RESUMO
PCDH12 is a member of the non-clustered protocadherins that mediate cell-cell adhesion, playing crucial roles in many biological processes. Among these, PCDH12 promotes cell-cell interactions at inter-endothelial junctions, exerting essential functions in vascular homeostasis and angiogenesis. However, its exact role in eye vascular and brain development is not completely understood. To date, biallelic loss of function variants in PCDH12 have been associated with a neurodevelopmental disorder characterized by the typical neuroradiological findings of diencephalic-mesencephalic junction dysplasia and intracranial calcifications, whereas heterozygous variants have been recently linked to isolated brain calcifications in absence of cognitive impairment or other brain malformations. Recently, the phenotypic spectrum associated with PCDH12 deficiency has been expanded including cerebellar and eye abnormalities. Here, we report two female siblings harboring a novel frameshift homozygous variant (c.2169delT, p.(Val724TyrfsTer8)) in PCDH12. In addition to the typical diencephalic-mesencephalic junction dysplasia, brain MRI showed dysmorphic basal ganglia and thalamus that were reminiscent of a tubulin-like phenotype, mild cerebellar vermis hypoplasia and extensive prominence of perivascular spaces in both siblings. The oldest sister developed profound and progressive monocular visual loss and the eye exam revealed exudative vitreoretinopathy. Similar but milder eye changes were also noted in her younger sister. In summary, our report expands the clinical (brain and ocular) spectrum of PCDH12-related disorders and adds a further line of evidence underscoring the important role of PCDH12 in retinal vascular and brain development.
Assuntos
Gânglios da Base/anormalidades , Deficiências do Desenvolvimento/genética , Vitreorretinopatias Exsudativas Familiares/genética , Protocaderinas/genética , Gânglios da Base/diagnóstico por imagem , Criança , Deficiências do Desenvolvimento/patologia , Vitreorretinopatias Exsudativas Familiares/patologia , Feminino , Mutação da Fase de Leitura , Homozigoto , Humanos , FenótipoAssuntos
Gânglios da Base/anormalidades , Plexo Corióideo/embriologia , Eminência Mediana/anormalidades , Malformações do Sistema Nervoso/diagnóstico por imagem , Ultrassonografia Pré-Natal , Aborto Eugênico , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/embriologia , Plexo Corióideo/diagnóstico por imagem , Neoplasias do Plexo Corióideo/diagnóstico por imagem , Neoplasias do Plexo Corióideo/embriologia , Cistos/diagnóstico por imagem , Cistos/embriologia , Diagnóstico Diferencial , Feminino , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/embriologia , Eminência Mediana/diagnóstico por imagem , Eminência Mediana/embriologia , Ilustração Médica , Malformações do Sistema Nervoso/embriologia , GravidezRESUMO
Childhood-onset dystonia with optic atrophy and basal ganglia abnormalities is an extremely rare autosomal recessive mitochondrial disease caused by biallelic mutations in MECR. Using whole-exome sequencing, we identified a novel homozygous MECR mutation (c.910G > T, p.Asp304Tyr) in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy. With lipoic acid treatment, the disease progression was under control, and neither visual impairment nor optic atrophy was observed. To our knowledge, this is the first study about MECR-related mitochondrial disease in a Chinese patient and the first to report that supplementation with lipoic acid is a possible effective therapeutic strategy for this disease.
Assuntos
Gânglios da Base/anormalidades , Distonia/diagnóstico , Sequenciamento do Exoma/métodos , Mutação de Sentido Incorreto , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Gânglios da Base/efeitos dos fármacos , Células Cultivadas , Criança , China , Cristalografia por Raios X , Distonia/tratamento farmacológico , Distonia/genética , Distonia/patologia , Homozigoto , Humanos , Masculino , Modelos Moleculares , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/química , Linhagem , Conformação Proteica , Ácido Tióctico/administração & dosagem , Ácido Tióctico/farmacologiaRESUMO
OBJECTIVE: Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed. METHODS: Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed. RESULTS: Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported). CONCLUSION: The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.
