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1.
Ann Neurol ; 86(2): 293-303, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31125140

RESUMO

OBJECTIVE: Thymidine kinase 2, encoded by the nuclear gene TK2, is required for mitochondrial DNA maintenance. Autosomal recessive TK2 mutations cause depletion and multiple deletions of mtDNA that manifest predominantly as a myopathy usually beginning in childhood and progressing relentlessly. We investigated the safety and efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies. METHODS: We administered deoxynucleoside monophosphates and deoxynucleoside to 16 TK2-deficient patients under a compassionate use program. RESULTS: In 5 patients with early onset and severe disease, survival and motor functions were better than historically untreated patients. In 11 childhood and adult onset patients, clinical measures stabilized or improved. Three of 8 patients who were nonambulatory at baseline gained the ability to walk on therapy; 4 of 5 patients who required enteric nutrition were able to discontinue feeding tube use; and 1 of 9 patients who required mechanical ventilation became able to breathe independently. In motor functional scales, improvements were observed in the 6-minute walk test performance in 7 of 8 subjects, Egen Klassifikation in 2 of 3, and North Star Ambulatory Assessment in all 5 tested. Baseline elevated serum growth differentiation factor 15 levels decreased with treatment in all 7 patients tested. A side effect observed in 8 of the 16 patients was dose-dependent diarrhea, which did not require withdrawal of treatment. Among 12 other TK2 patients treated with deoxynucleoside, 2 adults developed elevated liver enzymes that normalized following discontinuation of therapy. INTERPRETATION: This open-label study indicates favorable side effect profiles and clinical efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies for TK2 deficiency. ANN NEUROL 2019;86:293-303.

2.
Brain ; 142(6): 1547-1560, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31081514

RESUMO

Next generation sequencing techniques were recently used to show mutations in COL13A1 cause synaptic basal lamina-associated congenital myasthenic syndrome type 19. Animal studies showed COL13A1, a synaptic extracellular-matrix protein, is involved in the formation and maintenance of the neuromuscular synapse that appears independent of the Agrin-LRP4-MuSK-DOK7 acetylcholine receptor clustering pathway. Here, we report the phenotypic spectrum of 16 patients from 11 kinships harbouring homozygous or heteroallelic mutations in COL13A1. Clinical presentation was mostly at birth with hypotonia and breathing and feeding difficulties often requiring ventilation and artificial feeding. Respiratory crisis related to recurrent apnoeas, sometimes triggered by chest infections, were common early in life but resolved over time. The predominant pattern of muscle weakness included bilateral ptosis (non-fatigable in adulthood), myopathic facies and marked axial weakness, especially of neck flexion, while limb muscles were less involved. Other features included facial dysmorphism, skeletal abnormalities and mild learning difficulties. All patients tested had results consistent with abnormal neuromuscular transmission. Muscle biopsies were within normal limits or showed non-specific changes. Muscle MRI and serum creatine kinase levels were normal. In keeping with COL13A1 mutations affecting both synaptic structure and presynaptic function, treatment with 3,4-diaminopyridine and salbutamol resulted in motor and respiratory function improvement. In non-treated cases, disease severity and muscle strength improved gradually over time and several adults recovered normal muscle strength in the limbs. In summary, patients with COL13A1 mutations present mostly with severe early-onset myasthenic syndrome with feeding and breathing difficulties. Axial weakness is greater than limb weakness. Disease course improves gradually over time, which could be consistent with the less prominent role of COL13A1 once the neuromuscular junction is mature. This report emphasizes the role of collagens at the human muscle endplate and should facilitate the recognition of this disorder, which can benefit from pharmacological treatment.

3.
Hum Mutat ; 40(7): 865-878, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31026367

RESUMO

Mendelian diseases have shown to be an and efficient model for connecting genotypes to phenotypes and for elucidating the function of genes. Whole-exome sequencing (WES) accelerated the study of rare Mendelian diseases in families, allowing for directly pinpointing rare causal mutations in genic regions without the need for linkage analysis. However, the low diagnostic rates of 20-30% reported for multiple WES disease studies point to the need for improved variant pathogenicity classification and causal variant prioritization methods. Here, we present the exome Disease Variant Analysis (eDiVA; http://ediva.crg.eu), an automated computational framework for identification of causal genetic variants (coding/splicing single-nucleotide variants and small insertions and deletions) for rare diseases using WES of families or parent-child trios. eDiVA combines next-generation sequencing data analysis, comprehensive functional annotation, and causal variant prioritization optimized for familial genetic disease studies. eDiVA features a machine learning-based variant pathogenicity predictor combining various genomic and evolutionary signatures. Clinical information, such as disease phenotype or mode of inheritance, is incorporated to improve the precision of the prioritization algorithm. Benchmarking against state-of-the-art competitors demonstrates that eDiVA consistently performed as a good or better than existing approach in terms of detection rate and precision. Moreover, we applied eDiVA to several familial disease cases to demonstrate its clinical applicability.

