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1.
Gene ; 704: 97-102, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30978478

RESUMO

In the current study, we report three cases of Asparagine Synthetase (ASNS) Deficiency from two consanguineous families. Family 1 had two early neonatal deaths due to a novel mutation in the ASNS gene c.788C > T (p.S263F) and both the children presented with microcephaly and one of them had severe intracranial haemorrhage. The proband from the second family was homozygous for c.146G > A (p.R49Q) and manifested myoclonic seizures, developmental delay, coarse hair and diffuse cortical atrophy. Molecular docking studies of both the mutations revealed alteration in the ligand binding site. Till date, 26 mutations were reported in ASNS gene in 29 affected children indicating high degree of genetic heterogeneity and high mortality. Although asparagine depletion is not of diagnostic utility, multiple linear regression model suggested that asparagine levels vary to the extent of 20.6% based on glutamine and aspartate levels and ASNS deficiency results in depletion of asparagine synthesis. ASNS deficiency should be suspected in any neonate with microcephaly and epileptic encephalopathy.


Assuntos
Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/genética , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Grupo com Ancestrais do Continente Asiático , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/deficiência , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/patologia , Família , Feminino , Humanos , Índia , Lactente , Recém-Nascido , Hemorragias Intracranianas/congênito , Hemorragias Intracranianas/genética , Masculino , Microcefalia/patologia , Técnicas de Diagnóstico Molecular , Morte Perinatal , Convulsões/complicações , Convulsões/genética
2.
Genome Med ; 11(1): 12, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819258

RESUMO

BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.


Assuntos
Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Mutação INDEL , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Síndrome de Smith-Magenis/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/patologia , Síndrome de Smith-Magenis/patologia , Fatores de Transcrição/metabolismo , Adulto Jovem
3.
Mol Genet Genomic Med ; 7(5): e629, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30829465

RESUMO

BACKGROUND: We present a patient with Rett syndrome (RTT; MECP2) and autosomal-recessive succinic semialdehyde dehydrogenase deficiency (SSADHD; ALDH5A1 (aldehyde dehydrogenase 5a1 = SSADH), in whom the current phenotype exhibits features of SSADHD (hypotonia, global developmental delay) and RTT (hand stereotypies, gait anomalies). METHODS: γ-Hydroxybutyric acid (GHB) was quantified by UPLC-tandem mass spectrometry, while mutation analysis followed standard methodology of whole-exome sequencing. RESULTS: The biochemical hallmark of SSADHD, GHB was increased in the proband's dried bloodspot (DBS; 673 µM; previous SSADHD DBSs (n = 7), range 124-4851 µM); control range (n = 2,831), 0-78 µM. The proband was compound heterozygous for pathogenic ALDH5A1 mutations (p.(Asn418IlefsTer39); maternal; p.(Gly409Asp); paternal) and a de novo RTT nonsense mutation in MECP2 (p.Arg255*). CONCLUSION: The major inhibitory neurotransmitter, γ-aminobutyric acid (GABA), is increased in SSADHD but normal in RTT, although there are likely regional changes in GABA receptor distribution. GABAergic anomalies occur in both disorders, each featuring an autism spectrum phenotype. What effect the SSADHD biochemical anomalies (elevated GABA, GHB) might play in the neurodevelopmental/epileptic phenotype of our patient is currently unknown.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Deficiências do Desenvolvimento/genética , Proteína 2 de Ligação a Metil-CpG/genética , Fenótipo , Síndrome de Rett/genética , Succinato-Semialdeído Desidrogenase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Síndrome de Rett/patologia , Succinato-Semialdeído Desidrogenase/genética
4.
Early Hum Dev ; 130: 51-56, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30677638