Assuntos
Síndrome de Aicardi/diagnóstico por imagem , Gânglios da Base/anormalidades , Adolescente , Adulto , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Ingestão de Líquidos , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/etiologia , Ingestão de Alimentos , Eletroencefalografia , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Destreza Motora , Retina/diagnóstico por imagem , Estudos Retrospectivos , Convulsões/diagnóstico por imagem , Convulsões/etiologia , Convulsões/fisiopatologia , Resultado do Tratamento , Adulto JovemRESUMO
Leigh syndrome is an inherited neurodegenerative disorder of infancy that typically manifests between 3 and 12 months of age. The common neurological manifestations are developmental delay or regression, progressive cognitive decline, dystonia, ataxia, brainstem dysfunction, epileptic seizures, and respiratory dysfunction. Although the disorder is clinically and genetically heterogeneous, the histopathological and radiological features characteristically show focal and bilaterally symmetrical, necrotic lesions in the basal ganglia and brainstem. The syndrome has a characteristic histopathological signature that helps in clinching the diagnosis. We discuss these unique findings on autopsy and radiology in a young infant who succumbed to a subacute, progressive neurological illness suggestive of Leigh syndrome. Our case highlights that Leigh syndrome should be considered in the differential diagnosis of infantile-onset, subacute neuroregression with dystonia and seizures, a high anion gap metabolic acidosis, normal ketones, elevated lactates in blood, brain, and urine, and bilateral basal ganglia involvement.
Assuntos
Humanos , Masculino , Lactente , Doença de Leigh/patologia , Autopsia , Gânglios da Base/anormalidades , Dano Encefálico Crônico/patologia , Doenças Neurodegenerativas , Diagnóstico Diferencial , Manifestações NeurológicasRESUMO
Recessive congenital methemoglobinemia type II is a very rare autosomal recessive hematologic disorder due to NADH-cytochrome b5 reductase deficiency, usually caused by full-stop mutations or deletions. This disease classically presents with mild neonatal cyanosis, early onset severe progressive developmental delay, movement disorders, and progressive microcephaly. We report two siblings with recessive congenital methemoglobinemia type II whose evaluation revealed a novel p.Arg92Trp missense mutation of the CYB5R3 gene and a peculiar imaging finding of basal ganglia hypoplasia. Brain magnetic resonance imaging was performed at age 10 months in the older sibling and at age three months in the younger sibling. It revealed similar findings of bilateral small size of the lentiform and caudate nuclei and reduced frontotemporal brain volume. Our patient cases highlight that basal ganglia hypoplasia is an interesting clue to the very rare and frequently unsuspected diagnosis of recessive congenital methemoglobinemia type II, that may explain the associated movement disorders. The novel missense mutation is one of very few identified missense mutations known to cause severe type II recessive congenital methemoglobinemia.
Assuntos
Gânglios da Base/anormalidades , Gânglios da Base/diagnóstico por imagem , Citocromos b5/genética , Imageamento por Ressonância Magnética/métodos , Metemoglobinemia/congênito , Pré-Escolar , Humanos , Lactente , Espectroscopia de Ressonância Magnética , Masculino , Metemoglobinemia/diagnóstico por imagem , Metemoglobinemia/genética , Mutação , IrmãosRESUMO
Microdeletion of 2q31 involving the HOXD gene cluster is a rare syndrome. The deletion of the HOXD gene cluster is thought to result in skeletal anomalies in these patients. HOX genes encode highly conserved transcription factors that control cell fate and the regional identities along the primary body and limb axes. We experienced a new patient with 2q31 microdeletion encompassing the HOXD gene cluster and some neighboring genes including the ZNF385B. The patient showed digital anomalies, growth failure, epileptic seizures, and intellectual disability. Magnetic resonance imaging showed delayed myelination and low signal intensity in the basal ganglia. The ZNF385B is a zinc finger protein expressed in brain. Disruption of ZNF385B was suspected to be responsible for the neurological features of this syndrome.
