RESUMEN
Autism Spectrum Disorder (ASD) exhibits an ~4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1 gene, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ~1Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS. While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been examined, in part because there is no apparent functional murine orthologue. Through clinical testing, here, we identified 6 males and 1 female with ASD from 6 unrelated families carrying rare, predicted-damaging or loss-of-function variants in DDX53. Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 24 additional individuals with ASD harboring rare, damaging DDX53 variations, including the same variants detected in two families from the original clinical analysis. In this extended cohort of 31 participants with ASD (28 male, 3 female), we identified 25 mostly maternally-inherited variations in DDX53, including 18 missense changes, 2 truncating variants, 2 in-frame variants, 2 deletions in the 3' UTR and 1 copy number deletion. Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mouse, may also influence the design and interpretation of murine-modelling of ASD.
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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids (SLs), cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity. We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased SL synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause peripheral hereditary sensory and autonomic neuropathy type 1 (HSAN1) due to the synthesis of 1-deoxysphingolipids (1-deoxySLs) that form when SPT metabolizes L-alanine instead of L-serine. Limiting L-serine availability in SPTLC1-ALS-expressing cells increased 1-deoxySL and shifted the SL profile from an ALS to an HSAN1-like signature. This effect was corroborated in an SPTLC1-ALS pedigree in which the index patient uniquely presented with an HSAN1 phenotype, increased 1-deoxySL levels, and an L-serine deficiency. These data demonstrate how pathogenic variants in different domains of SPTLC1 give rise to distinct clinical presentations that are nonetheless modifiable by substrate availability.
Asunto(s)
Esclerosis Amiotrófica Lateral , Neuropatías Hereditarias Sensoriales y Autónomas , Proteínas de la Membrana/metabolismo , Enfermedades Neurodegenerativas , Esclerosis Amiotrófica Lateral/genética , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Humanos , Serina/química , Serina C-Palmitoiltransferasa/química , Serina C-Palmitoiltransferasa/genética , Esfingolípidos/genética , Esfingolípidos/metabolismoRESUMEN
Gaucher disease (GD) is an autosomal recessive inherited lysosomal storage disease that often presents in early childhood and is associated with damage to multiple organ systems. Many challenges associated with GD diagnosis and management arise from the considerable heterogeneity of disease presentations and natural history. Phenotypic classification has traditionally been based on the absence (in type 1 GD) or presence (in types 2 and 3 GD) of neurological involvement of varying severity. However, patient management and prediction of prognosis may be best served by a dynamic, evolving definition of individual phenotype rather than by a rigid system of classification. Patients may experience considerable delays in diagnosis, which can potentially be reduced by effective screening programs; however, program implementation can involve ethical and practical challenges. Variation in the clinical course of GD and an uncertain prognosis also complicate decisions concerning treatment initiation, with differing stakeholder perspectives around efficacy and acceptable cost/benefit ratio. We review the challenges faced by physicians in the diagnosis and management of GD in pediatric patients. We also consider future directions and goals, including acceleration of accurate diagnosis, improvements in the understanding of disease heterogeneity (natural history, response to treatment, and prognosis), the need for new treatments to address unmet needs for all forms of GD, and refinement of the tools for monitoring disease progression and treatment efficacy, such as specific biomarkers.
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Enfermedad de Gaucher , Biomarcadores , Niño , Preescolar , Progresión de la Enfermedad , Enfermedad de Gaucher/diagnóstico , Enfermedad de Gaucher/genética , Enfermedad de Gaucher/terapia , Humanos , Lisosomas , FenotipoRESUMEN
Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease.
