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1.
Am J Hum Genet ; 105(5): 1023-1029, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31630788

RESUMO

We describe unrelated individuals with ichthyosis, failure to thrive, thrombocytopenia, photophobia, and progressive hearing loss. Each have bi-allelic mutations in AP1B1, the gene encoding the ß subunit of heterotetrameric adaptor protein 1 (AP-1) complexes, which mediate endomembrane polarization, sorting, and transport. In affected keratinocytes the AP-1 ß subunit is lost, and the γ subunit is greatly reduced, demonstrating destabilization of the AP-1 complex. Affected cells and tissue contain an abundance of abnormal vesicles and show hyperproliferation, abnormal epidermal differentiation, and derangement of intercellular junction proteins. Transduction of affected cells with wild-type AP1B1 rescues the vesicular phenotype, conclusively establishing that loss of AP1B1 function causes this disorder.

2.
Nat Commun ; 10(1): 4112, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511512

RESUMO

Many neuropsychiatric risk genes contribute to epigenetic regulation but little is known about specific chromatin-associated mechanisms governing the formation of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46, a nuclear protein encoded in the chromosome 11p13 WAGR risk locus. C11orf46 haploinsufficiency was associated with hypoplasia of the corpus callosum. C11orf46 knockdown disrupted transcallosal projections and was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with intellectual disability. Multiple genes encoding key regulators of axonal development, including Sema6a, were hyperexpressed in C11orf46-knockdown neurons. RNA-guided epigenetic editing of Sema6a gene promoters via a dCas9-SunTag system with C11orf46 binding normalized SEMA6A expression and rescued transcallosal dysconnectivity via repressive chromatin remodeling by the SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain's connectome via gene-targeted designer activators and repressor proteins.

3.
J Med Internet Res ; 21(8): e14871, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31441430

RESUMO

BACKGROUND: While individual access to health records has traditionally been through paper and other physical media, there has been a recent push toward digitizing this process. Direct patient access to health data through application programming interfaces (APIs) is an important part of current United States policy initiatives, and Apple has created the product "Health Records on iPhone" to leverage APIs for this purpose. OBJECTIVE: The objective of this study was to examine the characteristics of patients at our institution who connected their personal iPhone devices to our electronic health records (EHRs) system through "Health Records on iPhone", as compared to patients at our institution who used our patient portal but did not connect a personal device to our system. METHODS: We examined adult patients at our institution who had authorized an iPhone device to download their health data from the Partners HealthCare EHR via APIs through "Health Records on iPhone" from February 18, 2018 (the date this feature was enabled at our health system) until February 17, 2019. We compared these patients to adult patients who used our portal at least once during this period but did not authorize an iPhone device to download their data via APIs. RESULTS: Variables associated with an increased likelihood of using "Health Records on iPhone" included male gender (adjusted OR 3.36; 95% CI 3.11-3.62; P<.001) and younger age, particularly below 50 years of age. With each decade of age over 50, people were less likely to be "Health Records on iPhone" product users. Asian patients were more likely to use the product than Caucasian patients (adjusted OR 1.32; 95% CI 1.16-1.51; P<.001), though there was no significant difference between African Americans and Caucasians (adjusted OR 1.15; 95% CI 0.94-1.41; P=.17). Patients who resided in higher ZIP code income quartiles were more likely to be users than those in the lowest quartile. CONCLUSIONS: Early results from the implementation of patient-facing APIs at a single institution suggest that there are opportunities for expanding these technologies to ensure all patients are aware of, and have access to, their health data on their personal devices. More work is needed on expanding these technologies to different patient populations.