RESUMO

BACKGROUND: There is a special concern regarding substance using pregnant women due to the possible adverse effects on the infant. While the immediate effects of prenatal substance exposure are well known, the long-term data on the infants' neurodevelopment is inconclusive. AIMS: The purpose of this study was to assess early neurobehavior of infants of mothers with substance use using the Dubowitz examination and to follow their neuromotor development until one year of age. STUDY DESIGN AND SUBJECTS: Ninety-five pregnant women with a recent history of substance use were recruited and followed up at the maternity outpatient clinic. Follow-up data was collected from hospital records and maternal interviews. The Dubowitz neurological examination was performed to the 54 clinically healthy term infants. The results were converted into optimality scores and compared to normative values from clinically healthy term infants derived from a separate normative population. The infant's neuromotor development was followed up to one year of age. RESULTS: Only 7% of the infants born to women with recent or current substance use reached optimal scores (<30.5) in the Dubowitz neurological examination compared to 95% reported in normative population. Sixty-three percent of the newborns needed follow-up based on physiotherapeutic assessment of neurobehavior. By 12 months of age, the neuromotor status of 88% (n = 30) of these infants was found normal. CONCLUSIONS: A high percentage of infants of mothers who were referred prenatally to hospital due to substance use showed suboptimal neurological findings during their first days of life.


Assuntos
Deficiências do Desenvolvimento/epidemiologia , Complicações na Gravidez/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto , Índice de Apgar , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Comportamento do Lactente , Recém-Nascido , Masculino , Exame Neurológico/métodos , Gravidez
5.
Mol Genet Genomic Med ; 7(2): e00507, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30614210

RESUMO

BACKGROUND: Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. METHODS: We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. RESULTS: We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. CONCLUSION: Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.


Assuntos
Anormalidades Múltiplas/genética , Transtorno do Espectro Autista/genética , Duplicação Cromossômica/genética , Deficiências do Desenvolvimento/genética , Síndrome de DiGeorge/genética , Penetrância , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Transtorno do Espectro Autista/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 22/genética , Deficiências do Desenvolvimento/patologia , Síndrome de DiGeorge/patologia , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Duplicações Segmentares Genômicas , Síndrome
6.
J Hum Genet ; 64(3): 253-255, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30542208

RESUMO

In view of conflicting reports on the pathogenicity of 15q11.2 CNVs of the breakpoints 1-2 (BP1-BP2) region and lack of association with a specific phenotype, we collected phenotypic data on 51,462 patients referred for genetic testing at two centers (Magee-Womens Hospital of UPMC and Baylor Genetics Laboratories, Baylor College of Medicine). Using array CGH, 262 patients with deletions and 215 with duplications were identified and tested for their association with four phenotypes (developmental delay, dysmorphic features, autism group of disorders, and epilepsy/seizures). Only association of deletions with dysmorphic features was observed (P = 0.013) with low penetrance (3.8%). Our results, viewed in the context of other reports suggesting the lack of a clear phenotypic outcome, underscore the need for detailed phenotypic studies to better understand the pathogenicity of 15q11.2 (BP1-BP2) CNVs.


Assuntos
Transtorno Autístico/genética , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 15/genética , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Deficiência Intelectual/genética , Transtorno Autístico/patologia , Estudos de Coortes , Deficiências do Desenvolvimento/patologia , Epilepsia/patologia , Humanos , Deficiência Intelectual/patologia , Fenótipo
7.
Hum Genet ; 137(9): 753-768, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30167850

RESUMO

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.


Assuntos
Proteínas de Transporte/genética , Canalopatias/genética , Deficiências do Desenvolvimento/genética , Marcadores Genéticos , Variação Genética , Proteínas de Membrana/genética , Canais de Sódio/genética , Adolescente , Adulto , Canalopatias/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Adulto Jovem
8.
Handb Clin Neurol ; 155: 407-413, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891075