Assuntos
Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Laringomalácia/genética , Convulsões/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Gânglios da Base/anormalidades , Gânglios da Base/diagnóstico por imagem , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 2/química , Cromossomos Humanos Par 2/genética , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/patologia , Proteínas de Ligação a DNA/deficiência , Deleção de Genes , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Laringomalácia/diagnóstico por imagem , Laringomalácia/patologia , Imageamento por Ressonância Magnética , Masculino , Convulsões/diagnóstico por imagem , Convulsões/patologiaRESUMO
ZNF335 was first reported in 2012 as a causative gene for microcephaly. Because only 1 consanguineous pedigree has ever been reported, the key clinical features associated with ZNF335 mutations remain unknown. In this article, we describe another family harboring ZNF335 mutations. The female proband was the first child of nonconsanguineous Japanese parents. At birth, microcephaly was absent; her head circumference was 32.0 cm (-0.6 SD). At 3 months, microcephaly was noted, (head circumference, 34.0 cm [-4.6 SD]). Brain MRI showed invisible basal ganglia, cerebral atrophy, brainstem hypoplasia, and cerebellar atrophy. At 33 months, (head circumference, 41.0 cm [-5.1 SD]), she had severe psychomotor retardation. After obtaining informed consent from her parents, we performed exome sequencing in the proband and identified 1 novel and 1 known mutation in ZNF335, namely, c.1399T>C (p.C467R) and c.1505A>G (p.Y502C), respectively. The mutations were individually transmitted by her parents, indicating that the proband was compound heterozygous for the mutations. Her brain imaging findings, including invisible basal ganglia, were similar to those observed in the previous case with ZNF335 mutations. We speculate that invisible basal ganglia may be the key feature of ZNF335 mutations. For infants presenting with both microcephaly and invisible basal ganglia, ZNF335 mutations should be considered as a differential diagnosis.
Assuntos
Gânglios da Base/anormalidades , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Proteínas Nucleares/genética , Atrofia , Encéfalo/patologia , Tronco Encefálico/anormalidades , Proteínas de Ligação a DNA , Feminino , Humanos , Lactente , Japão , Imageamento por Ressonância Magnética , Microcefalia/genética , Transtornos Psicomotores/etiologia , Fatores de TranscriçãoRESUMO
IMPORTANCE: Patients with attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) share impaired inhibitory control. However, it is unknown whether impairments are mediated by shared or disorder-specific neurostructural and neurofunctional abnormalities. OBJECTIVE: To establish shared and disorder-specific structural, functional, and overlapping multimodal abnormalities in these 2 disorders through a voxel-based meta-analytic comparison of whole-brain gray matter volume (GMV) and functional magnetic resonance imaging (fMRI) studies of inhibition in patients with ADHD and OCD. DATA SOURCES: Literature search using PubMed, ScienceDirect, Web of Knowledge, and Scopus up to September 30, 2015. STUDY SELECTION: Whole-brain voxel-based morphometry (VBM) or fMRI studies during inhibitory control comparing children and adults with ADHD or OCD with controls. DATA EXTRACTION AND SYNTHESIS: Voxel-wise meta-analyses of GMV or fMRI differences were performed using Seed-based d-Mapping. Regional structure and function abnormalities were assessed within each patient group and then a quantitative comparison was performed of abnormalities (relative to controls) between ADHD and OCD. MAIN OUTCOMES AND MEASURES: Meta-analytic disorder-specific and shared abnormalities in GMV, in inhibitory fMRI, and in multimodal functional and structural measures. RESULTS: The search revealed 27 ADHD VBM data sets (including 931 patients with ADHD and 822 controls), 30 OCD VBM data sets (928 patients with OCD and 942 controls), 33 ADHD fMRI data sets (489 patients with ADHD and 591 controls), and 18 OCD fMRI data sets (287 patients with OCD and 284 controls). Patients with ADHD showed disorder-contrasting multimodal structural (left z = 1.904, P < .001; right z = 1.738, P < .001) and functional (left z = 1.447, P < .001; right z = 1.229, P < .001) abnormalities in bilateral basal ganglia/insula, which were decreased in GMV and function in patients with ADHD relative to those with OCD (and controls). In OCD