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1.
Eur J Med Genet ; : 103777, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31580924

RESUMO

Snyder-Robinson syndrome (SRS) is an X-linked syndromic intellectual disability condition caused by variants in the spermine synthase gene (SMS). The syndrome is characterized by facial dysmorphism, thin body build, kyphoscoliosis, osteoporosis, hypotonia, developmental delay and associated neurological features (seizures, unsteady gait, abnormal speech). Until now, only missense variants with a functionally characterized partial loss of function (LoF) have been described. Here we describe the first complete LoF variant, Met303Lysfs*, in a male patient with a severe form of Snyder-Robinson syndrome. He presented with multiple malformations and severly delayed development, and died at 4 months of age. Functional in vitro assays showed a complete absence of functional SMS protein. Taken together, our findings and those of previously reported patients confirm that pathogenic variants of SMS are indeed LoF and that there might exist a genotype-phenotype correlation between the type of variant and the severity of the syndrome.

3.
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.

4.
Clin Genet ; 95(4): 462-478, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30677142

RESUMO

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, specific facial features, and marked autonomic nervous system dysfunction, especially with disturbances of regulating respiration and intestinal mobility. It is caused by variants in the transcription factor TCF4. Heterogeneity in the clinical and molecular diagnostic criteria and care practices has prompted a group of international experts to establish guidelines for diagnostics and care. For issues, for which there was limited information available in international literature, we collaborated with national support groups and the participants of a syndrome specific international conference to obtain further information. Here, we discuss the resultant consensus, including the clinical definition of PTHS and a molecular diagnostic pathway. Recommendations for managing particular health problems such as dysregulated respiration are provided. We emphasize the need for integration of care for physical and behavioral issues. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimization of diagnostics and care.

5.
Clin Genet ; 95(3): 420-426, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30633342

RESUMO

Rubinstein-Taybi syndrome (RSTS; OMIM 180849) is an autosomal dominant developmental disorder characterized by facial dysmorphism, broad thumbs and halluces associated with intellectual disability. RSTS is caused by alterations in CREBBP (about 60%) and EP300 genes (8%). RSTS is often diagnosed at birth or during early childhood but generally not suspected during antenatal period. We report nine cases of well-documented fetal RSTS. Two cases were examined after death in utero at 18 and 35 weeks of gestation and seven cases after identification of ultrasound abnormalities and termination of pregnancy. On prenatal sonography, a large gallbladder was detected in two cases, and brain malformations were noted in four cases, especially cerebellar hypoplasia. However, the diagnosis of RSTS has not been suggested during pregnancy. Fetal autopsy showed that all fetuses had large thumbs and/or suggestive facial dysmorphism. A CREBBP gene anomaly was identified in all cases. Alterations were similar to those found in typical RSTS children. This report will contribute to a better knowledge of the fetal phenotype to consider the hypothesis of RSTS during pregnancy. Genotyping allows reassuring genetic counseling.

6.
Brain Dev ; 40(9): 768-774, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29861155

RESUMO

OBJECTIVE: Heterozygous mutations in the ATP1A3 gene are responsible for various neurological disorders, ranging from early-onset alternating hemiplegia of childhood to adult-onset dystonia-parkinsonism. Next generation sequencing allowed the description of other phenotypes, including early-onset epileptic encephalopathy in two patients. We report on three more patients carrying ATP1A3 mutations with a close phenotype and discuss the relationship of this phenotype to alternating hemiplegia of childhood. METHODS: The patients' DNA underwent next generation sequencing. A retrospective analysis of clinical case records is reported. RESULTS: Each of the three patients had an unreported heterozygous de novo sequence variant in ATP1A3. These patients shared a similar phenotype characterized by early-onset attacks of movement disorders, some of which proved to be epileptic, and severe developmental delay. (Hemi)plegic attacks had not been considered before genetic testing. SIGNIFICANCE: Together with the two previously reported cases, our patients confirm that ATP1A3 mutations are associated with a phenotype combining features of early-onset encephalopathy, epilepsy and dystonic fits, as in the most severe forms of alternating hemiplegia of childhood, but in which (hemi)plegic attacks are absent or only suspected retrospectively.