4.
Am J Med Genet A ; 179(10): 2049-2055, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31400068

RESUMO

Histone Gene Cluster 1 Member E, HIST1H1E, encodes Histone H1.4, is one of a family of epigenetic regulator genes, acts as a linker histone protein, and is responsible for higher order chromatin structure. HIST1H1E syndrome (also known as Rahman syndrome, OMIM #617537) is a recently described intellectual disability (ID) syndrome. Since the initial description of five unrelated individuals with three different heterozygous protein-truncating variants (PTVs) in the HIST1H1E gene in 2017, we have recruited 30 patients, all with HIST1H1E PTVs that result in the same shift in frame and that cluster to a 94-base pair region in the HIST1H1E carboxy terminal domain. The identification of 30 patients with HIST1H1E variants has allowed the clarification of the HIST1H1E syndrome phenotype. Major findings include an ID and a recognizable facial appearance. ID was reported in all patients and is most frequently of moderate severity. The facial gestalt consists of a high frontal hairline and full lower cheeks in early childhood and, in later childhood and adulthood, affected individuals have a strikingly high frontal hairline, frontal bossing, and deep-set eyes. Other associated clinical features include hypothyroidism, abnormal dentition, behavioral issues, cryptorchidism, skeletal anomalies, and cardiac anomalies. Brain magnetic resonance imaging (MRI) is frequently abnormal with a slender corpus callosum a frequent finding.

5.
Am J Med Genet A ; 179(10): 2144-2151, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31287223

RESUMO

Warsaw breakage syndrome (WABS), caused by bi-allelic variants in the DDX11 gene, is a rare cohesinopathy characterized by pre- and postnatal growth retardation, microcephaly, intellectual disability, facial dysmorphia, and sensorineural hearing loss due to cochlear hypoplasia. The DDX11 gene codes for an iron-sulfur DNA helicase in the Superfamily 2 helicases and plays an important role in genomic stability and maintenance. Fourteen individuals with WABS have been previously reported in the medical literature. Affected individuals have been of various ethnic backgrounds with different pathogenic variants. We report two unrelated individuals of Ashkenazi Jewish descent affected with WABS, who are homozygous for the c.1763-1G>C variant in the DDX11 gene. Their phenotype is consistent with previously reported individuals. RNA studies showed that this variant causes an alternative splice acceptor site leading to a frameshift in the open reading frame. Carrier screening of the c.1763-1G>C variant in the Jewish population revealed a high carrier frequency of 1 in 68 in the Ashkenazi Jewish population. Due to the high carrier frequency and the low number of affected individuals, we hypothesize a high rate of miscarriage of homozygous fetuses and/or subfertility for carrier couples. If the carrier frequency is reproducible in additional Ashkenazi Jewish populations, we suggest including DDX11 to Ashkenazi Jewish carrier screening panels.

6.
Genet Med ; 21(9): 2036-2042, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30739909

RESUMO

PURPOSE: To define the clinical characteristics of patients with variants in TCF20, we describe 27 patients, 26 of whom were identified via exome sequencing. We compare detailed clinical data with 17 previously reported patients. METHODS: Patients were ascertained through molecular testing laboratories performing exome sequencing (and other testing) with orthogonal confirmation; collaborating referring clinicians provided detailed clinical information. RESULTS: The cohort of 27 patients all had novel variants, and ranged in age from 2 to 68 years. All had developmental delay/intellectual disability. Autism spectrum disorders/autistic features were reported in 69%, attention disorders or hyperactivity in 67%, craniofacial features (no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Additional features affecting various organ systems were described in 93%. In a majority of patients, we did not observe previously reported findings of postnatal overgrowth or craniosynostosis, in comparison with earlier reports. CONCLUSION: We provide valuable data regarding the prognosis and clinical manifestations of patients with variants in TCF20.

7.
Am J Med Genet A ; 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30346093

RESUMO

The GATA zing finger domain-containing protein 2B (GATAD2B) gene encodes the p66beta protein, a subunit of the MeCP1-Mi2/ nucleosome remodeling and deacetylase complex, which is involved in transcription regulation and chromatin remodeling. Pathogenic variants in the GATAD2B gene have recently been associated with a recognizable neurodevelopmental syndrome, characterized by intellectual disability, limited speech, childhood hypotonia, and dysmorphic features. The majority of reported patients resulted from de novo loss of function (LOF) variants. We report a patient identified through whole exome sequencing analysis where a healthy mother was found to be low level mosaic for the pathogenic LOF variant found in her child, who is affected with GATAD2B-associated neurodevelopmental disorder (GAND). This variant was only found with the use of next generation sequencing technology in the mother and confirmed by digital droplet PCR. We summarize additional patients with GATAD2B LOF variants from a literature review and with our patient we contribute to delineate the phenotypic spectrum of GAND. We highlight the importance of detailed genetic testing, testing method, and counseling for cases of somatic mosaicism in an unaffected parent of children with GAND. This inheritance may be underreported and has a direct impact on reproductive planning and prenatal diagnosis.