patients, they were enhanced relative to controls. Patients with OCD showed disorder-specific reduced function and structure in rostral and dorsal anterior cingulate/medial prefrontal cortex (fMRI z = 2.113, P < .001; VBM z = 1.622, P < .001), whereas patients with ADHD showed disorder-specific underactivation predominantly in the right ventrolateral prefrontal cortex (z = 1.229, P < .001). Ventromedial prefrontal GMV reduction was shared in both disorders relative to controls. CONCLUSIONS AND RELEVANCE: Shared impairments in inhibitory control, rather than representing a transdiagnostic endophenotype in ADHD and OCD, were associated with disorder-differential functional and structural abnormalities. Patients with ADHD showed smaller and underfunctioning ventrolateral prefrontal/insular-striatal regions whereas patients with OCD showed larger and hyperfunctioning insular-striatal regions that may be poorly controlled by smaller and underfunctioning rostro/dorsal medial prefrontal regions.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Encéfalo/anormalidades , Encéfalo/fisiopatologia , Imageamento por Ressonância Magnética , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/fisiopatologia , Adulto , Tonsila do Cerebelo/anormalidades , Tonsila do Cerebelo/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Gânglios da Base/anormalidades , Gânglios da Base/fisiopatologia , Estudos de Casos e Controles , Córtex Cerebral/anormalidades , Córtex Cerebral/fisiopatologia , Criança , Dominância Cerebral/fisiologia , Feminino , Giro do Cíngulo/anormalidades , Giro do Cíngulo/fisiopatologia , Humanos , Masculino , Inibição Neural/fisiologia , Córtex Pré-Frontal/anormalidades , Córtex Pré-Frontal/fisiopatologia , Valores de ReferênciaRESUMO
We discussed the cross section studies and the meta-analysis of published data in children and adolescents with ADHD (both drug naive and receiving stimulant medications), in comparison with healthy children and adolescents of the same age. In children and adolescents with ADHD the deceleration of the maturation dynamics of discrete CNS structures is found, volume reduction and decreased grey matter in prefrontal and occipital regions, which is accompanied by reverse asymmetry of the basal ganglia volume (putamen, nucleus caudate). The above mentioned developmental characteristics are valid only for the ADHD children, who have not been treated by stimulant medications. The stimulant treatment eliminates the mentioned changes into various extend. These developmental changes of CNS structures volume are missing in girls.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Gânglios da Base/anormalidades , Encéfalo/anormalidades , Estimulantes do Sistema Nervoso Central/uso terapêutico , Adolescente , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Criança , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Tamanho do Órgão/efeitos dos fármacosAssuntos
Gânglios da Base/anormalidades , Leucemia Linfocítica Crônica de Células B/patologia , Síndromes Paraneoplásicas do Sistema Nervoso/diagnóstico , Transtornos Parkinsonianos/diagnóstico por imagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gânglios da Base/diagnóstico por imagem , Encéfalo , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/diagnóstico por imagem , Masculino , Síndromes Paraneoplásicas do Sistema Nervoso/diagnóstico por imagem , Síndromes Paraneoplásicas do Sistema Nervoso/patologiaRESUMO
A deletion on human chromosome 16p11.2 is associated with autism spectrum disorders. We deleted the syntenic region on mouse chromosome 7F3. MRI and high-throughput single-cell transcriptomics revealed anatomical and cellular abnormalities, particularly in cortex and striatum of juvenile mutant mice (16p11(+/-)). We found elevated numbers of striatal medium spiny neurons (MSNs) expressing the dopamine D2 receptor (Drd2(+)) and fewer dopamine-sensitive (Drd1(+)) neurons in deep layers of cortex. Electrophysiological recordings of Drd2(+) MSN revealed synaptic defects, suggesting abnormal basal ganglia circuitry function in 16p11(+/-) mice. This is further supported by behavioral experiments showing hyperactivity, circling, and deficits in movement control. Strikingly, 16p11(+/-) mice showed a complete lack of habituation reminiscent of what is observed in some autistic individuals. Our findings unveil a fundamental role of genes affected by the 16p11.2 deletion in establishing the basal ganglia circuitry and provide insights in the pathophysiology of autism.