4.
J Neurol ; 266(5): 1107-1112, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30767057

RESUMO

Collagen XIII is a non-fibrillar transmembrane collagen which has been long recognized for its critical role in synaptic maturation of the neuromuscular junction. More recently, biallelic COL13A1 loss-of-function mutations were identified in three patients with congenital myasthenic syndrome (CMS), a rare inherited condition with defective neuromuscular transmission, causing abnormal fatigability and fluctuating muscle weakness and often successfully treated with acetylcholinesterase inhibitors. Here we report six additional CMS patients from three unrelated families with previously unreported homozygous COL13A1 loss-of-function mutations (p.Tyr216*, p.Glu543fs and p.Thr629fs). The phenotype of our cases was similar to the previously reported patients including respiratory distress and severe dysphagia at birth that often resolved or improved in the first days or weeks of life. All individuals had prominent eyelid ptosis with only minor ophthalmoparesis as well as generalized muscle weakness, predominantly affecting facial, bulbar, respiratory and axial muscles. Response to acetylcholinesterase inhibitor treatment was generally negative while salbutamol proved beneficial. Our data further support the causality of COL13A1 variants for CMS and suggest that this type of CMS might be clinically homogenous and requires alternative pharmacological therapy.


Assuntos
Colágeno Tipo XIII/genética , Mutação/genética , Síndromes Miastênicas Congênitas/genética , Criança , Consanguinidade , Análise Mutacional de DNA , Saúde da Família , Feminino , Humanos , Masculino , Síndromes Miastênicas Congênitas/patologia , Síndromes Miastênicas Congênitas/fisiopatologia , Receptor trkA/genética , Adulto Jovem
5.
Muscle Nerve ; 59(4): 436-444, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30578674

RESUMO

INTRODUCTION: The manner in which imaging patterns change over the disease course and with increasing disability in dysferlinopathy is not fully understood. METHODS: Fibroadipose infiltration of 61 muscles was scored based on whole-body MRI of 33 patients with dysferlinopathy and represented in a heatmap. We trained random forests to predict disease duration, Motor Function Measure dimension 1 (MFM-D1), and modified Rankin scale (MRS) score based on muscle scoring and selected the most important muscle for predictions. RESULTS: The heatmap delineated positive and negative fingerprints in dysferlinopathy. Disease duration was related to infiltration of infraspinatus, teres major-minor, and supraspinatus muscles. MFM-D1 decreased with higher infiltration of teres major-minor, triceps, and sartorius. MRS related to infiltration of vastus medialis, gracilis, infraspinatus, and sartorius. DISCUSSION: Dysferlinopathy shows a recognizable muscle MRI pattern. Fibroadipose infiltration in specific muscles of the thigh and the upper limb appears to be an important marker for disease progression. Muscle Nerve 59:436-444, 2019.


Assuntos
Avaliação da Deficiência , Músculo Esquelético/diagnóstico por imagem , Distrofia Muscular do Cíngulo dos Membros/diagnóstico por imagem , Tecido Adiposo/patologia , Adulto , Feminino , Fibrose/diagnóstico por imagem , Fibrose/patologia , Humanos , Aprendizado de Máquina , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Manguito Rotador/diagnóstico por imagem , Adulto Jovem
6.
Muscle Nerve ; 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30066418

RESUMO

INTRODUCTION: Particular fibroadipose infiltration patterns have been recently described by muscle imaging in congenital and later onset forms of LMNA-related muscular dystrophies (LMNA-RD). METHODS: Scores for fibroadipose infiltration of 23 lower limb muscles in 34 patients with LMNA-RD were collected from heat maps of 2 previous studies. Scoring systems were homogenized. Relationships between muscle infiltration and disease duration and age of onset were modeled with random forests. RESULTS: The pattern of infiltration differs according to disease duration but not to age of disease onset. The muscles whose progression best predicts disease duration were semitendinosus, biceps femoris long head, gluteus medius, and semimembranosus. DISCUSSION: In LMNA-RD, our synthetic analysis of lower limb muscle infiltration did not find major differences between forms with different ages of onset but allowed the identification of muscles with characteristic infiltration during disease progression. Monitoring of these specific muscles by quantitative MRI may provide useful imaging biomarkers in LMNA-RD. Muscle Nerve, 2018.

