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1.
Medicine (Baltimore) ; 96(3): e5694, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28099331

RESUMO

The general aim of this study was to evaluate the disease spectrum in patients presenting with a pure polymyositis (pPM) phenotype. Specific objectives were to characterize clinical features, autoantibodies (aAbs), and membrane attack complex (MAC) in muscle biopsies of patients with treatment-responsive, statin-exposed necrotizing autoimmune myositis (NAM). Patients from the Centre hospitalier de l'Université de Montréal autoimmune myositis (AIM) Cohort with a pPM phenotype, response to immunosuppression, and follow-up ≥3 years were included. Of 17 consecutive patients with pPM, 14 patients had a NAM, of whom 12 were previously exposed to atorvastatin (mean 38.8 months). These 12 patients were therefore suspected of atorvastatin-induced AIM (atorAIM) and selected for study. All had aAbs to 3-hydroxy-3-methylglutaryl coenzyme A reductase, and none had overlap aAbs, aAbs to signal recognition particle, or cancer. Three stages of myopathy were recognized: stage 1 (isolated serum creatine kinase [CK] elevation), stage 2 (CK elevation, normal strength, and abnormal electromyogram [EMG]), and stage 3 (CK elevation, proximal weakness, and abnormal EMG). At diagnosis, 10/12 (83%) patients had stage 3 myopathy (mean CK elevation: 7247 U/L). The presenting mode was stage 1 in 6 patients (50%) (mean CK elevation: 1540 U/L), all of whom progressed to stage 3 (mean delay: 37 months) despite atorvastatin discontinuation. MAC deposition was observed in all muscle biopsies (isolated sarcolemmal deposition on non-necrotic fibers, isolated granular deposition on endomysial capillaries, or mixed pattern). Oral corticosteroids alone failed to normalize CKs and induce remission. Ten patients (83%) received intravenous immune globulin (IVIG) as part of an induction regimen. Of 10 patients with ≥1 year remission on stable maintenance therapy, IVIG was needed in 50%, either with methotrexate (MTX) monotherapy or combination immunosuppression. In the remaining patients, MTX monotherapy or combination therapy maintained remission without IVIG. AtorAIM emerged as the dominant entity in patients with a pPM phenotype and treatment-responsive myopathy. Isolated CK elevation was the mode of presentation of atorAIM. The new onset of isolated CK elevation on atorvastatin and persistent CK elevation on statin discontinuation should raise early suspicion for atorAIM. Statin-induced AIM should be included in the differential diagnosis of asymptomatic hyperCKemia. Three patterns of MAC deposition, while nonpathognomonic, were pathological clues to atorAIM. AtorAIM was uniformly corticosteroid resistant but responsive to IVIG as induction and maintenance therapy.


Assuntos
Atorvastatina/efeitos adversos , Doenças Autoimunes/induzido quimicamente , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Polimiosite/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Quimioterapia de Indução , Estudos Longitudinais , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Polimiosite/tratamento farmacológico , Polimiosite/metabolismo , Polimiosite/patologia
2.
Mod Pathol ; 29(9): 962-76, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27230413

RESUMO

Hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC) is an autosomal recessive disease of the central and peripheral nervous system that presents as early-onset polyneuropathy. Patients are hypotonic and areflexic from birth, with abnormal facial features and atrophic muscles. Progressive peripheral neuropathy eventually confines them to a wheelchair in the second decade of life, and death occurs by the fourth decade. We here define the neuropathologic features of the disease in autopsy tissues from eight cases. Both developmental and neurodegenerative features were found. Hypoplasia or absence of the major telencephalic commissures and a hypoplasia of corticospinal tracts to half the normal size, were the major neurodevelopmental defects we observed. Despite being a neurodegenerative disease, preservation of brain weight and a conspicuous absence of neuronal or glial cell death were signal features of this disease. Small tumor-like overgrowths of axons, termed axonomas, were found in the central and peripheral nervous system, indicating attempted axonal regeneration. We conclude that the neurodegenerative deficits in HMSN/ACC are primarily caused by an axonopathy superimposed upon abnormal development, affecting peripheral but also central nervous system axons, all ultimately because of a genetic defect in the axonal cotransporter KCC3.