Assuntos
Transtorno Autístico/genética , Gânglios da Base/anormalidades , Deleção Cromossômica , Transtornos Cromossômicos/genética , Modelos Animais de Doenças , Deficiência Intelectual/genética , Transtornos Mentais/genética , Animais , Gânglios da Base/patologia , Cromossomos Humanos Par 16/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
BACKGROUND AND PURPOSE: Periventricular nodular heterotopia are common malformations of cortical development that are associated with many clinical syndromes and with many different neuroimaging phenotypes. The purpose of this study was to determine whether specific malformation phenotypes may be related to location, side, or number of PNH as assessed by MR imaging. MATERIALS AND METHODS: MR images of 200 patients previously diagnosed with PNH were retrospectively analyzed. PNH were classified according to their location along the ventricles (anterior, posterior, or diffuse), side (unilateral or bilateral), and number of nodules (<5, 6-10, or >10). The cerebrum, brain stem and cerebellum were analyzed to assess associated anomalies. Associations between PNH location and the presence of other anomalies were tested by using Fisher exact test and χ2 test. RESULTS: Posterior PNH were significantly associated with malformations of the cerebral cortex, diminished white matter volume, and mid-/hindbrain anomalies. Diffuse PNH were associated with diminished white matter volume, callosal "anomalies," and the presence of megacisterna magna. Unilateral PNH were strongly associated with cortical malformations. CONCLUSIONS: Certain malformation complexes are associated with PNH in specific locations: posterior PNH with cerebral cortical and mid-/hindbrain malformations and diffuse PNH with callosal anomalies and megacisterna magna. Knowledge of these associations should allow more directed analyses of brain MR imaging in patients with PNH. In addition, knowledge of these associations may help to direct studies to elucidate the causes of these malformation complexes.
Assuntos
Ventrículos Laterais/anormalidades , Imageamento por Ressonância Magnética , Heterotopia Nodular Periventricular/patologia , Adolescente , Adulto , Idoso , Gânglios da Base/anormalidades , Criança , Pré-Escolar , Cisterna Magna/anormalidades , Corpo Caloso/patologia , Feminino , Feto/anormalidades , Hipocampo/anormalidades , Humanos , Hipotálamo/anormalidades , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Tálamo/anormalidades , Adulto JovemRESUMO
BACKGROUND: Cavernous malformations (CMs) in deep locations account for 9% to 35% of brain malformations and are surgically challenging. OBJECTIVE: To study the clinical features and outcomes following surgery for deep CMs and the complication of hypertrophic olivary degeneration (HOD). METHODS: Clinical records, radiological findings, operative details, and complications of 176 patients with deep CMs were reviewed retrospectively. RESULTS: Of 176 patients with 179 CMs, 136 CMs were in the brainstem, 27 in the basal ganglia, and 16 in the thalamus. Cranial nerve deficits (51.1%), hemiparesis (40.9%), numbness (34.7%), and cerebellar symptoms (38.6%) presented most commonly. Hemorrhage presented in 172 patients (70 single, 102 multiple). The annual retrospective hemorrhage rate was 5.1% (assuming CMs are congenital with uniform hemorrhage risk throughout life); the rebleed rate was 31.5%/patient per year. Surgical approach depended on the proximity of the CM to the pial or ependymal surface. Postoperatively, 121 patients (68.8%) had no new neurological deficits. Follow-up occurred in 170 patients. Delayed postoperative HOD developed in 9/134 (6.7%) patients with brainstem CMs. HOD occurred predominantly following surgery for pontine CMs (9/10 patients). Three patients with HOD had palatal myoclonus, nystagmus, and oscillopsia, whereas 1 patient each had limb tremor and hemiballismus. At follow-up, 105 patients (61.8%) improved, 44 (25.9%) were unchanged, and 19 (11.2%) worsened neurologically. Good preoperative modified Rankin Score (98.2% vs 54.5%, P = .001) and single hemorrhage (89% vs 77.3%, P < .05) were predictive of good long-term outcome. CONCLUSION: Symptomatic deep CMs can be resected with acceptable morbidity and outcomes. Good preoperative modified Rankin Score and single hemorrhage are predictors of good long-term outcome.