7.
Rev. neurol. (Ed. impr.) ; 66(7): 241-250, 1 abr., 2018. ilus
Artigo em Espanhol | IBECS | ID: ibc-173310

RESUMO

El termino 'disgenesia troncoencefálica' se aplica a los pacientes que presentan afectación congénita de múltiples pares craneales, hipotonía muscular y signos leves de afectación de la vía piramidal. Este término es ventajoso respecto al uso de epónimos tales como Moebius, Robin, Cogan y Carey-Fineman-Ziter, ya que es menos restrictivo y ofrece un nuevo enfoque para comprender las causas y su patogenia, así como para mejorar el tratamiento de este grupo de alteraciones del desarrollo que afectan exclusiva o predominantemente al tronco del encéfalo. La revisión de la bibliografía y nuestra experiencia muestran que la mayoría de los casos con afectación selectiva del rombencéfalo se deben a lesiones disruptivas prenatales, mientras que en los casos con afectación del mesencéfalo y el cerebelo, así como en los síndromes polimalformativos con afectación destacada del troncoencéfalo, la topografía de las lesiones es más difusa y menos específica, y la causa hereditaria, más probable. Debido a la amplia heterogeneidad fenotípica asociada a la disgenesia troncoencefálica, es esencial realizar una evaluación individualizada y establecer un plan de tratamiento específico. Los programas de rehabilitación deben comenzar poco después del diagnóstico y centrarse en mejorar las habilidades motoras, dotando al paciente de las herramientas necesarias para afrontar las necesidades diarias en función de la morbilidad asociada. Aunque el pronóstico de la disgenesia troncoencefálica secundaria a lesiones disruptivas depende de la localización y la extensión del territorio vascular afectado, en general, el pronóstico de los pacientes con disgenesia troncoencefálica es mejor de lo que las manifestaciones clínicas iniciales harían suponer


Brainstem dysgenesis designates all those patients with congenital dysfunction of cranial nerves and muscle tone due to prenatal lesions or malformations of the brainstem. This generic term has the advantage over the eponyms Moebius 'expanded' or 'unrestricted', Robin, Cogan or Carey-Fineman-Ziter syndromes in that it has a less restrictive view and provides a frame work that enables a systematic approach to diagnosis and research of most developmental disorders involving the brainstem. The review of the literature and our experience shows that infants with a predominant rombencephalic involvement are due to brainstem prenatal disruptive vascular accidents, while cases with midbrain and cerebellar involvement and widespread malformative syndromes have most likely an underlying genetic cause. Due to phenotypic heterogeneity associated with brainstem dysgenesis, it is crucial to evaluate each case individually and to establish a specific therapeutic plan. Intervention programs should start soon after diagnosis and directed to improve functions needed for daily life activities. Even though the prognosis of patients with brainstem dysgenesis due to prenatal destructive lesions depends on the magnitude of the vascular territory involved, in most patients with brainstem dysgenesis, the prognosis is better than the initial clinical manifestations would indicate


Assuntos
Humanos , Síndrome de Möbius/complicações , Tronco Encefálico/anormalidades , Anquilose , Apraxias/complicações , Prognóstico , Paralisia Facial/congênito , Síndrome de Cogan/complicações , Síndrome de Pierre Robin/complicações , História Natural
9.
J Neurol Neurosurg Psychiatry ; 89(1): 72-77, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28889091