Assuntos
Epilepsia/genética , Transtornos dos Movimentos/genética , Mutação , Convulsões/genética , ATPase Trocadora de Sódio-Potássio/genética , Adolescente , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/fisiopatologia , Feminino , Hemiplegia/genética , Hemiplegia/fisiopatologia , Humanos , Masculino , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/fisiopatologia , Convulsões/diagnóstico , Convulsões/fisiopatologia
7.
Am J Med Genet A ; 176(1): 151-155, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29130637

RESUMO

A congenital myasthenia was suspected in two unrelated children with very similar phenotypes including several episodes of severe dyspnea. Both children had a 10q11.2 deletion revealed by Single Nucleotide Polymorphisms array or by Next Generation Sequencing analysis. The deletion was inherited from the healthy mother in the first case. These deletions unmasked a recessive mutation at the same locus in both cases, but in two different genes: CHAT and SLC18A3.


Assuntos
Colina O-Acetiltransferase/genética , Deleção Cromossômica , Cromossomos Humanos Par 10 , Genes Recessivos , Mutação , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/genética , Fenótipo , Proteínas Vesiculares de Transporte de Acetilcolina/genética , Sequência de Aminoácidos , Feminino , Estudos de Associação Genética , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único
8.
NPJ Genom Med ; 2: 32, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29263841

RESUMO

Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inherited SHANK3 deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.

9.
Can J Occup Ther ; 84(4-5): 242-252, 2017 Oct/Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28643527

RESUMO

BACKGROUND: Adopting a new model of clinical practice is complex. Professional development programs based on best-practice principles may facilitate this process. PURPOSE: This paper describes the development and evaluation of a multifaceted professional development program designed to support school-based occupational therapists to deliver a capacity-building model of service. METHOD: Twenty-two therapists participated in the program; completed pre-post evaluations of knowledge, skills, and beliefs; evaluated specific components of the training program; and participated in focus groups. Quantitative data were analyzed using descriptive and inferential statistics. Qualitative data were analyzed using a directed content analysis. FINDINGS: Therapists' perceptions of their knowledge and skills showed statistically significant change. Both training and mentorship were highly valued; however, having opportunities to build peer networks was considered essential. IMPLICATIONS: Multifaceted professional development programs designed using best-practice principles are an important mechanism for facilitating practice change. Including a process for peer support is advised.


Assuntos
Fortalecimento Institucional/organização & administração , Conhecimentos, Atitudes e Prática em Saúde , Terapia Ocupacional/organização & administração , Serviços de Saúde Escolar/organização & administração , Comportamento Cooperativo , Humanos , Capacitação em Serviço , Mentores , Cultura Organizacional , Grupo Associado
10.
Am J Hum Genet ; 100(4): 659-665, 2017 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-28318499

RESUMO

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.


Assuntos
Artrogripose/genética , Proteínas da Matriz Extracelular/genética , Mutação , Células de Schwann/metabolismo , Artrogripose/diagnóstico , Artrogripose/patologia , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Bainha de Mielina/metabolismo , Linhagem
11.
J Pediatr ; 185: 160-166.e1, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28284480

RESUMO

OBJECTIVE: To evaluate the role that chromosomal micro-rearrangements play in patients with both corpus callosum abnormality and intellectual disability, we analyzed copy number variations (CNVs) in patients with corpus callosum abnormality/intellectual disability STUDY DESIGN: We screened 149 patients with corpus callosum abnormality/intellectual disability using Illumina SNP arrays. RESULTS: In 20 patients (13%), we have identified at least 1 CNV that likely contributes to corpus callosum abnormality/intellectual disability phenotype. We confirmed that the most common rearrangement in corpus callosum abnormality/intellectual disability is inverted duplication with terminal deletion of the 8p chromosome (3.2%). In addition to the identification of known recurrent CNVs, such as deletions 6qter, 18q21 (including TCF4), 1q43q44, 17p13.3, 14q12, 3q13, 3p26, and 3q26 (including SOX2), our analysis allowed us to refine the 2 known critical regions associated with 8q21.1 deletion and 19p13.1 duplication relevant for corpus callosum abnormality; report a novel 10p12 deletion including ZEB1 recently implicated in corpus callosum abnormality with corneal dystrophy; and) report a novel pathogenic 7q36 duplication encompassing SHH. In addition, 66 variants of unknown significance were identified in 57 patients encompassed candidate genes. CONCLUSIONS: Our results confirm the relevance of using microarray analysis as first line test in patients with corpus callosum abnormality/intellectual disability.