Assuntos
Gânglios da Base/anormalidades , Tronco Encefálico/anormalidades , Malformações Vasculares do Sistema Nervoso Central/diagnóstico , Tálamo/anormalidades , Adolescente , Adulto , Idoso , Gânglios da Base/cirurgia , Tronco Encefálico/cirurgia , Malformações Vasculares do Sistema Nervoso Central/cirurgia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tálamo/cirurgia , Adulto JovemRESUMO
Williams-Beuren syndrome (WBS) is a rare genetic disorder caused by a hemizygous deletion of around 28 genes on the long arm of chromosome 7 (7q11.23), characterized by a unique spectrum of behavioral impairments, including mental retardation, deficits in visuospatial constructive cognition, hypersociability, anxiety and simple phobias. Physical characteristics include dysmorphic faces, short stature, oculomotor deficits, gross and fine coordination impairments, diminished control of balance and mild extrapyramidal signs as well as gait abnormalities resembling gait hypokinesia. Genes near the distal deletion breakpoint appear to contribute most to the WBS cognitive and behavioral profile and include the GTF family of transcription factors: GTF2I, GTF2IRD1, GTF2IRD2. We have previously shown that heterozygous deletions of GTF2IRD1 in humans and homozygous deletion in mice contributes to craniofacial abnormalities. Here we show an important role of this gene in motor coordination and anxiety ascertained from extensive behavioral mouse phenotyping. Gtf2ird1 null mice showed lower body weight, decreased spontaneous and circadian locomotor activity, diminished motor coordination and strength, gait abnormalities, increased anxiety and an elevated endocrinological response to stress. Gtf2ird1 heterozygous mice displayed lower body weight and decreased circadian activity, but only minor motor coordination and anxiety-related behavioral dysfunctions. Our study strongly supports a role for GTF2IRD1 in the motoric and anxiety-related abnormalities seen in Williams-Beuren syndrome, and suggests basal ganglia and potentially cerebellar abnormalities in Gtf2ird1 mice.
Assuntos
Ansiedade/etiologia , Hipocinesia/etiologia , Transtornos dos Movimentos/etiologia , Proteínas Musculares/deficiência , Proteínas Nucleares/deficiência , Transativadores/deficiência , Síndrome de Williams/complicações , Síndrome de Williams/genética , Análise de Variância , Animais , Ansiedade/genética , Gânglios da Base/anormalidades , Gânglios da Base/patologia , Peso Corporal , Ritmo Circadiano/genética , Corticosterona/sangue , Adaptação à Escuridão/genética , Modelos Animais de Doenças , Feminino , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/genética , Asseio Animal/fisiologia , Hipertireoxinemia/etiologia , Hipertireoxinemia/genética , Hipocinesia/genética , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/genética , Transtornos dos Movimentos/genética , Fenótipo , Desempenho Psicomotor/fisiologia , Caracteres Sexuais , Síndrome de Williams/patologiaRESUMO
PURPOSE: To evaluate patients with high-risk cerebral arteriovenous malformations (AVMs), based on eloquent brain location or large size, who underwent planned two-fraction proton stereotactic radiosurgery (PSRS). METHODS AND MATERIALS: From 1991 to 2009, 59 patients with high-risk cerebral AVMs received two-fraction PSRS. Median nidus volume was 23 cc (range, 1.4-58.1 cc), 70% of cases had nidus volume ≥ 14 cc, and 34% were in critical locations (brainstem, basal ganglia). Median AVM score based on age, AVM size, and location was 3.19 (range, 0.9-6.9). Many patients had prior surgery or embolization (40%) or prior PSRS (12%). The most common prescription was 16 Gy radiobiologic equivalent (RBE) in two fractions, prescribed to the 90% isodose. RESULTS: At a median follow-up of 56.1 months, 9 patients (15%) had total and 20 patients (34%) had partial obliteration. Patients with total obliteration received higher total dose than those with partial or no obliteration (mean dose, 17.6 vs. 15.5 Gy (RBE), p = 0.01). Median time to total obliteration was 62 months (range, 23-109 months), and 5-year actuarial rate of partial or total obliteration was 33%. Five-year actuarial rate of hemorrhage was 22% (95% confidence interval, 12.5%-36.8%) and 14% (n = 8) suffered fatal hemorrhage. Lesions with higher AVM scores were more likely to hemorrhage (p = 0.024) and less responsive to radiation (p = 0.026). The most common complication was Grade 1 headache acutely (14%) and long term (12%). One patient developed a Grade 2 generalized seizure disorder, and two had mild neurologic deficits. CONCLUSIONS: High-risk AVMs can be safely treated with two-fraction PSRS, although total obliteration rate is low and patients remain at risk for future hemorrhage. Future studies should include higher doses or a multistaged PSRS approach for lesions more resistant to obliteration with radiation.