8.
CPT Pharmacometrics Syst Pharmacol ; 7(7): 442-452, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29920993

RESUMO

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with heterogeneous clinical manifestations, including hepatosplenomegaly and infiltrative pulmonary disease, and is associated with significant morbidity and mortality. Olipudase alfa (recombinant human acid sphingomyelinase) is an enzyme replacement therapy under development for the non-neurological manifestations of ASMD. We present a quantitative systems pharmacology (QSP) model supporting the clinical development of olipudase alfa. The model is multiscale and mechanistic, linking the enzymatic deficiency driving the disease to molecular-level, cellular-level, and organ-level effects. Model development was informed by natural history, and preclinical and clinical studies. By considering patient-specific pharmacokinetic (PK) profiles and indicators of disease severity, the model describes pharmacodynamic (PD) and clinical end points for individual patients. The ASMD QSP model provides a platform for quantitatively assessing systemic pharmacological effects in adult and pediatric patients, and explaining variability within and across these patient populations, thereby supporting the extrapolation of treatment response from adults to pediatrics.

9.
Am J Hum Genet ; 102(1): 69-87, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29290338

RESUMO

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.

10.
Hum Mutat ; 39(5): 666-675, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29330883

RESUMO

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype-phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.

11.
Am J Med Genet A ; 173(12): 3158-3164, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28941020

RESUMO

The association between 1p32-p31 contiguous gene deletions and a distinct phenotype that includes anomalies of the corpus callosum, ventriculomegaly, developmental delay, seizures, and dysmorphic features has been long recognized and described. Recently, the observation of overlapping phenotypes in patients with chromosome translocations that disrupt NFIA (Nuclear factor I/A), a gene within this deleted region, and NFIA intragenic deletions has led to the hypothesis that NFIA is a critical gene within this region. The wide application and increasing accessibility of whole exome sequencing (WES) has helped identify new cases to support this hypothesis. Here, we describe four patients with loss-of-function variants in the NFIA gene identified through WES. The clinical presentation of these patients significantly overlaps with the phenotype described in previously reported cases of 1p32-p31 deletion syndrome, NFIA gene disruptions and intragenic NFIA deletions. Our cohort includes a mother and daughter as well as an unrelated individual who share the same nonsense variant (c.205C>T, p.Arg69Ter; NM_001145512.1). We also report a patient with a frameshift NFIA variant (c.159_160dupCC, p.Gln54ProfsTer49). We have compared published cases of 1p32-p31 microdeletion syndrome, translocations resulting in NFIA gene disruption, intragenic deletions, and loss-of-function mutations (including our four patients) to reveal that abnormalities of the corpus callosum, ventriculomegaly/hydrocephalus, macrocephaly, Chiari I malformation, dysmorphic features, developmental delay, hypotonia, and urinary tract defects are common findings. The consistent overlap in clinical presentation provides further evidence of the critical role of NFIA haploinsufficiency in the development of the 1p32-p31 microdeletion syndrome phenotype.


Assuntos
Agenesia do Corpo Caloso/genética , Malformação de Arnold-Chiari/genética , Deficiências do Desenvolvimento/genética , Megalencefalia/genética , Fatores de Transcrição NFI/genética , Malformações do Sistema Nervoso/genética , Adolescente , Adulto , Agenesia do Corpo Caloso/diagnóstico , Malformação de Arnold-Chiari/diagnóstico , Criança , Deleção Cromossômica , Cromossomos Humanos Par 1 , Estudos de Coortes , Deficiências do Desenvolvimento/diagnóstico , Feminino , Haploinsuficiência , Humanos , Mutação com Perda de Função , Masculino , Megalencefalia/diagnóstico , Malformações do Sistema Nervoso/diagnóstico , Sequenciamento Completo do Exoma
12.
Case Rep Endocrinol ; 2017: 3905905, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28620554

RESUMO

We present the clinical phenotype of a toddler who presented with vitamin D-resistant rickets, with one of the highest initial levels of alkaline phosphatase and parathyroid hormone (PTH) levels reported in the literature. The toddler had novel compound heterozygous mutations in the ligand-binding site of the vitamin D receptor and had an excellent response to calcitriol (1,25(OH)2D).