Assuntos
Agenesia do Corpo Caloso/genética , Variações do Número de Cópias de DNA , Deficiência Intelectual/genética , Adolescente , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Ciclo Celular/genética , Criança , Pré-Escolar , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 7 , Cromossomos Humanos Par 8 , Feminino , Proteínas Hedgehog/genética , Humanos , Masculino , Análise em Microsséries , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Adulto Jovem , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
12.
Am J Hum Genet ; 99(4): 928-933, 2016 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-27616481

RESUMO

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through linkage analysis, homozygosity mapping, and exome sequencing in four unrelated families affected by lethal AMC, we identified biallelic mutations in GLDN in the affected individuals. GLDN encodes gliomedin, a secreted cell adhesion molecule involved in the formation of the nodes of Ranvier. Transmission electron microscopy of the sciatic nerve from one of the affected individuals showed a marked lengthening defect of the nodes. The GLDN mutations found in the affected individuals abolish the cell surface localization of gliomedin and its interaction with its axonal partner, neurofascin-186 (NF186), in a cell-based assay. The axoglial contact between gliomedin and NF186 is essential for the initial clustering of Na+ channels at developing nodes. These results indicate a major role of gliomedin in node formation and the development of the peripheral nervous system in humans. These data indicate that mutations of GLDN or CNTNAP1 (MIM: 616286), encoding essential components of the nodes of Ranvier and paranodes, respectively, lead to inherited nodopathies, a distinct disease entity among peripheral neuropathies.


Assuntos
Artrogripose/genética , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Nós Neurofibrosos/metabolismo , Alelos , Axônios/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Exoma/genética , Feminino , Morte Fetal , Humanos , Recém-Nascido , Masculino , Proteínas de Membrana/metabolismo , Fatores de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Linhagem , Ligação Proteica/genética , Nós Neurofibrosos/ultraestrutura
13.
Prenat Diagn ; 35(4): 337-41, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25475607

RESUMO

OBJECTIVE: The association of periventricular nodular heterotopia (PVNH) with posterior fossa cyst (PFC) is documented after birth. We report this association in a series of fetuses. METHODS: Eleven cases (7 females) of PVNH and PFC diagnosed at prenatal imaging were collected in this retrospective multicenter study. The patients were referred to tertiary centers for targeted ultrasonography (US) and Magnetic Resonance Imaging (MRI) following detection of PFC on routine US. Mutations of the filamin A gene (FLNA) were searched for (n = 6). Maternal brain MRI was performed (n = 8). Post-mortem or postnatal data were recorded. RESULTS: Targeted US was performed at a mean gestational age of 29 (range; 23-35) weeks and identified PVNH in 4 cases. At MRI, performed at a mean gestational age of 31 (range; 29-35) weeks, PVNH and PFC were visible in all cases. Those findings were confirmed by postnatal MRI (n = 3), autopsy (n = 7) and/or post-mortem MRI (n = 2) or US (n = 1). Maternal brain MRI showed PVNH in one case. A de novo FLNA mutation was found in four cases. CONCLUSION: We describe a series of PVNH and PFC in fetuses, which underlines the importance of searching for PVNH when PFC is identified at prenatal US. © 2014 John Wiley & Sons, Ltd.


Assuntos
Neoplasias Infratentoriais/diagnóstico , Imagem por Ressonância Magnética/métodos , Heterotopia Nodular Periventricular/diagnóstico , Ultrassonografia Pré-Natal/métodos , Cistos , Feminino , Humanos , Neoplasias Infratentoriais/complicações , Masculino , Mutação , Heterotopia Nodular Periventricular/complicações , Gravidez , Estudos Retrospectivos
14.
Hum Mol Genet ; 23(1): 171-81, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23966205