Assuntos
Malformações Arteriovenosas Intracranianas/cirurgia , Radiocirurgia/métodos , Adolescente , Adulto , Idoso , Gânglios da Base/anormalidades , Gânglios da Base/irrigação sanguínea , Tronco Encefálico/anormalidades , Tronco Encefálico/irrigação sanguínea , Criança , Feminino , Seguimentos , Transtornos da Cefaleia Secundários/etiologia , Humanos , Malformações Arteriovenosas Intracranianas/complicações , Malformações Arteriovenosas Intracranianas/mortalidade , Malformações Arteriovenosas Intracranianas/patologia , Hemorragias Intracranianas/etiologia , Hemorragias Intracranianas/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia com Prótons , Radiocirurgia/efeitos adversos , Dosagem Radioterapêutica , Risco , Ruptura Espontânea/complicações , Ruptura Espontânea/mortalidade , Adulto JovemRESUMO
Cerebellar and brainstem hypoplasia may occur in different conditions, including those disorders designated as pontocerebellar hypoplasia (PCH). In particular, when PCH is combined with severe supratentorial white matter involvement and cerebral atrophy, mutations in the mitochondrial arginyl-tRNA synthethase (RARS2) gene causing PCH6 are possible. We describe a patient with a lethal mitochondrial encephalomyopathy due to a mtDNA deletion and no alterations in RARS2, whose magnetic resonance (MR) findings mimicked PCH6. A thorough diagnostic work-up for mitochondrial disorders should be carried out when facing with a PCH-like and severe white matter and basal ganglia involvement on brain MR imaging in children, even if clinical and laboratory mitochondrial "stigmata" are scant or nonspecific.
Assuntos
DNA Mitocondrial/genética , Deleção de Genes , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Encefalomiopatias Mitocondriais/genética , Atrofias Olivopontocerebelares/diagnóstico , Atrofias Olivopontocerebelares/genética , Gânglios da Base/anormalidades , Encéfalo/patologia , Tronco Encefálico/anormalidades , Pré-Escolar , Diagnóstico Diferencial , Humanos , Leucoencefalopatias/metabolismo , Imageamento por Ressonância Magnética , Encefalomiopatias Mitocondriais/patologia , Atrofias Olivopontocerebelares/patologiaRESUMO
BACKGROUND: To clarify the timing of injury in utero causing respiratory inhibition after crying (RIAC), the relationship between asphyxia and RIAC was investigated in infants whose gestational age was ≥ 36 weeks. METHODS: RIAC and cranial ultrasound abnormalities were examined for retrospectively in infants treated in the neonatal intensive care unit from April 2004 through March 2009. All included infants were gestational age ≥ 36 weeks and had an Apgar score <4 points at 1 min. The relationship between RIAC and perinatal factors was also examined. RESULTS: Twenty-six infants were included. Three infants had RIAC, seven infants had poor prognosis, and nine infants had ultrasound abnormalities in the ganglionic eminence (GE). There was a significant relationship between RIAC and ultrasound abnormalities in the GE (P= 0.032). Poor prognosis was significantly associated with low Apgar score at 5 min (P ≤ 0.001), disseminated intravascular coagulation (P= 0.047), hypoxic ischemic encephalopathy (P= 0.028), and brain hypothermia therapy (P= 0.028). There was no significant relationship between RIAC and poor prognosis. All infants had ultrasound abnormalities in the GE on the day of birth. CONCLUSION: Damage occurring in utero prior to 36 weeks gestation might cause increased echogenicity or cyst formation in the GE, potentially disturbing maturation of the respiratory center with the development of RIAC.