RESUMO

The cerebellum is now at the forefront of research in neuroscience. This is not just a coincidence, occurring about 250 years after the first description of the human cerebellum. The cerebellum contains the majority of neurons in the central nervous system and it is heavily connected with almost all cortical and subcortical areas of the supratentorial region as well as with the brainstem and the spinal cord. Cerebellar circuits are embedded in large-scale networks contributing to motor control and neurocognition. From a phenotypic standpoint, damage to cerebellar lobules interconnected with the sensorimotor cortices leads to a cerebellar motor syndrome, whereas lesions of the posterolateral cerebellum cause cognitive and neuropsychiatric impairments which may or may not be subtle. This topographic rule is valid in children and adults. Midline posterior vermal lesions cause behavioral/affective dysregulation, especially in kids. The extent of the spectrum of human cerebellar disorders is increasingly recognized from the fetus to the elderly, with recognition of consequences for the quality of life and socioeconomic costs due to lifelong morbidity of many cerebellar ataxias/pathologies. The prolonged duration of human cerebellar development makes the cerebellum especially susceptible to developmental disruption, both genetic and nongenetic. This explains the current emphasis on the clarification of the developmental course and impact of the cerebellum. The understanding of how germinal matrix zones and migration of neurons and glial cells end in a highly organized and foliated human cerebellum is essential. This is greatly accelerated by inputs from rodent developmental studies, in particular because cerebellar anatomy is conserved across species. Still, numerous questions on human fetal development remain unanswered. Although both advanced neuroimaging and genetic studies are currently leading to a better definition and understanding of the multitude of cerebellar symptoms, there is a gap, with a great need to develop therapies aiming at first, protection of the cerebellum during development, and second, restoration of cerebellar function in children and in adults. Dynamic profiles of the compensatory processes from newborns to elderly require specific studies.


Assuntos
Doenças Cerebelares/patologia , Cerebelo/embriologia , Cerebelo/crescimento & desenvolvimento , Transtornos Mentais/patologia , Transtornos Cognitivos/patologia , Deficiências do Desenvolvimento/patologia , Feto , Humanos
9.
Handb Clin Neurol ; 154: 109-128, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29903435

RESUMO

The cerebellar system is a series of axonal projections and synaptic circuits as networks, similar to those of the limbic system and those subserving the propagation and spread of seizures. Three principal cerebellar networks are identified and cerebellar disease often affects components of the networks other than just the cerebellar cortex. Contemporary developmental neuropathology of the cerebellum is best considered in the context of alterations of developmental processes: embryonic segmentation and genetic gradients along the three axes of the neural tube, individual neuronal and glial cell differentiation, migration, synaptogenesis, and myelination. Precisely timed developmental processes may be delayed or precocious rhombencephalosynapsis and pontocerebellar hypoplasia exemplify opposite gradients in the horizontal axis. Chiari II malformation may be reconsidered as a disorder of segmentation rather than simply due to mechanical forces upon normally developing hindbrain structures. Cellular nodules in the roof of the fourth ventricle are heterotopia of histologically differentiated but architecturally disoriented and disorganized neurons and glial cells; they often are less mature immunocytochemically than similar cells in adjacent normal folia. Cell rests are nodules of undifferentiated neuroepithelial cells. Both are frequent in human fetuses and neonates. Axonal projections from heterotopia to adjacent cerebellar folia or nuclei are few or absent, hence these nodules are clinically silent despite neuronal differentiation.


Assuntos
Doenças Cerebelares/patologia , Deficiências do Desenvolvimento/patologia , Rede Nervosa/fisiologia , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Neurônios/fisiologia , Animais , Doenças Cerebelares/complicações , Deficiências do Desenvolvimento/complicações , Humanos
10.
J Radiol Case Rep ; 12(3): 18-27, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29875990

RESUMO

We report the imaging appearances of a case of pathologically proven, neonatal neuroblastoma 4S with diffuse hepatic metastatic involvement at presentation. Patient had an abnormal appearing liver both by ultrasound and MR. There was no evidence for associated adrenal tumor by imaging. Lack of an associated adrenal mass led to initial misinterpretation of diffuse hepatic accumulation of MIBG seen with radionuclide scintigraphy. To the best our knowledge, this is the first report of metastatic neonatal 4S neuroblastoma without an adrenal (or extra-adrenal) primary identified either on pre- or post-natal imaging.