13.
Am J Hum Genet ; 100(1): 128-137, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28017372

RESUMO

Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.


Assuntos
Mutação , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Ataxia/genética , Sistema Nervoso Central/anormalidades , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Genitália/anormalidades , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Hipotonia Muscular/genética , Distúrbios da Fala/genética , Síndrome , Dedos de Zinco/genética
14.
J Pediatr Endocrinol Metab ; 29(7): 867-71, 2016 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-27180336

RESUMO

Gonadotropin independent sexual precocity (SP) may be due to congenital adrenal hyperplasia (CAH), and its timing usually depends on the type of mutation in the CYP21A2 gene. Compound heterozygotes are common and express phenotypes of varying severity. The objective of this case report was to investigate the hormonal pattern and unusual genetic profile in a 7-year-old boy who presented with pubic hair, acne, an enlarged phallus, slightly increased testicular volume and advanced bone age. Clinical, hormonal and genetic studies were undertaken in the patient as well as his parents. We found elevated serum 17-hydroxyprogesterone (17-OHP) and androstenedione that were suppressed with dexamethasone, and elevated testosterone that actually rose after giving dexamethasone, indicating activity of the hypothalamic-pituitary-gonadal (HPG) axis. An initial search for common mutations was negative, but a more detailed genetic analysis of the CYP21A2 gene revealed two mutations including R341W, a non-classical mutation inherited from his mother, and g.823G>A, a novel not previously reported consensus donor splice site mutation inherited from his father, which is predicted to be salt wasting. However, the child had a normal plasma renin activity. He was effectively treated with low-dose dexamethasone and a GnRH agonist. His father was an unaffected carrier, but his mother had evidence of mild non-classical CAH. In a male child presenting with gonadotropin independent SP it is important to investigate adrenal function with respect to the androgen profile, and to carry out appropriate genetic studies.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Mutação , Esteroide 21-Hidroxilase/genética , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Hiperplasia Suprarrenal Congênita/fisiopatologia , Substituição de Aminoácidos , Criança , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Heterozigoto , Humanos , Íntrons , Leuprolida/uso terapêutico , Masculino , Puberdade Precoce/etiologia , Puberdade Precoce/prevenção & controle , Testosterona/antagonistas & inibidores , Testosterona/sangue , Resultado do Tratamento
15.
Eur J Hum Genet ; 24(10): 1436-44, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27004616

RESUMO

Sequence variants in CRB2 cause a syndrome with greatly elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein levels, cerebral ventriculomegaly and renal findings similar to Finnish congenital nephrosis. All reported patients have been homozygotes or compound heterozygotes for sequence variants in the Crumbs, Drosophila, Homolog of, 2 (CRB2) genes. Variants affecting CRB2 function have also been identified in four families with steroid resistant nephrotic syndrome, but without any other known systemic findings. We ascertained five, previously unreported individuals with biallelic variants in CRB2 that were predicted to affect function. We compiled the clinical features of reported cases and reviewed available literature for cases with features suggestive of CRB2-related syndrome in order to better understand the phenotypic and genotypic manifestations. Phenotypic analyses showed that ventriculomegaly was a common clinical manifestation (9/11 confirmed cases), in contrast to the original reports, in which patients were ascertained due to renal disease. Two children had minor eye findings and one was diagnosed with a B-cell lymphoma. Further genetic analysis identified one family with two affected siblings who were both heterozygous for a variant in NPHS2 predicted to affect function and separate families with sequence variants in NPHS4 and BBS7 in addition to the CRB2 variants. Our report expands the clinical phenotype of CRB2-related syndrome and establishes ventriculomegaly and hydrocephalus as frequent manifestations. We found additional sequence variants in genes involved in kidney development and ciliopathies in patients with CRB2-related syndrome, suggesting that these variants may modify the phenotype.