Assuntos
Apneia/etiologia , Asfixia Neonatal/complicações , Gânglios da Base/embriologia , Choro/fisiologia , Adulto , Índice de Apgar , Apneia/sangue , Apneia/diagnóstico por imagem , Apneia/embriologia , Gânglios da Base/anormalidades , Gânglios da Base/diagnóstico por imagem , Gasometria , Ecoencefalografia , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Modelos Logísticos , Masculino , Oxigênio/sangue , Prognóstico , Estudos Retrospectivos , Ultrassonografia Pré-NatalRESUMO
BACKGROUND: Whether autism spectrum maps onto a spectrum of brain abnormalities and whether Asperger's syndrome (ASP) is distinct from high-functioning autism (HFA) are debated. White-matter maldevelopment is associated with autism and disconnectivity theories of autism are compelling. However, it is unknown whether children with ASP and HFA have distinct white-matter abnormalities. METHOD: Voxel-based morphometry mapped white-matter volumes across the whole brain in 91 children. Thirty-six had autism spectrum disorder. A history of delay in phrase speech defined half with HFA; those without delay formed the ASP group. The rest were typically developing children, balanced for age, IQ, gender, maternal language and ethnicity. White-matter volumes in HFA and ASP were compared and each contrasted with controls. RESULTS: White-matter volumes around the basal ganglia were higher in the HFA group than ASP and higher in both autism groups than controls. Compared with controls, children with HFA had less frontal and corpus callosal white matter in the left hemisphere; those with ASP had less frontal and corpus callosal white matter in the right hemisphere with more white matter in the left parietal lobe. CONCLUSIONS: HFA involved mainly left hemisphere white-matter systems; ASP affected predominantly right hemisphere white-matter systems. The impact of HFA on basal ganglia white matter was greater than ASP. This implies that aetiological factors and management options for autism spectrum disorders may be distinct. History of language acquisition is a potentially valuable marker to refine our search for causes and treatments in autism spectrum.
Assuntos
Síndrome de Asperger/patologia , Transtorno Autístico/patologia , Encéfalo/patologia , Inteligência/fisiologia , Imageamento por Ressonância Magnética , Fibras Nervosas Mielinizadas/patologia , Agenesia do Corpo Caloso , Síndrome de Asperger/diagnóstico , Síndrome de Asperger/psicologia , Transtorno Autístico/diagnóstico , Transtorno Autístico/psicologia , Gânglios da Base/anormalidades , Gânglios da Base/patologia , Encéfalo/anormalidades , Mapeamento Encefálico , Criança , Corpo Caloso/patologia , Dominância Cerebral/fisiologia , Feminino , Lobo Frontal/anormalidades , Lobo Frontal/patologia , Humanos , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/patologia , Transtornos do Desenvolvimento da Linguagem/psicologia , Masculino , Tamanho do Órgão/fisiologia , Valores de ReferênciaRESUMO
X-linked lissencephaly with abnormal genitalia (XLAG) is characterized by lissencephaly, absent corpus callosum and ambiguous genitalia. We examined hypothalamic dysfunctions in a XLAG case with a novel mutation of the ARX gene, and performed immunohistochemical evaluation of the diencephalons in autopsy brain. A 1-year-old boy showed intractable epilepsy, persistent diarrhea and disturbed temperature regulation. This case had abnormalities in circadian rhythms and pituitary hormone reserve test. He died of pneumonia. The globus pallidus and subthalamic nucleus was not identified, and the putamen and thalamus were dysplasic. The suprachiasmatic nucleus was absent. A few neurons immunoreactive for vasopressin seemed to form the ectopic supraoptic-like nucleus. The diencephalons were disturbed differently in each sub-region, and the changes may be related to various hypothalamic dysfunctions.