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Esclerosis Amiotrófica Lateral/metabolismo , Esfingolípidos/biosíntesis , Adolescente , Adulto , Alelos , Secuencia de Aminoácidos , Esclerosis Amiotrófica Lateral/enzimología , Esclerosis Amiotrófica Lateral/genética , Sistemas CRISPR-Cas , Niño , Femenino , Genes Dominantes , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Mutación , Serina C-Palmitoiltransferasa/genética , Serina C-Palmitoiltransferasa/metabolismo , Adulto JovenRESUMEN
Oral-facial-digital syndromes (OFDS) are a heterogeneous and rare group of Mendelian disorders characterized by developmental abnormalities of the oral cavity, face, and digits caused by dysfunction of the primary cilium, a mechanosensory organelle that exists atop most cell types that facilitates organ patterning and growth. OFDS is inherited both in an X-linked dominant, X-linked recessive, and autosomal recessive manner. Importantly, though many of the causal genes for OFDS have been identified, up to 40% of OFD syndromes are of unknown genetic basis. Here we describe three children with classical presentations of OFDS including lingual hamartomas, polydactyly, and characteristic facial features found by exome sequencing to harbor variants in causal genes not previously associated with OFDS. We describe a female with hypothalamic hamartoma, urogenital sinus, polysyndactyly, and multiple lingual hamartomas consistent with OFDVI with biallelic pathogenic variants in CEP164, a gene associated with ciliopathy-spectrum disease, but never before with OFDS. We additionally describe two unrelated probands with postaxial polydactyly, multiple lingual hamartomas, and dysmorphic features both found to be homozygous for an identical TOPORS missense variant, c.29 C>A; (p.Pro10Gln). Heterozygous TOPORS pathogenic gene variants are associated with autosomal dominant retinitis pigmentosa, but never before with syndromic ciliopathy. Of note, both probands are of Dominican ancestry, suggesting a possible founder allele.
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Alelos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Síndromes Orofaciodigitales/diagnóstico , Síndromes Orofaciodigitales/genética , Femenino , Pruebas Genéticas , Genotipo , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Mutación , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Fenotipo , Ubiquitina-Proteína Ligasas/genética , Secuenciación del ExomaRESUMEN
BACKGROUND: The purpose of the current study is to report the anatomical and functional results of off-label human amniotic membrane graft as primary intervention to repair large to giant macular holes and in reoperations when wide internal limiting membrane peeling was unsuccessful. METHODS: Retrospective chart review was carried out in five different centers to identify all cases that had undergone off-label human amniotic membrane graft for the treatment of large or failed macular holes (MH). Data collected included age, gender, other concomitant diagnosis, symptoms duration, lens status, number of previous surgeries, macular hole measurements (minimum and base linear diameters), mean post-operative follow-up (months), and pre- and post-operative best corrected visual acuity (BCVA). Main outcome measures were anatomical MH closure rates and final BCVA (in logMAR). Nonparametric Wilcoxon rank-sum test was used because the data was not normally distributed, a P values < 0.05 were considered statistically significant. RESULTS: Nineteen eyes of 19 patients were identified and included in the study. Mean age was 66.21 ± 14.96 years and predominantly females (84%). All eyes had successfully closed MH with a single intervention with no recurrences during a mean of 9 ± 3.87 months follow-up. The median BCVA in logMAR preoperative was 1.30 ± 0.44 (0.80-2.0), approximately 20/400 on Snellen chart and the median BCVA in logMAR postoperative was 1.0 ± 0.72 (0.4-3.0) approximately 20/200 (p < 0.0001) with median of three lines of visual improvement. CONCLUSION: The use of human amniotic membrane graft seems to be a viable and effective alternative for the treatment of large and persistent macular holes. However, further larger prospective controlled studies are necessary to confirm our preliminary results of this new surgical technique.