Assuntos
Neoplasias Encefálicas/patologia , Dedos/anormalidades , Deficiência Intelectual/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Microcefalia/patologia , Hipotonia Muscular/patologia , Miopia/patologia , Neuroblastoma/secundário , Obesidade/patologia , 3-Iodobenzilguanidina , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/análise , Biópsia , Neoplasias Encefálicas/tratamento farmacológico , Meios de Contraste , Deficiências do Desenvolvimento/patologia , Diagnóstico Diferencial , Feminino , Dedos/patologia , Humanos , Recém-Nascido , Neoplasias Hepáticas/tratamento farmacológico , Imagem por Ressonância Magnética , Estadiamento de Neoplasias , Neuroblastoma/tratamento farmacológico , Compostos Organometálicos , Degeneração Retiniana , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X
11.
J Obstet Gynaecol Res ; 44(6): 1031-1035, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29517144

RESUMO

AIM: This study was aimed to determine reference ranges for fetal cerebellar hemisphere biometry, including the transverse cerebellar diameter (TCD), anteroposterior cerebellar diameter (APCD) and APCD/TCD ratio in normal fetuses. In addition, we investigated which parameter would be useful for cerebellar hypoplasia in trisomy 18. METHODS: This retrospective study included 340 normal singleton pregnancies and 15 cases of trisomy 18, in all of which fetal cerebellar biometry was performed between 14 and 40 weeks of gestational age (GA). The TCD, APCD and APCD/TCD ratio were assessed ultrasonographically. RESULTS: In normal fetuses, the TCD (rs = 0.876, P < 0.001) and APCD (rs = 0.791, P < 0.001) were strongly correlated with GA. However, the APCD/TCD ratio was not correlated with GA (rs = 0.058, P = 0.289), with median values of 0.52. Low TCD, APCD and APCD/TCD ratio values were detected in 53%, 100% and 100% of trisomy 18 cases, respectively. The median APCD/TCD ratio for trisomy 18 was 0.39 (range, 0.30-0.43), which was significantly lower than that of normal fetuses (P < 0.001). A cut-off APCD/TCD ratio of 0.44 served as a good predictor for trisomy 18 (sensitivity 100%, specificity 95.3% and negative predictive value 100%). CONCLUSION: This study shows that TCD and APCD are correlated with GA, while the APCD/TCD ratio is a fixed value throughout gestation. Using the APCD/TCD ratio to assess cerebellar hypoplasia in trisomy 18 is useful because it does not require the individual evaluation of the TCD and APCD.


Assuntos
Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Malformações do Sistema Nervoso/diagnóstico por imagem , Síndrome da Trissomía do Cromossomo 18/diagnóstico por imagem , Ultrassonografia Pré-Natal/normas , Cerebelo/patologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Malformações do Sistema Nervoso/etiologia , Malformações do Sistema Nervoso/patologia , Gravidez , Sensibilidade e Especificidade , Síndrome da Trissomía do Cromossomo 18/complicações , Síndrome da Trissomía do Cromossomo 18/patologia
12.
Dev Med Child Neurol ; 60(7): 672-679, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29573407

RESUMO

AIM: If increased muscle stiffness and contractures in children with cerebral palsy (CP) are related to impaired muscle growth, reduced muscle growth should precede or coincide with increased muscle stiffness during development. Here, we compared the volume of the medial gastrocnemius muscle and the passive (non-neural) stiffness of the triceps surae musculotendinous unit in typically developing children and children with CP from birth until 4 years of age. METHOD: Forty-one children with CP and 45 typically developing children were included. Freehand three-dimensional ultrasound was used to evaluate the volume of the medial gastrocnemius muscle. Biomechanical and electrophysiological measures were used to determine passive and reflex mediated stiffness of the triceps surae musculotendinous unit. RESULTS: Medial gastrocnemius muscle volume increased with the same rate in typically developing and children with CP until 12 months of age, when a significant smaller rate of growth was observed in children with CP. Passive stiffness of the triceps surae musculotendinous unit showed a linear increase with age in typically developing children. Children with CP older than 27 months showed a significant increase in passive stiffness. Reflex mediated stiffness was only pathologically increased in four children with CP. INTERPRETATION: The deviation of medial gastrocnemius muscle volume, earlier than musculotendinous unit stiffness, is consistent with the hypothesis. The data also point out that muscle atrophy and muscle stiffness already develops within the first 1 to 2 years. This emphasizes the necessity of early interventions to promote lower limb muscle growth in this population. WHAT THIS PAPER ADDS: Medial gastrocnemius muscle growth is reduced in children with cerebral palsy (CP) around 12 months after birth. Triceps surae musculotendinous unit stiffness is increased in children with CP around 27 months after birth. Reflex excitability is rarely increased in children with CP. Reduced muscle growth may be involved in the pathophysiology of contractures.


