thought that a person with epilepsy can get married. A person with epilepsy is able to study according to 92.7% of respondents, but 66.3% assumed that he/she suffers from difficulty concentrating. Subjects younger than 45â¯years were more aware of the ability of people with epilepsy to study and get married. We did not find any significant differences in knowledge and attitudes between subjects familiar with epilepsy and the rest of the population. CONCLUSION: The public knowledge and attitudes toward epilepsy were acceptable with regard to this study. However, negative attitudes and misunderstanding still exist.
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Epilepsia , Conocimientos, Actitudes y Práctica en Salud , Estudios Transversales , Epilepsia/epidemiología , Femenino , Humanos , Masculino , Estigma Social , Encuestas y Cuestionarios , Túnez/epidemiologíaRESUMEN
INTRODUCTION: Rett syndrome (RTT) is a neuro-developmental disorder affecting almost exclusively females and it divided into classical and atypical forms of the disease. RTT-like syndrome was also described and presents an overlapping phenotype of RTT. RTT-like syndrome has been associated with several genes including MECP2 and CDKL5 having common biological pathways and regulatory interactions especially during neural maturation and synaptogenesis. METHODS: We report patient with Rett-like syndrome for whom clinical features and their progression guided toward the screening of two candidate genes MECP2 and CDKL5 by sequencing. Severity score was evaluated by "Rett Assessment Rating Scale" (R.A.R.S.). Predictions of pahogenicity and functional effects used several bioinformatic tools and qRT-PCR was conducted to evaluate gene expression. RESULTS: Mutational screening revealed two mutations c.1065 C > A (p.S355R) in MECP2 gene and c.616 G > A (p.D206N) mutation in CDKL5 gene in the patient with a high R.A.R.S. Bioinformatic investigations predicted a moderate effect of p.S355R in MECP2 gene but a more pathogenic one of p.D206N mutation in CDKL5. Effect of c.616 G > A mutation on structure and stability of CDKL5 mRNA was confirmed by qRT-PCR. Additionally, analysis of gene expression revealed a drastic effect of CDKL5 mutant on its MeCP2 and Dnmt1 substrates and also on its MYCN regulator. CONCLUSIONS: The co-existence of the two mutations in CDKL5 and MECP2 genes could explain the severe phenotype in our patient with RTT-Like and is consistent with the data related to the interactions of CDKL5 with MeCP2 and Dnmt1 proteins.
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Proteínas Serina-Treonina Quinasas , Síndrome de Rett , Femenino , Expresión Génica , Humanos , Proteína 2 de Unión a Metil-CpG/genética , Mutación , Fenotipo , Proteínas Serina-Treonina Quinasas/genética , Síndrome de Rett/genéticaRESUMEN
INTRODUCTION: West Syndrome is a severe epileptic encephalopathy characterized by epileptic spasms, hypsarrhythmia, and regression of psychomotor acquisitions beginning in the first year of life. ARX and CDKL5 genes were identified as linked to the most frequent genetic causes of West Syndrome. METHODS: The present study reports the clinical, molecular and bioinformatic investigation of the patient with severe West syndrome. RESULTS: Molecular analysis of the two candidate genes, i.e. ARX and CDKL5 showed the presence of a novel insertion c.2788insG in exon 19 of CDKL5 gene. This mutation causes changes in cis regulation elements of exon 19 splicing and in secondary pre-mRNA structure leading probably to inclusion of alternative exon 19 in hCDKL5_5 isoform for which foetal brain expression was recently confirmed. This insertion led also to a frameshift mutation and generated a premature stop codon (p.E930Gfs9X) in the C- terminal domain and causing the lack of a part of the signal recognized by proteasome as well as the lack of peptidase I serine active site. Moreover, we review previously described, truncated mutations occurring in different regions of the C- terminal domain, and we compared the subcellular mutated protein localization and their resulting patients' phenotypes. CONCLUSIONS: The impairment of alternative splicing of exon 19 and the lack of a part of the proteasome signal due to c.2788insG mutation could disrupt the dynamic regulation of isoform levels especially hCDKL5_5 and hCDKL5_1 during pre and postnatal neurodevelopment and then could cause pathogenic phenotype. Signal peptidase I serine active site seems to modulate hCDKL5_5 movements between nucleus and cytoplasm. We noticed that the resulting phenotypes from truncated mutations among the C-terminal domain of hCDKL5 are almost similar and are always severe.