RESUMO

OBJECTIVES: To characterise the pattern and spectrum of involvement on muscle MRI in a large cohort of patients with sarcoglycanopathies, which are limb-girdle muscular dystrophies (LGMD2C-2F) caused by mutations in one of the four genes coding for muscle sarcoglycans. METHODS: Lower limb MRI scans of patients with LGMD2C-2F, ranging from severe childhood variants to milder adult-onset forms, were collected in 17 neuromuscular referral centres in Europe and USA. Muscle involvement was evaluated semiquantitatively on T1-weighted images according to a visual score, and the global pattern was assessed as well. RESULTS: Scans from 69 patients were examined (38 LGMD2D, 18 LGMD2C, 12 LGMD2E and 1 LGMD2F). A common pattern of involvement was found in all the analysed scans irrespective of the mutated gene. The most and earliest affected muscles were the thigh adductors, glutei and posterior thigh groups, while lower leg muscles were relatively spared even in advanced disease. A proximodistal gradient of involvement of vasti muscles was a consistent finding in these patients, including the most severe ones. CONCLUSIONS: Muscle involvement on MRI is consistent in patients with LGMD2C-F and can be helpful in distinguishing sarcoglycanopathies from other LGMDs or dystrophinopathies, which represent the most common differential diagnoses. Our data provide evidence about selective susceptibility or resistance to degeneration of specific muscles when one of the sarcoglycans is deficient, as well as preliminary information about progressive involvement of the different muscles over time.


Assuntos
Imagem por Ressonância Magnética/métodos , Sarcoglicanopatias/genética , Sarcoglicanas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Mutação , Fenótipo , Sarcoglicanas/deficiência , Estados Unidos
10.
PLoS One ; 12(10): e0185327, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28981531

RESUMO

Fas Apoptosis Inhibitory Molecule (FAIM) is an evolutionarily highly conserved death receptor antagonist, widely expressed and known to participate in physiological and pathological processes. Two FAIM transcript variants have been characterized to date, namely FAIM short (FAIM-S) and FAIM long (FAIM-L). FAIM-S is ubiquitously expressed and serves as an anti-apoptotic protein in the immune system. Furthermore, in neurons, this isoform promotes NGF-induced neurite outgrowth through NF-кB and ERK signaling. In contrast FAIM-L is found only in neurons, where it exerts anti-apoptotic activity against several stimuli. In addition to these two variants, in silico studies point to the existence of two additional isoforms, neither of which have been characterized to date. In this regard, here we confirm the presence of these two additional FAIM isoforms in human fetal brain, fetal and adult testes, and placenta tissues. We named them FAIM-S_2a and FAIM-L_2a since they have the same sequence as FAIM-S and FAIM-L, but include exon 2a. PCR and western blot revealed that FAIM-S_2a shows ubiquitous expression in all the tissues and cellular models tested, while FAIM-L_2a is expressed exclusively in tissues of the nervous system. In addition, we found that, when overexpressed in non-neuronal cells, the splicing factor nSR100 induces the expression of the neuronal isoforms, thus identifying it as responsible for the generation of FAIM-L and FAIM-L_2a. Functionally, FAIM-S_2a and FAIM-L_2a increased neurite outgrowth in response to NGF stimulation in a neuronal model. This observation thus, supports the notion that these two isoforms are involved in neuronal differentiation. Furthermore, subcellular fractionation experiments revealed that, in contrast to FAIM-S and FAIM-L, FAIM-S_2a and FAIM-L_2a are able to localize to the nucleus, where they may have additional functions. In summary, here we report on two novel FAIM isoforms that may have relevant roles in the physiology and pathology of the nervous system.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Isoformas de Proteínas/metabolismo , Processamento Alternativo , Animais , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular , Éxons , Humanos , Conformação de Ácido Nucleico , Células PC12 , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Estabilidade Proteica , RNA Mensageiro/química , RNA Mensageiro/genética , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Termodinâmica
11.
Hum Mutat ; 38(11): 1477-1484, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28726266

RESUMO

Biallelic GLDN mutations have recently been identified among infants with lethal congenital contracture syndrome 11 (LCCS11). GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report six infants and children from four unrelated families with biallelic GLDN mutations, four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support. Our findings expand the genotypic and phenotypic spectrum of LCCS11 and demonstrate that the condition may not necessarily be lethal in the neonatal period.