Assuntos
Proteínas de Transporte/genética , Genótipo , Hidrocefalia/genética , Proteínas de Membrana/genética , Nefrose/genética , Fenótipo , Feminino , Humanos , Hidrocefalia/diagnóstico , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Mutação , Nefrose/diagnóstico , Linhagem , Proteínas/genética , Síndrome
16.
Ann Clin Transl Neurol ; 2(6): 623-35, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26125038

RESUMO

OBJECTIVE: To determine the cause and course of a novel syndrome with progressive encephalopathy and brain atrophy in children. METHODS: Clinical whole-exome sequencing was performed for global developmental delay and intellectual disability; some patients also had spastic paraparesis and evidence of clinical regression. Six patients were identified with de novo missense mutations in the kinesin gene KIF1A. The predicted functional disruption of these mutations was assessed in silico to compare the calculated conformational flexibility and estimated efficiency of ATP binding to kinesin motor domains of wild-type (WT) versus mutant alleles. Additionally, an in vitro microtubule gliding assay was performed to assess the effects of de novo dominant, inherited recessive, and polymorphic variants on KIF1A motor function. RESULTS: All six subjects had severe developmental delay, hypotonia, and varying degrees of hyperreflexia and spastic paraparesis. Microcephaly, cortical visual impairment, optic neuropathy, peripheral neuropathy, ataxia, epilepsy, and movement disorders were also observed. All six patients had a degenerative neurologic course with progressive cerebral and cerebellar atrophy seen on sequential magnetic resonance imaging scans. Computational modeling of mutant protein structures when compared to WT kinesin showed substantial differences in conformational flexibility and ATP-binding efficiency. The de novo KIF1A mutants were nonmotile in the microtubule gliding assay. INTERPRETATION: De novo mutations in KIF1A cause a degenerative neurologic syndrome with brain atrophy. Computational and in vitro assays differentiate the severity of dominant de novo heterozygous versus inherited recessive KIF1A mutations. The profound effect de novo mutations have on axonal transport is likely related to the cause of progressive neurologic impairment in these patients.

17.
J Med Genet ; 52(8): 541-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26041762

RESUMO

BACKGROUND: L-serine plays an essential role in neuronal development and function. Although a non-essential amino acid, L-serine must be synthesised within the brain because of its poor permeability by the blood-brain barrier. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1. METHODS AND RESULTS: Using exome analysis we identified the recessive mutations, p.E256K, p.L315fs, and p.R457W, in SLC1A4, the gene encoding ASCT1, in patients with developmental delay, microcephaly and hypomyelination; seizure disorder was variably present. When expressed in a heterologous system, the mutations did not affect the protein level at the plasma membrane but abolished or markedly reduced L-serine transport for p.R457W and p.E256K mutations, respectively. Interestingly, p.E256K mutation displayed a lower L-serine and alanine affinity but the same substrate selectivity as wild-type ASCT1. CONCLUSIONS: The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community.


Assuntos
Sistema ASC de Transporte de Aminoácidos/genética , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Adolescente , Transporte Biológico/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Triagem de Portadores Genéticos , Células HEK293 , Heterozigoto , Humanos , Masculino , Bainha de Mielina/metabolismo , Linhagem , Serina/metabolismo
18.
Artigo em Inglês | MEDLINE | ID: mdl-25861997

RESUMO

Beckwith-Wiedemann syndrome (BWS) is the most common genetic overgrowth syndrome, and it is frequently clinically recognizable because of characteristic features. These features include macrosomia, hemihypertrophy, macroglossia, facial nevus flammeus, earlobe creases and pits, omphalocele, and organomegaly. The most common molecular cause is hypomethylation of the maternal imprinting control region 2 (ICR2) in 11p15. Other molecular causes include hypermethylation of the maternal ICR1 in 11p15, mutations in CDKN1C, mosaic uniparental disomy 11p15, and chromosomal abnormalities involving 11p15. Some of these abnormalities are testable, and DNA methylation tests of 11p15 confirm about 60% of cases with BWS. The main management issues in pediatrics are hypoglycemia at birth, macroglossia, and surveillance for embryonal tumors, especially Wilms and hepatoblastoma.