Assuntos
Paralisia Cerebral/complicações , Paralisia Cerebral/patologia , Deficiências do Desenvolvimento/etiologia , Rigidez Muscular/etiologia , Músculo Esquelético/fisiopatologia , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Eletromiografia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Rigidez Muscular/diagnóstico por imagem , Músculo Esquelético/diagnóstico por imagem , Amplitude de Movimento Articular/fisiologia , Índice de Gravidade de Doença , Ultrassonografia
13.
Dev Med Child Neurol ; 60(7): 660-671, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29405265

RESUMO

AIM: The aim of this study was to identify and examine the psychometric properties of muscle tone assessments for children aged 0 to 12 years. METHOD: Four electronic databases were searched to identify studies that included assessments of resting and/or active muscle tone. Methodological quality and overall psychometric evidence of studies were rated using the COnsensus-based Standards for the selection of health Measurement INstruments checklist. RESULTS: Twenty-one assessments were identified from 97 included studies. All assessments were broad developmental assessments that included muscle tone items or subscales. Most assessments (16/21) were designed for young children (<2y). Four assessments measured resting and active tone and demonstrated at least moderate validity or reliability: the Amiel-Tison Neurological Assessment (ATNA) at term, Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS), Premie-Neuro for newborn infants, and the Hammersmith Infant Neurological Examination (HINE) for infants aged 2 months to 2 years. For children over 2 years, the Neurological Sensory Motor Developmental Assessment (NSMDA) assesses resting and active tone but has limited validity. INTERPRETATION: The ATNA at term, NNNS, Premie-Neuro, HINE, and NSMDA can assess resting and active tone in infants and/or children. Further psychometric research is required to extend reliability, validity, and responsiveness data, particularly for older children. WHAT THIS PAPER ADDS: This is the first review of muscle tone assessments for children aged 0 to 12 years. Twenty-one assessments contain muscle tone items and 16 are for children under 2 years. Four assessments are reliable or valid to measure both resting and active tone.


Assuntos
Deficiências do Desenvolvimento/patologia , Músculo Esquelético/fisiopatologia , Doenças Musculares/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Humanos , Lactente , Recém-Nascido , Músculo Esquelético/crescimento & desenvolvimento , Doenças Musculares/complicações
14.
Gene ; 655: 65-70, 2018 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-29477873

RESUMO

Lamb-Shaffer syndrome (OMIM: 616803) is a neurodevelopmental disorder characterized by developmental delay, mild to moderate intellectual disability, speech delay, and mild characteristic facial appearance caused by SOX5 haploinsufficiency on chromosome 12p12.1. There are clinical variabilities among the patients with genomic alterations, such as intragenic deletions, a point mutation, and a chromosomal translocation of t(11;12)(p13;p12.1), in SOX5. We report herein a 5-year-old Japanese male with a de novo balanced reciprocal translocation t(12;20)(p12.1;p12.3) presenting a mild intellectual disability, speech delay, characteristic facial appearance, and autistic features. We determined the translocation breakpoints of the patient to be in intron 4 of SOX5 and the intergenic region in 20p12.3 via FISH and nucleotide sequence analyses. Thus, the present patient has SOX5 haploinsufficiency affecting 2 long forms of SOX5 and is the second reported case of Lamb-Shaffer syndrome caused by a de novo balanced reciprocal translocation. This report confirmed that haploinsufficiency of the 2 long forms of SOX5 presents common clinical features, including mild intellectual disability and autistic features, which could be useful for the clinical diagnosis of Lamb-Shaffer syndrome.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 20 , Haploinsuficiência , Fatores de Transcrição SOXD/genética , Translocação Genética , Transtorno Autístico/genética , Transtorno Autístico/patologia , Pré-Escolar , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 20/genética , Análise Mutacional de DNA , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino
15.
Fetal Pediatr Pathol ; 37(1): 15-21, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29336640