Assuntos
Artrogripose/diagnóstico , Artrogripose/genética , Genes Letais , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Artrogripose/mortalidade , Biópsia , Análise Mutacional de DNA , Evolução Fatal , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Raízes Nervosas Espinhais/ultraestrutura , Sequenciamento Completo do Exoma
12.
Eur J Med Genet ; 60(10): 517-520, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28711742

RESUMO

Microcephaly with simplified gyration, epilepsy and permanent neonatal diabetes syndrome (MEDS) is a recently described, autosomal recessive-inherited syndrome. We report the case of an infant presenting with lethargy at age five weeks and clinical findings of persistent hyperglycaemia and microcephaly with simplified gyration, suggestive of MEDS. The diagnosis was confirmed by the detection of a known c.233 T > C mutation in the IER3IP1 gene. Only eight cases of MEDS have been reported in the literature. We reviewed these with the aim of better delineating their clinical manifestations, which should allow earlier and more accurate diagnosis and genetic counseling.


Assuntos
Proteínas de Transporte/genética , Diabetes Mellitus/genética , Epilepsia/genética , Proteínas de Membrana/genética , Microcefalia/genética , Diabetes Mellitus/diagnóstico , Epilepsia/diagnóstico , Humanos , Lactente , Masculino , Microcefalia/diagnóstico , Mutação Puntual , Síndrome
14.
Eur J Med Genet ; 60(6): 303-307, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28344185

RESUMO

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized mainly by cardiovascular, craniofacial and skeletal features. We report on a patient with LDS, whose prenatal examination was compatible with the diagnosis of arthrogryposis multiplex congenita. Neonatal assessment showed craniofacial and cardiovascular findings suggestive of LDS whose diagnosis was confirmed by the detection of a novel mutation (HGVN: NM_003242.5 (TGFBR2): c.1381T > C (p.(Cys461Arg))) in the TGFBR2 gene. Few prenatal and neonatal cases of LDS have been reported in the literature. We reviewed all cases reported to date with perinatal onset to delineate the clinical manifestations that allow us to prompt diagnosis of this syndrome at an early stage to prevent fatal cardiovascular complications. Furthermore we discuss the multidisciplinary follow up required in these patients.


Assuntos
Artrogripose/genética , Síndrome de Loeys-Dietz/genética , Mutação de Sentido Incorreto , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Artrogripose/diagnóstico , Feminino , Humanos , Recém-Nascido , Síndrome de Loeys-Dietz/diagnóstico , Receptor do Fator de Crescimento Transformador beta Tipo II
15.
BMC Genomics ; 15: 91, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24484525

RESUMO

BACKGROUND: Mutations in the gene encoding thymidine kinase 2 (TK2) result in the myopathic form of mitochondrial DNA depletion syndrome which is a mitochondrial encephalomyopathy presenting in children. In order to unveil some of the mechanisms involved in this pathology and to identify potential biomarkers and therapeutic targets we have investigated the gene expression profile of human skeletal muscle deficient for TK2 using cDNA microarrays. RESULTS: We have analysed the whole transcriptome of skeletal muscle from patients with TK2 mutations and compared it to normal muscle and to muscle from patients with other mitochondrial myopathies. We have identified a set of over 700 genes which are differentially expressed in TK2 deficient muscle. Bioinformatics analysis reveals important changes in muscle metabolism, in particular, in glucose and glycogen utilisation, and activation of the starvation response which affects aminoacid and lipid metabolism. We have identified those transcriptional regulators which are likely to be responsible for the observed changes in gene expression. CONCLUSION: Our data point towards the tumor suppressor p53 as the regulator at the centre of a network of genes which are responsible for a coordinated response to TK2 mutations which involves inflammation, activation of muscle cell death by apoptosis and induction of growth and differentiation factor 15 (GDF-15) in muscle and serum. We propose that GDF-15 may represent a potential novel biomarker for mitochondrial dysfunction although further studies are required.


Assuntos
Perfilação da Expressão Gênica , Fator 15 de Diferenciação de Crescimento/genética , Miopatias Mitocondriais/genética , Timidina Quinase/genética , Proteína Supressora de Tumor p53/metabolismo , Adolescente , Adulto , Biomarcadores/metabolismo , Caspase 3/metabolismo , Criança , Pré-Escolar , Biologia Computacional , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Fator 15 de Diferenciação de Crescimento/sangue , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Lactente , Miopatias Mitocondriais/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Transdução de Sinais , Timidina Quinase/metabolismo
16.
PLoS One ; 8(9): e74179, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24058525