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Our objective was to further expand the spectrum of clinical characteristics of the IGSF1 deficiency syndrome in affected males. These characteristic include almost universal congenital central hypothyroidism (CeH) with disharmonious pubertal development (normally timed testicular growth, but delayed rise of serum testosterone), macroorchidism, increased body mass index (BMI), and decreased attentional control. In addition, a subset of patients show prolactin deficiency, transient partial growth hormone deficiency in childhood and increased growth hormone secretion in adulthood. We present a family in which the proband was diagnosed with CeH and low serum prolactin. Severe weight gain started at two years old, with a BMI of 42.3 at 13.9 years. Testicular enlargement (5-6 mL, 3.8-4.3 standard deviation score) started aged three years. A pathogenic variant was found in the IGSF1 gene: c.3411_3412del, p.(Tyr1137*). His brother was referred for short stature at age 13 years and was diagnosed with CeH, normal serum prolactin and IGF-1, and disharmonious puberty. In four male relatives (the proband's brother and three cousins) with the variant (one adult), free thyroxine (fT4) was below the lower limit of the reference range in two, and just above this limit in the other two. Three were overweight or obese, adolescents had disharmonious pubertal development and the adult had profound macroorchidism. In conclusion, male hemizygous carriers of a pathogenic IGSF1 variant can present with fT4 concentration above the lower limit of the reference range while severe early onset obesity or premature testicular growth are part of the phenotypic spectrum.
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Hipotiroidismo Congénito , Trastornos Gonadales , Inmunoglobulinas , Proteínas de la Membrana , Obesidad , Prolactina/sangre , Testículo/crecimiento & desarrollo , Tiroxina/sangre , Adolescente , Hipotiroidismo Congénito/sangre , Hipotiroidismo Congénito/genética , Trastornos Gonadales/sangre , Trastornos Gonadales/genética , Humanos , Inmunoglobulinas/deficiencia , Inmunoglobulinas/genética , Masculino , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Obesidad/sangre , Obesidad/genética , Obesidad Mórbida/sangre , Obesidad Mórbida/genética , Obesidad Infantil/sangre , Obesidad Infantil/genética , Linaje , SíndromeRESUMEN
Resumo O estudo buscou analisar e estudar a prevalência e as circunstâncias de urgências e emergências oftalmológicas no Pronto Socorro do Hospital de Clínicas de Uberlândia da Universidade Federal de Uberlândia (HCU-UFU) e no Ambulatório Amélio Marques no período de agosto de 2016 a agosto de 2017. Faz-se necessário tal estudo, pois emergências oftalmológicas são importantes causas de morbidades na sociedade(1). Ademais, através dele políticas de prevenção poderão ser feitas, além de maior capacitação de profissionais a partir do conhecimento das principais causas de atendimento. A metodologia proposta incluiu a coleta de dados do prontuário, sendo colhidas as informações sexo, idade e ocupação/profissão. Trata-se de um estudo epidemiológico exploratório observacional predominantemente descritivo do tipo transversal. O trabalho evidenciou que o sexo masculino foi o mais acometido e a faixa etária mais incidente foi entre 19 e 45 anos. Das causas de procura pelo pronto-atendimento oftalmológico, o trauma ocular por corpo estranho é a mais comum havendo uma estreita relação com as atividades laborais (mecânicos e ferragistas). Dessa forma, os dados serão um recurso importante para o auxiliar na compreensão do perfil epidemiológico do pronto-atendimento oftalmológico visando otimizar a administração do mesmo e para estimular a adoção de políticas públicas de prevenção no âmbito da saúde do trabalhador.
Abstract The study aimed to analyze and study the prevalence and circumstances of ophthalmic emergencies and urgencies in the Emergency Room of the Hospital de Clínicas de Uberlândia and the Central Ambulatory (Amélio Marques) of the Federal University of Uberlândia (HCU-UFU) from August 2016 to August 2017. This is a necessary study since ophthalmic emergencies are important causes of morbidities in society(1). In addition, this study will help to develop prevention policies and to make greater training of professionals based on knowledge of the main causes of eye emergencies. The proposed methodology included the collection of data from the medical record, with the information of sex, age and occupation/profession being collected. This is an observational, descriptive, transversal, exploratory epidemiological study. The study showed that males were the most affected and the most incident age group was between 19 and 45 years old. Eye trauma due to a foreign body is the most common cause of demand for ophthalmologic emergency care with a close relationship with work activities (mechanics and ironmongers). In this way, the data will be an important resource to assist in understanding the epidemiological profile of the ophthalmology emergency room in order to optimize its administration and to encourage the adoption of public prevention policies within the scope of occupational health.