RESUMO

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent adult muscular dystrophies. The common clinical signs usually appear during the second decade of life but when the first molecular dysregulations occur is still unknown. Our aim was to determine whether molecular dysregulations can be identified during FSHD fetal muscle development. We compared muscle biopsies derived from FSHD1 fetuses and the cells derived from some of these biopsies with biopsies and cells derived from control fetuses. We mainly focus on DUX4 isoform expression because the expression of DUX4 has been confirmed in both FSHD cells and biopsies by several laboratories. We measured DUX4 isoform expression by using qRT-PCR in fetal FSHD1 myotubes treated or not with an shRNA directed against DUX4 mRNA. We also analyzed DUX4 downstream target gene expression in myotubes and fetal or adult FSHD1 and control quadriceps biopsies. We show that both DUX4-FL isoforms are already expressed in FSHD1 myotubes. Interestingly, DUX4-FL expression level is much lower in trapezius than in quadriceps myotubes, which is confirmed by the level of expression of DUX4 downstream genes. We observed that TRIM43 and MBD3L2 are already overexpressed in FSHD1 fetal quadriceps biopsies, at similar levels to those observed in adult FSHD1 quadriceps biopsies. These results indicate that molecular markers of the disease are already expressed during fetal life, thus opening a new field of investigation for mechanisms leading to FSHD.


Assuntos
Proteínas de Homeodomínio/genética , Fibras Musculares Esqueléticas/metabolismo , Distrofia Muscular Facioescapuloumeral/embriologia , Distrofia Muscular Facioescapuloumeral/genética , Adulto , Células Cultivadas , Feminino , Feto , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Desenvolvimento Muscular , Fibras Musculares Esqueléticas/patologia , Distrofia Muscular Facioescapuloumeral/patologia , Isoformas de Proteínas/genética , Músculo Quadríceps/embriologia , Músculo Quadríceps/metabolismo , Isoformas de RNA/genética , Isoformas de RNA/metabolismo , RNA Interferente Pequeno/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Músculos Superficiais do Dorso/embriologia , Músculos Superficiais do Dorso/metabolismo
15.
Eur J Hum Genet ; 22(1): 71-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23632794

RESUMO

Copy number variants (CNVs) have repeatedly been found to cause or predispose to autism spectrum disorders (ASDs). For diagnostic purposes, we screened 194 individuals with ASDs for CNVs using Illumina SNP arrays. In several probands, we also analyzed candidate genes located in inherited deletions to unmask autosomal recessive variants. Three CNVs, a de novo triplication of chromosome 15q11-q12 of paternal origin, a deletion on chromosome 9p24 and a de novo 3q29 deletion, were identified as the cause of the disorder in one individual each. An autosomal recessive cause was considered possible in two patients: a homozygous 1p31.1 deletion encompassing PTGER3 and a deletion of the entire DOCK10 gene associated with a rare hemizygous missense variant. We also identified multiple private or recurrent CNVs, the majority of which were inherited from asymptomatic parents. Although highly penetrant CNVs or variants inherited in an autosomal recessive manner were detected in rare cases, our results mainly support the hypothesis that most CNVs contribute to ASDs in association with other CNVs or point variants located elsewhere in the genome. Identification of these genetic interactions in individuals with ASDs constitutes a formidable challenge.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Cromossomos Humanos Par 15/genética , Variações do Número de Cópias de DNA/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Criança , Transtornos Globais do Desenvolvimento Infantil/etiologia , Transtornos Globais do Desenvolvimento Infantil/patologia , Pré-Escolar , Cromossomos Humanos Par 5/genética , Hibridização Genômica Comparativa , Síndrome do Miado do Gato/genética , Metilação de DNA/genética , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Trissomia/genética
16.
Brain Dev ; 35(2): 172-6, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22541666

RESUMO

Mutations in the SLC9A6 gene cause Christianson syndrome in boys. This X-linked syndrome is characterized by profound mental retardation with autistic behavior, microcephaly, epilepsy, ophthalmoplegia, and ataxia. Progressive cerebellar atrophy with motor regression is a remarkable feature in some patients. We report on a 22year-old male patient with Christianson syndrome carrying the novel p.Gln306X mutation. The infantile phenotype suggested pervasive developmental disorder, then profound mental retardation ensued. In later childhood, progressive cerebellar atrophy was diagnosed on serial brain MRIs and motor regression occurred. Furthermore, ophthalmological evaluations showed a retinitis pigmentosum previously unreported in this condition. We conclude that the natural history of the disease in this patient tends to confirm the degenerative nature of Christianson syndrome, and that retinal degeneration may be part of the condition. Before the onset of degeneration, the syndromic association of severe mental retardation, autistic behavior, external ophthalmoplegia, and facial dysmorphism in male patients is a clue to the diagnosis.