RESUMO

Type 2 diabetes has been associated with decreased risk of prostate cancer in observational studies, and this inverse association has been recently confirmed in several large cohort studies. However the mechanisms involved in this protective effect remain to be elucidated. The aim of the present study was to explore whether different features of type 2 diabetes (hyperinsulinemia, hyperglycemia and tumor necrosis factor alpha [TNF-α]) protect against the development of prostate cancer. For this purpose LNCaP cells were used for in vitro experiments and nude mice in which PAC120 (hormone-dependent human prostate cancer) xenografts had been implanted were used for in vivo examinations. We provide evidence that increasing glucose concentrations downregulate androgen receptor (AR) mRNA and protein levels through NF-κB activation in LNCaP cells. Moreover, there was a synergic effect of glucose and TNFα in downregulating the AR in LNCaP cells. By contrast, insulin had no effect on AR regulation. In vivo experiments showed that streptozotocin-induced diabetes (STZ-DM) produces tumor growth retardation and a significant reduction in AR expression in PAC120 prostate cancer mice. In conclusion, our results suggest that hyperglycemia and TNF-α play an important role in protecting against prostate cancer by reducing androgen receptor levels via NF-κB.


Assuntos
Adenocarcinoma/genética , Diabetes Mellitus Experimental/genética , Glucose/farmacologia , Hiperglicemia/genética , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Fator de Necrose Tumoral alfa/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Animais , Linhagem Celular Tumoral , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Regulação da Expressão Gênica , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Insulina/farmacologia , Masculino , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Transplante de Neoplasias , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/prevenção & controle , Receptores Androgênicos/metabolismo , Transdução de Sinais , Estreptozocina , Transplante Heterólogo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
17.
J Child Neurol ; 28(11): 1531-1534, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23034978

RESUMO

The mitochondrial DNA m.13513G>A mutation in the ND5 subunit gene is a frequent cause of Leigh syndrome. Patients harboring this mutation typically present with ptosis and cardiac conduction abnormalities, particularly Wolff-Parkinson-White syndrome, and have a late clinical onset, which contrasts with the typical infantile form. The authors describe a patient presenting with intrauterine growth retardation and visual impairment at 3 months of age, followed by infantile spasms, severe gastrointestinal dysmotility, and neurological regression. The patient had hyperlactacidemia and bilateral basal ganglia and brainstem lesions on MRI. Although he did not present cardiac conduction abnormalities, his mother had been diagnosed with Wolff-Parkinson-White syndrome. The m.13513G>A mutation was found in the patient's muscle and in several tissues of his mother. The present results expand the phenotype of Leigh syndrome associated with the m.13513G>A mutation, which should be suspected in patients with early-onset mitochondrial encephalopathy with infantile spasms or prominent gastrointestinal smooth muscle involvement.

18.
Carcinogenesis ; 34(2): 268-76, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23108190

RESUMO

Neuroblastic tumors (NTs) include the neuroblastomas, ganglioneuroblastomas and ganglioneuromas. We have reported previously that the calcium-sensing receptor is expressed in differentiated, favorable NTs but almost undetectable in unfavorable neuroblastomas. We have now detected hypermethylation of a particular region within the CpG island encompassing the CaSR gene promoter 2 in neuroblastoma cell lines and 25% primary neuroblastomas. Hypermethylation of this region was associated with reduced CaSR messenger RNA expression and several predictors of poor outcome in neuroblastomas, including MYCN amplification. Treatment with 5'aza-2-deoxycitidine and/or trichostatin A restored CaSR expression in MYCN-amplified cell lines. Following 5'aza-2-deoxycitidine exposure, decreased percentages of methylated CpG sites were observed at the above-mentioned region. By interphase fluorescence in situ hybridization, variable percentages of nuclei with monosomy of chromosome 3, where the human CaSR gene resides, were observed in more than 90% of primary NTs of all subgroups. Nuclei harboring this alteration were heterogeneously distributed among tumor cells. Ectopic overexpression of the calcium-sensing receptor in two MYCN-amplified neuroblastoma cell lines in which this gene is silenced by promoter hypermethylation significantly reduced their in vitro proliferation rates and almost abolished their capacity to generate xenografts in immunocompromised mice. Finally, upon acute exposure to calcium, the primary activator of this receptor, calcium-sensing receptor-overexpressing neuroblastoma cells underwent apoptosis, a process dependent on sustained activation of ERK1/2. These data would support the hypothesis that epigenetic silencing of the CaSR gene is neither an in vitro artefact in neuroblastoma cell lines nor an irrelevant, secondary event in primary NTs, but a significant mechanism for neuroblastoma survival.