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Humanos , Masculino , Femenino , Recién Nacido , Lactante , Preescolar , Niño , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Accidentes de Trabajo/prevención & control , Cuerpos Extraños en el Ojo , Lesiones Oculares/prevención & control , Registros Médicos , Salud Laboral , Urgencias Médicas/epidemiología , Servicios Médicos de Urgencia , Oftalmopatías/prevención & control , Hospitales Universitarios , Epidemiología Descriptiva , Estudios Transversales , Estudio ObservacionalRESUMEN
INTRODUCTION: Pigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko's lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 (TFE3) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions. MATERIALS AND METHODS: Subsequent data sharing allowed the clustering of de novo TFE3 variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or without PM. RESULTS: We describe the detailed clinical and molecular data of 17 individuals harbouring a de novo TFE3 variant, including the patients that initially allowed reporting TFE3 as a new disease-causing gene. The 12 females and 5 males presented with pigmentation anomalies on Blaschko's lines, severe ID, epilepsy, storage disorder-like features, growth retardation and recognisable facial dysmorphism. The variant was at a mosaic state in at least two male patients. All variants were missense except one splice variant. Eleven of the 13 variants were localised in exon 4, 2 in exon 3, and 3 were recurrent variants. CONCLUSION: This series further delineates the specific storage disorder-like phenotype with PM ascribed to de novo TFE3 mutation in exons 3 and 4. It confirms the identification of a novel X-linked human condition associated with mosaicism and dysregulation within the mechanistic target of rapamycin (mTOR) pathway, as well as a link between lysosomal signalling and human development.
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Epilepsia/genética , Discapacidad Intelectual/genética , Trastornos de la Pigmentación/genética , Adolescente , Adulto , Niño , Preescolar , Epilepsia/complicaciones , Epilepsia/patología , Femenino , Genes Ligados a X/genética , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/patología , Masculino , Mosaicismo , Patología Molecular/normas , Trastornos de la Pigmentación/complicaciones , Trastornos de la Pigmentación/patología , Secuenciación del Exoma , Adulto JovenRESUMEN
BACKGROUND: Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disorder that can present as a severe, infantile form also known as Wolman disease. We sought to determine the outcomes and clinical needs of infants diagnosed with LAL-D, treated with enzyme replacement therapy (ERT). METHODS: A chart review was conducted on two infantile-onset LAL-D patients to determine clinical outcomes based on laboratory results, abdominal imaging, growth and dietary records, cardiology, endocrinology, ophthalmology, hematology, and neurocognitive evaluations. RESULTS: Two patients, both diagnosed and treated before 6 months old, demonstrated clinical improvement following weekly ERT. They required dosage increases to optimize growth and symptomatology. Both received a formula low in long chain triglycerides and high in medium chain triglycerides, an intervention that allowed significant catch-up growth. Patient 1 required treatment for partial adrenal insufficiency and hypothyroidism. Both patients demonstrated reduction in liver and spleen size and varying degrees of improved liver function. Neither experienced serious adverse reactions to ERT. CONCLUSION: ERT has led to longer and healthier survival of affected infants. It is imperative that dietary interventions and systemic clinical care become integral to the management. Continued evidence of survival and clinical improvement in this population, coupled with available mass spectrometry enzyme assay from dried blood spots, raises the question of this rare and possibly underdiagnosed disorder's candidacy for newborn screening.