Assuntos
Retardo Mental Ligado ao Cromossomo X/genética , Mutação/fisiologia , Retinite Pigmentosa/genética , Trocadores de Sódio-Hidrogênio/genética , Ataxia/etiologia , Atrofia , Doenças Cerebelares/genética , Códon sem Sentido/genética , Análise Mutacional de DNA , Progressão da Doença , Eletroencefalografia , Humanos , Imagem por Ressonância Magnética , Masculino , Retardo Mental Ligado ao Cromossomo X/psicologia , Mutação/genética , Degeneração Retiniana/etiologia , Degeneração Retiniana/patologia , Retinite Pigmentosa/psicologia , Síndrome , Adulto Jovem
17.
Neurology ; 79(18): 1898-907, 2012 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-23077007

RESUMO

OBJECTIVE: Fragile X-associated tremor ataxia syndrome (FXTAS) is defined by FMR1 premutation, cerebellar ataxia, intentional tremor, and middle cerebellar peduncle (MCP) hyperintensities. We delineate the clinical, neurophysiologic, and morphologic characteristics of FXTAS. METHODS: Clinical, morphologic (brain MRI, (123)I-ioflupane SPECT), and neurophysiologic (tremor recording, nerve conduction studies) study in 22 patients with FXTAS, including 4 women. RESULTS: A total of 43% of patients had no family history of fragile X syndrome (FXS), which contrasts with previous FXTAS series. A total of 86% of patients had tremor and 81% peripheral neuropathy. We identified 3 electroclinical tremor patterns: essential-like (35%), cerebellar (29%), and parkinsonian (12%). Two electrophysiologic patterns evocative of non-length-dependent (56%) and length-dependent sensory neuropathy (25%) were identified. Corpus callosum splenium (CCS) hyperintensity was as frequent (68%) as MCP hyperintensities (64%). Sixty percent of patients had parkinsonism and 47% abnormal (123)I-ioflupane SPECT. Unified Parkinson's Disease Rating Scale motor score was correlated to abnormal (123)I-ioflupane SPECT (p = 0.02) and to CGG repeat number (p = 0.0004). Scale for the assessment and rating of ataxia correlated with dentate nuclei hyperintensities (p = 0.03) and CCS hyperintensity was a marker of severe disease progression (p = 0.04). CONCLUSIONS: We recommend to include in the FXTAS testing guidelines both CCS hyperintensity and peripheral neuropathy and to consider them as new major radiologic and minor clinical criterion, respectively, for the diagnosis of FXTAS. FXTAS should also be considered in women or when tremor, MCP hyperintensities, or family history of FXS are lacking. Our study broadens the spectrum of tremor, peripheral neuropathy, and MRI abnormalities in FXTAS, hence revealing the need for revised criteria.


Assuntos
Ataxia/diagnóstico , Síndrome do Cromossomo X Frágil/diagnóstico , Transtornos Parkinsonianos/diagnóstico , Doenças do Sistema Nervoso Periférico/diagnóstico , Tremor/diagnóstico , Adulto , Idoso , Ataxia/genética , Ataxia/fisiopatologia , Feminino , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Neurologia/normas , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/fisiopatologia , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/fisiopatologia , Guias de Prática Clínica como Assunto/normas , Tremor/genética , Tremor/fisiopatologia
18.
Eur J Med Genet ; 55(10): 541-7, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22683461

RESUMO

Myhre syndrome is a very rare condition described thirty years ago and related to mutations in the SMAD4 gene. It has been reported in 19 patients, including 13 males and 6 females before the recent finding of heterozygous mutations in the SMAD4 gene in 19 patients. It is characterized by mental retardation, short stature, muscle hypertrophy, limitation of joints movements, deafness, skeletal anomalies, and facial dysmorphism. Ophthalmological involvement includes hypermetropia and congenital cataract. We report here the new finding of retinal involvement including retinitis pigmentosa and maculopathy in two unrelated patients with Myhre syndrome. The patient with retinitis pigmentosa carried the p.I500T mutation in SMAD4, but no mutation was found in the patient with the maculopathy.