Assuntos
Apoptose , Metilação de DNA , Epigênese Genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neuroblastoma/patologia , Receptores de Detecção de Cálcio/genética , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Animais , Western Blotting , Proliferação de Células , Ilhas de CpG , Feminino , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Hibridização in Situ Fluorescente , Lactente , Camundongos , Camundongos Nus , Monossomia , Proteína Proto-Oncogênica N-Myc , Estadiamento de Neoplasias , Neuroblastoma/genética , Neuroblastoma/mortalidade , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Fosforilação , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Detecção de Cálcio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Orphanet J Rare Dis ; 7: 82, 2012 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-23092449

RESUMO

BACKGROUND: Between 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X-chromosome inactivation (XCI) favouring predominant expression of the DMD mutant allele. However the prognostic use of XCI analysis is controversial. We aimed to evaluate the correlation between X-chromosome inactivation and development of clinical symptoms in a series of symptomatic female carriers of dystrophinopathy. METHODS: We reviewed the clinical, pathological and genetic features of twenty-four symptomatic carriers covering a wide spectrum of clinical phenotypes. DMD gene analysis was performed using MLPA and whole gene sequencing in blood DNA and muscle cDNA. Blood and muscle DNA was used for X-chromosome inactivation (XCI) analysis thought the AR methylation assay in symptomatic carriers and their female relatives, asymptomatic carriers as well as non-carrier females. RESULTS: Symptomatic carriers exhibited 49.2% more skewed XCI profiles than asymptomatic carriers. The extent of XCI skewing in blood tended to increase in line with the severity of muscle symptoms. Skewed XCI patterns were found in at least one first-degree female relative in 78.6% of symptomatic carrier families. No mutations altering XCI in the XIST gene promoter were found. CONCLUSIONS: Skewed XCI is in many cases familial inherited. The extent of XCI skewing is related to phenotype severity. However, the assessment of XCI by means of the AR methylation assay has a poor prognostic value, probably because the methylation status of the AR gene in muscle may not reflect in all cases the methylation status of the DMD gene.


Assuntos
Distrofina/genética , Triagem de Portadores Genéticos , Distrofias Musculares/genética , Inativação do Cromossomo X , Adolescente , Adulto , Idoso , Biópsia , Criança , Pré-Escolar , Feminino , Humanos , Músculo Esquelético/patologia , Distrofias Musculares/patologia , Mutação , Prognóstico , Regiões Promotoras Genéticas , Adulto Jovem
20.
Rev Neurol ; 55(6): 321-9, 2012 Sep 16.
Artigo em Espanhol | MEDLINE | ID: mdl-22972573

RESUMO

INTRODUCTION: The study of polymicrogyria with magnetic resonance imaging (MRI) has made possible the report of several series of patients in which the main clinical manifestations differ considerably. The aims of the study were to review the literature and to know the clinical variability of the patients attended in a neuropediatric service. PATIENTS AND METHODS: A retrospective study was conducted between 1989-2011 for the patients attended in our neuro-pediatric service and diagnosed of polymicrogyria by MRI. RESULTS: On the totality of 44 patients having polymicrogyria, 9 did not satisfy de inclusion criteria (Barkovich's radiological criteria). The polymicrogyria was bilateral in 22/35 patients (1 frontal, 22 perisylvian) and unilateral in 13/35 (2 frontal, the rest perisylvian). All patients with bilateral polymicrogyria had intellectual disability, 71% had global development delay, 75% had oromotor disorder and 40% had epilepsy. Patients with unilateral polymicrogyria had the following symptoms: 65% intellectual disability, 55% global development delay, 55% oromotor disorder, 55% epilepsy and 2 patients where free of symptoms (the oldest 2 year old). The initial symptoms were depending upon the age: the oromotor disorder was the most common in the newborn period, global development delay if the symptoms started before 2 years old and after 2 years epilepsy was the initial most common symptom. CONCLUSION: In our study the most common symptom was intellectual disability (independently of the type of poly-microgyria), followed by oromotor disorder and, with fewer proportion, epilepsy (in contrast with other series).


Assuntos
Malformações do Desenvolvimento Cortical/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos
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