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Terapia de Reemplazo Enzimático/métodos , Enfermedad de Wolman/diagnóstico , Enfermedad de Wolman/tratamiento farmacológico , Aspartato Aminotransferasas/uso terapéutico , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Espectrometría de Masas , Tamizaje Neonatal , Triglicéridos/uso terapéutico , Enfermedad de Wolman/enzimología , Enfermedad de WolmanRESUMEN
Reversible infantile respiratory chain deficiency, previously termed reversible infantile cytochrome c oxidase (COX) deficiency myopathy, is a rare mitochondrial disorder that is characterized by severe hypotonia and generalized muscle weakness in infancy that is associated with lactic acidosis. Affected infants will spontaneously recover, if they survive the first months of life. Here, we present the case of a 4-week-old girl who initially presented with hyperammonemia, hypotonia, and failure to thrive, for which she was referred for genetic evaluation. After several tests, a distinct genetic syndrome could not be identified and she continued to deteriorate. A muscle biopsy was performed and demonstrated severe mitochondrial myopathy with abundant COX-negative fibers. Ultrastructural abnormalities of the mitochondria, diagnostic of mitochondrial myopathy, were identified on electron microscopy. Molecular studies revealed the classic homoplasmic disease causing mutation, m.14674 T>C in the MT-TE gene, associated with reversible COX deficiency. Although hyperammonemia is an unusual presentation for mitochondrial myopathies, specifically reversible infantile respiratory chain deficiency, it should be included in the list of possible presenting symptoms for this condition.
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Deficiencia de Citocromo-c Oxidasa/diagnóstico , Insuficiencia de Crecimiento/etiología , Hiperamonemia/etiología , Hipotonía Muscular/etiología , Deficiencia de Citocromo-c Oxidasa/complicaciones , Deficiencia de Citocromo-c Oxidasa/patología , Deficiencia de Citocromo-c Oxidasa/fisiopatología , Insuficiencia de Crecimiento/diagnóstico , Femenino , Humanos , Hiperamonemia/diagnóstico , Lactante , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/patologíaRESUMEN
We present eight patients with de novo, deleterious sequence variants in the PBX1 gene. PBX1 encodes a three amino acid loop extension (TALE) homeodomain transcription factor that forms multimeric complexes with TALE and HOX proteins to regulate target gene transcription during development. As previously reported, Pbx1 homozygous mutant mice (Pbx1-/-) develop malformations and hypoplasia or aplasia of multiple organs, including the craniofacial skeleton, ear, branchial arches, heart, lungs, diaphragm, gut, kidneys, and gonads. Clinical findings similar to those in Pbx mutant mice were observed in all patients with varying expressivity and severity, including external ear anomalies, abnormal branchial arch derivatives, heart malformations, diaphragmatic hernia, renal hypoplasia and ambiguous genitalia. All patients but one had developmental delays. Previously reported patients with congenital anomalies affecting the kidney and urinary tract exhibited deletions and loss of function variants in PBX1. The sequence variants in our cases included missense substitutions adjacent to the PBX1 homeodomain (p.Arg184Pro, p.Met224Lys, and p.Arg227Pro) or within the homeodomain (p.Arg234Pro, and p.Arg235Gln), whereas p.Ser262Glnfs*2, and p.Arg288* yielded truncated PBX1 proteins. Functional studies on five PBX1 sequence variants revealed perturbation of intrinsic, PBX-dependent transactivation ability and altered nuclear translocation, suggesting abnormal interactions between mutant PBX1 proteins and wild-type TALE or HOX cofactors. It is likely that the mutations directly affect the transcription of PBX1 target genes to impact embryonic development. We conclude that deleterious sequence variants in PBX1 cause intellectual disability and pleiotropic malformations resembling those in Pbx1 mutant mice, arguing for strong conservation of gene function between these two species.