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Mutación/genética , Proteínas Serina-Treonina Quinasas/genética , Espasmos Infantiles/genética , Niño , Biología Computacional , Análisis Mutacional de ADN , Electroencefalografía , Estudios de Asociación Genética , Humanos , Lactante , Estudios Longitudinales , MasculinoRESUMEN
Congenital heart defects represent a characteristic part of several genetic syndromes associated with chromosomal abnormalities such as 22q11.2 deletion syndrome; many genes located in this locus, mainly TBX1, are candidate genes for congenital heart defects. In our cohort of 27 subjects with congenital heart defect, both karyotype analysis and Fluorescence in situ hybridization (FISH) were performed. The TBX1 gene was sequenced in patients lacking chromosomal abnormalities. FISH analysis showed a de novo 22q11.2 deletion in two patients. The screening of TBX1 coding sequence identified a novel missense mutation c.569Câ¯>â¯A (p.P190Q) in six unrelated patients and detected two associated known single nucleotide polymorphisms; the c.664Câ¯>â¯T (rs2301558) in three patients and the c.420Tâ¯>â¯C (p.Phe140 Phe) (rs41298814) in one patient. Bioinformatic tools show that the novel missense mutation c.569Câ¯>â¯A could modify the function and the stability of the TBX1 protein. The c.569Câ¯>â¯A mutation was not found in 50 healthy controls. Ours results suggest a deleterious role of the c.569Câ¯>â¯A mutation and strengthen the hypothesis that this mutation might be responsible for the same phenotype spectrum as the 22q11.2 deletion syndrome.
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Cardiopatías Congénitas/genética , Mutación Missense/genética , Proteínas de Dominio T Box/genética , Secuencia de Aminoácidos , Secuencia de Bases , Cromosomas Humanos Par 22/genética , Simulación por Computador , Análisis Mutacional de ADN , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Modelos Moleculares , Síndrome , Proteínas de Dominio T Box/químicaRESUMEN
INTRODUCTION: West syndrome is a rare epileptic encephalopathy of early infancy, characterized by epileptic spasms, hypsarrhythmia, and psychomotor retardation beginning in the first year of life. METHODS: The present study reports the clinical, molecular and bioinformatic investigation in the three studied West patients. RESULTS: The results revealed a complex genotype with more than one mutation in each patient including the known mutations c.1910C>G (P2, P3); c.2372A>C in P3 and c.2395C>G in P1 and novel variants including c.616G>A, shared by the three patients P1, P2 and P3; c.1403G>C shared by P2 and P3 and c.2288A>G in patient P1. CONCLUSIONS: All the mutations were at somatic mosaic state and were de novo in the patients except ones (c.2372A>C). To our knowledge; the somatic mosaic state is described for the first time in patients with West syndrome. Five identified mutations were located in the C-terminal domain of the protein, while the novel mutation (c.616G>A) was in the catalytic domain. Bioinformatic tools predicted that this latter is the most pathogenic substitution affecting 3D protein structure and the secondary mRNA structure. Complex genotype composed of different combinations of mutations in each patient seems to be related to the phenotype variability.
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Genotipo , Mutación , Fenotipo , Proteínas Serina-Treonina Quinasas/genética , Espasmos Infantiles/genética , Adolescente , Niño , Preescolar , Humanos , Lactante , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Rett syndrome is an X-linked neurodevelopmental disorder, primarily caused by MECP2 mutations. In this study, clinical, molecular and bioinformatics analyses were performed in Rett patients to understand the relationship between MECP2 mutation type and the clinical severity. Two double MeCP2 mutations were detected: a novel one (p.G185 V in cis with p.R255X) in P1 and a known one (p.P179 S in cis with p.R255X) in P2. Besides, a novel synonymous mutation (c.807C>T; p.G269G), which could affect mRNA splicing, was identified in P3. The results from clinical severity analysis have shown that P1 was more severely affected than P2 with CSS being 35 and 14, respectively. Therefore, the phenotypic variability in P1 and P2 could be explained by the potential pathogenic effect of the RTT-causing missense mutation p.G185 V in the AT-hook1. In conclusion, clinical, molecular, and in silico investigations in the studied patients have been proven to be substantial for the genotype-phenotype correlation.
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Biología Computacional , Predisposición Genética a la Enfermedad/genética , Proteína 2 de Unión a Metil-CpG/genética , Mutación Missense/genética , Síndrome de Rett/genética , Adolescente , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Modelos Moleculares , Síndrome de Rett/fisiopatología , Índice de Severidad de la EnfermedadRESUMEN
Vitamin B12 deficiency may be responsible of serious hematologic and neurodevelopmental abnormalities. We report the case of an infant who was hospitalized because of recurrent infections, failure to thrive, hypotonia, and weakness. He was 8 months old and had been exclusively breastfed. Blood cell count showed pancytopenia with megaloblastic bone marrow. The serum IgG concentration was low. Vitamin B12 level was very low and associated with increased urinary methylmalonic acid. Cobalamin deficiency was caused by mother's unrecognized pernicious anemia. Vitamin B12 supply led to rapid clinical and hematologic improvement.