RESUMO

INTRODUCTION: RNASET2 mutation has been reported in patients with cystic leukoencephalopathy without megalencephaly and the Aicardi-Goutieres syndrome. Both disorders are Mendelian mimics of congenital cytomegalovirus infection with overlapping features, including leukoencephalopathy, white matter alterations, intracranial calcification, delayed psychomotor development, intelligence disability and seizures. Only eight families with RNASET2 mutation have been previously reported. METHODS: Whole exome sequencing was performed and copy number variants were described by read-depth strategy. RESULTS: We identified a novel nonsense variant c.128G>A (p. W43*) and a 430 Kb 6q27 microdeletion encompassing RNASET2. Our patient did not show anterior temporal lobe subcortical cysts, hearing loss, dystonia or extra-neurological features. CONCLUSION: Our results provided further genetic and phenotypic information of RNASET2 mutation in Chinese patients and highlighted the importance for physicians to consider RNASET2-related disorders when diagnosing patients with congenital brain infection-like phenotypes.


Assuntos
Deficiências do Desenvolvimento/genética , Ribonucleases/genética , Proteínas Supressoras de Tumor/genética , Grupo com Ancestrais do Continente Asiático/genética , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Genótipo , Humanos , Mutação , Fenótipo
16.
Eur J Med Genet ; 61(5): 248-252, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29274487

RESUMO

Non-recurrent microdeletion (≤2 Mb in size) in 7p22.1 is a rarely described cytogenetic aberration, only recently reported in patients with developmental delay/intellectual disability, short stature and microcephaly. The size of the deletions ranged from 0.37 to 1.5 Mb, and reported genotype-phenotype correlations identified a minimum deleted region of 0.37 Mb involving the FBLX18, ACTB, FSCN1, RNF216 and ZNF815P genes. The authors suggested that deletion of ACTB, which encodes ß-actin, an essential component of the cytoskeleton, could be responsible for the clinical features observed in the patients with a 7p22.1 microdeletion. Here, we describe a 23-month-old child displaying developmental delay, short stature, microcephaly and distinctive facial features. Chromosomal microarray analysis performed using high-resolution SNP-array platform revealed a de novo interstitial 60 Kb microdeletion in the 7p22.1 region (from 5,509,127 bp to 5,569,096 bp, hg19) encompassing only two genes: FBXL18 and ACTB. To the best of our knowledge, this is the smallest deletion at 7p22.1 to date reported in medical literature (Pubmed). Combining our data with phenotypic and genotypic data of cases from literature, we were able to narrow the minimal critical region, which contained only two genes, i.e., FBXL18 and ACTB. Our finding is useful to perform a more accurate genotype-phenotype correlation and strongly strengthen the hypothesis that haploinsufficiency of ACTB is the main cause of the clinical phenotype observed in the patients with 7p22.1 microdeletions, facilitating genetic diagnosis and counseling.


Assuntos
Actinas/genética , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Haploinsuficiência , Humanos , Lactente , Fenótipo , Síndrome
17.
Int J Dev Neurosci ; 65: 83-90, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29126862

RESUMO

Developmental Coordination Disorder (DCD) is as a neurodevelopmental condition characterized by poor motor proficiency, which impacts academic performance and activities of daily living. Several studies have determined that children with DCD activate different regions of the brain when performing motor skills in comparison to typically developing (TD) children. However, none have used Functional Near-Infrared Spectroscopy (fNIRS) to explore cortical activation in this population. With that, the goal of this preliminary study was to investigate cortical activation using fNIRS in six children with DCD and six TD children between ages of 8 and 12 years. Three fine-motor tasks were performed: Finger Tapping (FT), Curve Tracing (CT), and Paragraph Writing (PW). Tasks were presented in counterbalanced order and had a baseline of 30s. Cortical activity elicited during performance of the FT, CT, and PW tasks was measured by fNIRS, and activation areas within each group were statistically compared. Results indicated that participant groups used different focal activation areas as well as different neural networks to perform the tasks. These distinct patterns were also task-specific, with differences in the right Pre-Motor Cortex (Pre-MC) and Supplementary Motor Area (SMA) for CT, and the right Dorsolateral Prefrontal Cortex (DLPFC) and the right Pre-MC for the PW task. These results add to the body of research exploring neurological alterations in children with DCD, and establish the feasibility of using fNIRS technology with this population.