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Discapacidad Intelectual/genética , Factor de Transcripción 1 de la Leucemia de Células Pre-B/genética , Factor de Transcripción 1 de la Leucemia de Células Pre-B/metabolismo , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Niño , Preescolar , Femenino , Pleiotropía Genética/genética , Proteínas de Homeodominio/genética , Humanos , Lactante , Recién Nacido , Masculino , Ratones , Embarazo , Unión Proteica , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: When no chromosomal variations are identified, patients with suspected genetic etiologies can be tested using next-generation sequencing utilizing epilepsy panels. The primary objective of this study was to analyze the diagnostic yield of next-generation sequencing epilepsy panels in medication-resistant epilepsy subjects with non-clinically significant comparative genomic hybridization microarray results. METHODS: We completed a single-center retrospective review of the diagnostic yield of next-generation sequencing epilepsy panels in medication-resistant epilepsy subjects aged 18 years or less who had non-clinically significant comparative genomic hybridization microarray results from January 2011 to December 2014. The primary end point was the yield of clinically significant next-generation sequencing results. RESULTS: Forty-nine subjects (21 male) with medication-refractory epilepsy and clinically in significant comparative genomic hybridization microarray results were identified. Next-generation sequencing abnormalities were seen in 28 subjects (57%): seven of these 28 subjects (25%) had clinically significant findings. Mutations were found in the SCN1A gene in three subjects, in the PCDH19 gene in two subjects, and in DLG3, MECP2, TSC2, and SLC9A6 genes in one subject each. Only the MECP2 mutation was found to be pathogenic in this last subject. The additional yield of next-generation sequencing with uninformative chromosomal microarray was 14%. Positive findings were primarily seen in those with Dravet syndrome, all with SCN1A mutations (42% of clinically significant results). Given the small sample size, a larger prospective study would help to determine the clinical yield of next-generation sequencing. CONCLUSION: Next-generation sequencing seizure panels could be a useful tool in the diagnosis of nonacquired pediatric medication-refractory epilepsy with uninformative comparative genomic hybridization microarray.
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Hibridación Genómica Comparativa , Epilepsia Refractaria/diagnóstico , Epilepsia Refractaria/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Análisis por Micromatrices , Adolescente , Niño , Preescolar , Femenino , Pruebas Genéticas , Humanos , Lactante , Recién Nacido , Masculino , Estudios RetrospectivosRESUMEN
Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.
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Sustitución de Aminoácidos , Codón , Mutación Missense , Neurofibromina 1/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Fenotipo , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Enanismo/genética , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Persona de Mediana Edad , Neurofibromina 1/química , Adulto JovenRESUMEN
BACKGROUND/AIMS: GH insensitivity and IGF deficiency may result from aberrations of the GH receptor (GHR). We describe a 4-year-old child with modest growth failure and normal serum concentrations of GH-binding protein (GHBP), but clinical evidence of GH insensitivity. METHOD: Serum and DNA samples from the proband and his parents were analyzed. RESULTS: The child had a height of -4 SD, elevated serum GH concentrations, abnormally low serum IGF-I and IGFBP-3 concentrations and normal GHBP concentrations. DNA analysis revealed compound heterozygosity for mutations of GHR, including a previously reported R211H mutation and a novel duplication of a nucleotide in exon 9 (899dupC), the latter resulting in a frameshift and a premature stop codon. Treatment with recombinant DNA-derived IGF-I resulted in growth acceleration. CONCLUSION: Mutations affecting the intracellular domain of the GHR can result in GH insensitivity and IGF deficiency, despite normal serum concentrations of GHBP. The presence of clinical and biochemical evidence of GH resistance is sufficient to consider the possibility of aberrations of the GHR, even in the presence of normal serum GHBP concentrations.
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Proteínas Portadoras/sangre , Mutación del Sistema de Lectura , Trastornos del Crecimiento/genética , Hormona de Crecimiento Humana/sangre , Factor I del Crecimiento Similar a la Insulina/deficiencia , Receptores de Somatotropina/genética , Secuencia de Aminoácidos , Preescolar , ADN/química , ADN/genética , Femenino , Trastornos del Crecimiento/sangre , Trastornos del Crecimiento/tratamiento farmacológico , Humanos , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Masculino , Datos de Secuencia Molecular , Mutación Puntual , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Glutaric aciduria type II is a rare disorder affecting the metabolism of fatty acid oxidation and several mitochondrial dehydrogenase enzymes. Narcolepsy and cataplexy is a disorder affecting sleep cycles and rapid eye movement activity. There is little information on outcome or management for either disorder in pregnancy. CASE: This is a case of a 16-year-old with glutaric aciduria type II and narcolepsy with cataplexy, treated with L-carnitine, riboflavin, fluoxetine, and modafinil during pregnancy. Intrapartum management included intravenous carnitine administration, and the patient underwent cesarean delivery at term without complication. CONCLUSION: This inborn error of metabolism and sleep disorder can be effectively treated during pregnancy with nutritional supplementation and stimulants. Because of the risk of cataplexy during labor, cesarean delivery is recommended to minimize the patient's risk.