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Anemia Megaloblástica/etiología , Anemia Perniciosa/diagnóstico , Lactancia Materna/efectos adversos , Deficiencia de Vitamina B 12/etiología , Adulto , Agammaglobulinemia/etiología , Anemia Perniciosa/metabolismo , Enfermedades Asintomáticas , Enfermedades Transmisibles/etiología , Insuficiencia de Crecimiento/etiología , Femenino , Gastritis Atrófica/complicaciones , Humanos , Inmunoglobulina G/sangre , Lactante , Masculino , Ácido Metilmalónico/sangre , Ácido Metilmalónico/orina , Leche Humana/química , Hipotonía Muscular/etiología , Recurrencia , Deficiencia de Vitamina B 12/diagnósticoAsunto(s)
Granuloma/genética , Linfadenitis/genética , Receptores de Interleucina-12/genética , Axila , Vacuna BCG/efectos adversos , Consanguinidad , Diagnóstico Diferencial , Granuloma/complicaciones , Granuloma/tratamiento farmacológico , Granuloma/patología , Humanos , Lactante , Isoniazida/administración & dosificación , Linfadenitis/complicaciones , Linfadenitis/tratamiento farmacológico , Linfadenitis/patología , Masculino , Receptores de Interleucina-12/deficiencia , Rifampin/administración & dosificaciónRESUMEN
BACKGROUND: Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disorder characterized by the early onset of rickets and is caused by mutations in the vitamin D receptor (VDR) gene. Some HVDRR patients also have alopecia. PATIENTS AND METHODS: We retrospectively studied the clinical features, laboratory findings, genetic defects, as well as responses to treatment in a series of children with HVDRR. RESULTS: Eight patients from 7 families met the inclusion criteria. Alopecia was noted in 7 patients. Two different homozygous mutations in the VDR gene were identified in 6 patients: the p.K45E mutation located in the DNA-binding domain (5 patients with alopecia) and a novel p.T415R mutation located in the ligand-binding domain. A p.E143del CYP24A1 mutation, in the gene encoding the 25-hydroxyvitamin D3-24-hydroxylase, was identified in 2 brothers carrying the VDR gene mutation p.K45E. Six patients were treated with intermittent intravenous calcium treatment via the peripheral route with a clear improvement in 5 cases. CONCLUSION: To the best of our knowledge, this is the first major series reporting on HVDRR in Tunisia. The same mutation (p.K45E) was found in 5 apparently unrelated affected individuals. We have also extended the mutation spectrum by studying 1 novel VDR mutation.
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Raquitismo Hipofosfatémico Familiar , Mutación Missense , Receptores de Calcitriol/genética , Sustitución de Aminoácidos , Preescolar , Raquitismo Hipofosfatémico Familiar/sangre , Raquitismo Hipofosfatémico Familiar/genética , Femenino , Humanos , Lactante , Masculino , TúnezRESUMEN
l-2-Hydroxyglutaric (l-2-HG) aciduria is a rare inherited metabolic disease usually observed in children. Patients present a very slowly progressive deterioration with cerebellar ataxia, mild or severe mental retardation, and various other clinical signs including extrapyramidal and pyramidal symptoms, and seizures Goffette et al. [1]. This leukencephalopathy was first described in 1980 Duran et al. [2]. Brain magnetic resonance imaging (MRI) demonstrates nonspecific subcortical white matter (WM) loss, cerebellar atrophy and changes in dentate nuclei and putamen Steenweg et al. [3]. The diagnosis is highlighted by increased levels of l-2-HG in body fluids such as urine and cerebrospinal fluid. The purpose of this study is to retrospectively describe the brain MRI features in l-2-HG aciduria.
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OBJECTIVES: To study the epidemiological, clinical and bacteriological aspects and outcome of purulent neonatal meningitis (PNM). METHODOLOGY: Retrospective analysis of 55 cases of PNM hospitalized in the pediatric ward of Hedi Chaker Hospital from 1990 to 2012. Infants less than 29 days of age were included. The diagnosis was made on either the presence of bacteria in the cerebrospinal fluid (CSF) or the combination of pleocytosis >30 cells/mm(3), protein level >1.3 g/l and glucose level <2.2 mmol/l or CSF/blood glucose ratio <0.4. RESULTS: The male:female sex ratio was 1.75. One or more maternal risk factors for infection were found in 24 cases. The main symptoms were fever and poor feeding. Soluble antigen was positive in four cases and cultures had isolated the bacteria in 28 cases. The mortality rate was 40%. The sequelae rate in the survivors was 16.4%. CONCLUSION: This study emphasizes the severity of PNM with high rates of mortality and neurological sequelae.