Assuntos
Mapeamento Encefálico , Deficiências do Desenvolvimento/patologia , Transtornos Psicomotores/patologia , Espectroscopia de Luz Próxima ao Infravermelho , Córtex Cerebral , Criança , Feminino , Escrita Manual , Hemoglobinas/metabolismo , Humanos , Masculino , Destreza Motora/fisiologia , Desempenho Psicomotor , Índice de Gravidade de Doença
18.
Muscle Nerve ; 57(1): 142-146, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28556387

RESUMO

INTRODUCTION: In this study we examined the feasibility of assessing motor milestone performance of infants with spinal muscular atrophy (SMA) using the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) in a phase 2 study of nusinersen. METHODS: Nineteen SMA infants were assessed using the HINE-2 at baseline (≤7 months of age), and periodically up to 39 months of age. We evaluated whether the HINE-2 was feasible, reliable, and sensitive to change. RESULTS: Motor milestone assessments in SMA infants were feasible using the HINE-2. Baseline test-retest reliability was excellent (R = 0.987; P < 0.0001). SMA infants were extremely low functioning at baseline and the HINE-2 was able to detect changes over time in 16 of 19 infants within all 8 domains. HINE-2 improvements were correlated with changes in other neuromuscular outcome measures. CONCLUSION: Results support the use of the HINE-2 motor milestone assessment in clinical trials of SMA infants. Muscle Nerve 57: 143-146, 2017.


Assuntos
Deficiências do Desenvolvimento/patologia , Exame Neurológico/métodos , Oligonucleotídeos/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Atrofias Musculares Espinais da Infância/patologia , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Masculino , Movimento , Variações Dependentes do Observador , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
19.
Congenit Anom (Kyoto) ; 58(1): 36-38, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28378413

RESUMO

Interstitial deletions in the 10q21.3q22.2 chromosomal region are rare. A de novo microdeletion in this region was identified in a patient with severe developmental delay and multiple congenital anomalies, including congenital heart defects. The identified 10.4-Mb deletion included 84 RefSeq genes. CTNNA3 and JMJD1C have been associated with cardiomyopathy and neurological impairments (autism and/or intellectual disability), respectively. Because there is no gene which shows one-to-one relation to clinical features observed in this patient, combinatory deletion of the genes in this region would be causative of the clinical features in this patient.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 10/química , Deficiências do Desenvolvimento/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Pré-Escolar , Mapeamento Cromossômico , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/patologia , Feminino , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Cariótipo
20.
Exp Neurol ; 299(Pt A): 199-206, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28434869

RESUMO

The small non-parasitic nematode Caenorhabditis elegans is widely used in neuroscience thanks to its well-understood development and lineage of the nervous system. Furthermore, C. elegans has been used to model many human developmental and neurological conditions to better understand disease mechanisms and identify potential therapeutic strategies. Autism spectrum disorder (ASD) is the most prevalent of all neurodevelopmental disorders, and the C. elegans system may provide opportunities to learn more about this complex disorder. Since basic cell biology and biochemistry of the C. elegans nervous system is generally very similar to mammals, cellular or molecular phenotypes can be investigated, along with a repertoire of behaviours. For instance, worms have contributed greatly to the understanding of mechanisms underlying mutations in genes coding for synaptic proteins such as neuroligin and neurexin. Using worms to model neurodevelopmental disorders like ASD is an emerging topic that harbours great, untapped potential. This review summarizes the numerous contributions of C. elegans to the field of neurodevelopment and introduces the nematode system as a potential research tool to study essential roles of genes associated with ASD.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Animais , Proteínas de Caenorhabditis elegans/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Modelos Animais de Doenças , Humanos
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