Assuntos
Criptorquidismo/complicações , Transtornos do Crescimento/complicações , Deformidades Congênitas da Mão/complicações , Hipertrofia/complicações , Deficiência Intelectual/complicações , Artropatias/complicações , Retinite Pigmentosa/genética , Adulto , Criança , Criptorquidismo/diagnóstico , Criptorquidismo/genética , Facies , Feminino , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Humanos , Hipertrofia/diagnóstico , Hipertrofia/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Artropatias/diagnóstico , Artropatias/genética , Macula Lutea/patologia , Masculino , Mutação de Sentido Incorreto , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/etiologia , Proteína Smad4/genética
19.
Can J Occup Ther ; 79(1): 41-50, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22439291

RESUMO

BACKGROUND: Developmental coordination disorder (DCD) is a common, chronic health condition that is poorly recognized and understood in school settings. Without appropriate support, children with DCD are at increased risk of depression, decreased fitness, and obesity. Evidence shows that occupational therapy intervention needs to shift from remediation of impairment to chronic disease management. PURPOSE: This paper describes Partnering for Change (P4C), an innovative, empirically derived school health service delivery model for children with DCD. KEY ISSUES: The model emphasizes the partnership of the occupational therapist with educators and parents to change the life and daily environment of a child. The P4C partnership focuses on capacity building through collaboration and coaching in context. The model uses a tiered approach which includes whole class instruction, dynamic performance analysis, and monitoring response to intervention. IMPLICATIONS: P4C is a model that responds to the needs of this population, addresses issues identified in research, and provides a continuum of services designed to build capacity.


Assuntos
Assistência à Saúde/métodos , Transtornos das Habilidades Motoras/terapia , Terapia Ocupacional/métodos , Serviços de Saúde Escolar , Fortalecimento Institucional , Criança , Docentes , Humanos , Pais
20.
Hum Mutat ; 33(1): 64-72, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22045651

RESUMO

Pitt-Hopkins syndrome (PTHS), characterized by severe intellectual disability and typical facial gestalt, is part of the clinical spectrum of Rett-like syndromes. TCF4, encoding a basic helix-loop-helix (bHLH) transcription factor, was identified as the disease-causing gene with de novo molecular defects. While PTHS appears to be a recognizable clinical entity, it seems to remain underdiagnosed, especially when facial gestalt is less typical. With the aim to facilitate the diagnosis of PTHS and to increase its rate and specificity, we have investigated 33 novel patients and defined a Clinical Diagnosis Score. Analysis of 112 individuals (79 previously reported and 33 novel patients) allowed us to delineate the TCF4 mutational spectrum, with 40% point mutations, 30% small deletions/insertions, and 30% deletions. Most of these were private mutations and generated premature stop codons. Missense mutations were localized in the bHLH domain, which is a mutational hotspot. No obvious difference was observed between patients harboring truncating, missense mutations, or deletions, further supporting TCF4 haploinsufficiency as the molecular mechanism underlying PTHS. In this study, we have summarized the current knowledge of TCF4 molecular pathology, reported all the mutations in the TCF4 database (http://www.LOVD.nl/TCF4), and present a novel and comprehensive diagnostic strategy for PTHS.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Cromossomos Humanos Par 18/genética , Hiperventilação/diagnóstico , Deficiência Intelectual/diagnóstico , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos Par 18/química , Bases de Dados Genéticas , Facies , Feminino , Estudos de Associação Genética , Variação Genética , Genótipo , Haploinsuficiência , Haplótipos , Humanos , Hiperventilação/genética , Lactente , Deficiência Intelectual/genética , Masculino , Mutação de Sentido Incorreto , Fenótipo , Estrutura Terciária de Proteína , Deleção de Sequência , Inversão de Sequência , Índice de Gravidade de Doença , Fator de Transcrição 4
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