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Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/complicaciones , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/terapia , Narcolepsia/complicaciones , Narcolepsia/terapia , Complicaciones del Embarazo/terapia , Adolescente , Femenino , Humanos , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/diagnóstico , Embarazo , Complicaciones del Embarazo/diagnóstico , Complicaciones del Embarazo/etiologíaAsunto(s)
Cromosomas Humanos Par 20/genética , Discapacidades del Desarrollo/genética , Enfermedades Fetales/genética , Mosaicismo , Diagnóstico Prenatal , Trisomía/diagnóstico , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Hibridación Fluorescente in Situ , Embarazo , Factores de TiempoRESUMEN
Biotinidase deficiency is a defect in the recycling of the vitamin biotin. Biotin supplementation can markedly improve the neurological and cutaneous symptoms of affected children and prevent symptoms in children identified by newborn screening or treated since birth. We have determined thirteen novel mutations in children with the disorder. Two nonsense mutations, eight single missense mutations, three allelic double missense mutations, and two are polymorphisms were identified in the biotinidase gene (BTD). One of the missense mutations, c.734G>A (p. C245Y), is the first to be reported that alters the cysteine in the putative location crucial for ester formation and binding of the biotinyl-moiety in the active site of the enzyme. These mutations add to the growing list of mutations that are helping to delineate structure/function relationships of the enzyme.
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Deficiencia de Biotinidasa/diagnóstico , Deficiencia de Biotinidasa/genética , Biotinidasa/genética , Mutación , Alelos , Sitios de Unión , Biotina/química , Deficiencia de Biotinidasa/fisiopatología , Femenino , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
Estudo polarográfico foi realizado em 15 ratos Wistar inoculados com tumor de Walker 256, implantando-se eletrodos de platina no tumor e no músculo, com o objetivo de padronizaçäo da polarografia no tumor de Walker 256. Os níveis de oxigênio foram sempre menores no tumor do que no músculo, tanto em condiçöes basais como após a oxigenaçäo. A resposta à oxigenaçäo foi mais lenta no tumor do que no músculo
Asunto(s)
Animales , Ratas , Carcinoma 256 de Walker , Polarografía/normas , Electrodos Implantados , Neoplasias Experimentales , Consumo de Oxígeno , Ratas WistarRESUMEN
The objective of the present study was to investigate the biomechanical changes of the small intestinal wall occurring in fecal peritonitis associated with diclofenac sodium (DS). Wistar rats were divided at random into the following groups: Group 1 (DS), 60 animals that received an intramuscular injection of diclofenac sodium at the dose of 2 mg/kg body weight; Group 2 (Per), 60 animals that received an intraperitoneal injection of a suspension of human feces, with interruption of peritonitis after 6 hours; Group 3 (Per+DS), 60 animals that received an intraperitoneal injection of a suspension of human feces and DS according to the same scheme as used for Groups 1 and 2; Control Group, 12 animals injected intramusculary. The animals in Groups 1, 2 and 3 were successively sacrificed on the 2nd, 7th and 14th days after the interruption of peritonitis and/or the beginning of treatment, when breaking strength was determined and tissue hydroxyproline was measured. No deaths occured among DS animals, two deaths occurred in the Per group and six the Per+DS group between the 2nd and 12th postoperative day. The breaking strength of the DS group returned to normal levels on the 14th day of treatment, whereas in the Per and Per+DS groups the breaking strength continued to be below normal levels. On the basis of the experimental conditions and methods used, we conclude that diclofenac sodium and peritonitis decrease the breaking strenght and the tissue collagen of the small intestine. When peritonitis was associated with diclofenac sodium there was a summation of the deleterious effects observed separately in the Per and DS groups.