Assuntos
Ansiedade/prevenção & controle , Síndrome de Beckwith-Wiedemann/diagnóstico , Neoplasias/prevenção & controle , Síndrome de Beckwith-Wiedemann/complicações , Síndrome de Beckwith-Wiedemann/psicologia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 11 , Hibridização Genômica Comparativa , Metilação de DNA , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias/etiologia , Neoplasias/psicologia , Pais/psicologia , Fenótipo , Relações Médico-Paciente , Conduta Expectante
19.
J Pediatr Orthop B ; 24(4): 373-6, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25768679

RESUMO

Potocki-Lupski syndrome (PTLS) is a rare chromosomal microduplication syndrome resulting in multiple congenital abnormalities including developmental delays, autistic features, and certain structural anomalies, with cardiovascular being the most common. The phenotype of this contiguous gene duplication syndrome is quite variable and may include musculoskeletal abnormalities. Given the infrequency and novelty of this disorder, full phenotypic characterization of PTLS has not yet been fully elucidated. We present a case of severe bilateral clubfoot in a patient with PTLS. Diagnosis was made by array-based comparative genomic hybridization and confirmed by fluorescence in-situ hybridization. Because clubfoot was also present in an apparently unaffected brother, the presence of PTLS may have acted as a modifier of the phenotype. This report highlights the complex interaction of chromosomal and familial factors that contribute to musculoskeletal birth defects.


Assuntos
Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/diagnóstico , Pé Torto Equinovaro/complicações , Pé Torto Equinovaro/diagnóstico , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/terapia , Transtornos Cromossômicos/terapia , Duplicação Cromossômica , Pé Torto Equinovaro/terapia , Humanos , Lactente , Recém-Nascido , Masculino
20.
BMC Gastroenterol ; 13: 106, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23815124

RESUMO

BACKGROUND: Complications of chronic anal fissure (CAF) treatments are prompting interest in lower-risk therapies. This study was conducted to compare nitroglycerin (NTG) 0.4% ointment with placebo for pain associated with CAF. METHODS: In this randomized, double-blind, placebo-controlled trial, patients with one CAF and moderate-to-severe pain (≥50 mm on a 100 mm visual analog scale [VAS]) received 375 mg NTG 0.4% (1.5 mg active ingredient) or 375 mg placebo ointment applied anally every 12 hours for 21 days. The primary end point was change from baseline VAS score in 24-hour pain averaged over days 14-18. Review of data from patients who withdrew early was blinded to treatment. To control for the confounding effects of analgesics, all patients received 650 mg acetaminophen for headache prophylaxis before each application. RESULTS: A total of 247 patients were enrolled (NTG, n = 123; placebo, n = 124). The prespecified baseline observation carried forward (BOCF) analysis found no significant difference between groups; however, a last observation carried forward (LOCF) analysis showed a significant advantage for NTG. A post hoc analysis (LOCF/BOCF hybrid) demonstrated a significant adjusted mean difference of -7.0 mm in favor of NTG 0.4% (95% CI -13.6, -0.4; P = .038). Headache was the most common adverse event in the NTG (69.9%) and placebo (47.6%) groups. CONCLUSIONS: This was the first placebo-controlled study that also controlled for the confounding effects of analgesics used to treat NTG-induced headache. In patients with moderate-to-severe CAF pain, NTG 0.4% ointment effectively reduced CAF pain compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00522041.


Assuntos
Analgésicos não Entorpecentes/administração & dosagem , Fissura Anal/complicações , Nitroglicerina/administração & dosagem , Dor/tratamento farmacológico , Acetaminofen/uso terapêutico , Adolescente , Adulto , Idoso , Analgésicos não Entorpecentes/efeitos adversos , Analgésicos não Entorpecentes/uso terapêutico , Método Duplo-Cego , Feminino , Cefaleia/induzido quimicamente , Cefaleia/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Nitroglicerina/efeitos adversos , Nitroglicerina/uso terapêutico , Pomadas , Dor/etiologia , Resultado do Tratamento , Adulto Jovem
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