Assuntos
Agenesia do Corpo Caloso/patologia , Axônios/patologia , Encéfalo/patologia , Doenças do Sistema Nervoso Periférico/patologia , Sistema Nervoso Periférico/patologia , Simportadores/genética , Adulto , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/metabolismo , Agenesia do Corpo Caloso/fisiopatologia , Autopsia , Axônios/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Degeneração Neural , Sistema Nervoso Periférico/metabolismo , Sistema Nervoso Periférico/fisiopatologia , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/fisiopatologia , Fenótipo , Prognóstico , Simportadores/metabolismo , Adulto Jovem
3.
Dev Med Child Neurol ; 58(1): 39-48, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26179148

RESUMO

AIM: Polymicrogyria (PMG) is one of the most common forms of cortical malformation yet the mechanism of its development remains unknown. This study describes the histopathological aspects of PMG in a large series including a significant proportion of fetal cases. METHOD: We have reviewed the neuropathology and medical records of 44 fetuses and 27 children and adults in whom the cortical architecture was focally or diffusely replaced by one or more festooning bands of neurons. RESULTS: The pial surface of the brain overlying the polymicrogyric cortex was abnormal in almost 90% of cases irrespective of the aetiology. This accords with animal studies indicating the importance of the leptomeninges in cortical development. The aetiology of PMG was highly heterogeneous and there was no correlation between cortical layering patterns and aetiology. PMG was almost always associated with other brain malformations. INTERPRETATION: The inclusion of many fetal cases has allowed us to examine the early developmental stages of PMG. The study indicates the significance of surface signals responsible for human corticogenesis and the complex interaction between genetic and environmental factors leading to this common endpoint of cortical maldevelopment.


Assuntos
Encéfalo/patologia , Feto/patologia , Polimicrogiria/patologia , Adolescente , Adulto , Autopsia , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Criança , Pré-Escolar , Feto/citologia , Humanos , Lactente , Recém-Nascido , Adulto Jovem
4.
AIDS Res Ther ; 11: 20, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25057277

RESUMO

Microsporidia have become increasingly recognized as opportunistic pathogens since the genesis of the AIDS epidemic. The incidence of microsporidiosis has decreased with the advent of combination antiretroviral therapy but it is frequently reported in non-HIV immunosuppressed patients and as a latent infection in immunocompetent individuals. Herein, we describe an HIV-infected male (46 years) with suspected progressive multifocal leukoencephalopathy that has not responded to optimal antiretroviral therapy, steroids, or cidofovir. Post-mortem examination revealed cerebral microsporidiosis. No diagnostic clue however, was found when the patient was alive. This report underscores the need for physicians to consider microsporidiosis (potentially affecting the brain) when no other etiology is established both in HIV, non-HIV immunosuppressed patients and in immunocompetent individuals.

5.
Muscle Nerve ; 49(1): 134-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23893323

RESUMO

INTRODUCTION: Erythromelalgia due to heterozygous gain-of-function SCN9A mutations usually presents as a pure sensory-autonomic disorder characterized by recurrent episodes of burning pain and redness of the extremities. METHODS: We describe a patient with an unusual phenotypic presentation of gross motor delay, childhood-onset erythromelalgia, extreme visceral pain episodes, hypesthesia, and self-mutilation. The investigation of the patient's motor delay included various biochemical analyses, a comparative genomic hybridization array (CGH), electromyogram (EMG), and muscle biopsy. Once erythromelalgia was suspected clinically, the SCN9A gene was sequenced. RESULTS: The EMG, CGH, and biochemical tests were negative. The biopsy showed an axonal neuropathy and neurogenic atrophy. Sequencing of SCN9A revealed a heterozygous missense mutation in exon 7; p.I234T. CONCLUSIONS: This is a case of global motor delay and erythromelalgia associated with SCN9A. The motor delay may be attributed to the extreme pain episodes or to a developmental perturbation of proprioceptive inputs.


Assuntos
Transtornos das Habilidades Motoras/genética , Mutação de Sentido Incorreto/genética , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Índice de Gravidade de Doença , Transtornos Somatoformes/genética , Carbamazepina/uso terapêutico , Pré-Escolar , Comorbidade , Eritromelalgia/tratamento farmacológico , Eritromelalgia/epidemiologia , Eritromelalgia/genética , Feminino , Humanos , Hipestesia/tratamento farmacológico , Hipestesia/epidemiologia , Hipestesia/genética , Mexiletina/uso terapêutico , Transtornos das Habilidades Motoras/tratamento farmacológico , Transtornos das Habilidades Motoras/epidemiologia , Transtornos Somatoformes/tratamento farmacológico , Transtornos Somatoformes/epidemiologia , Resultado do Tratamento
6.
PLoS One ; 8(7): e60581, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23861731

RESUMO

Most conditions detected by expanded newborn screening result from deficiency of one of the enzymes that degrade acyl-coenzyme A (CoA) esters in mitochondria. The role of acyl-CoAs in the pathophysiology of these disorders is poorly understood, in part because CoA esters are intracellular and samples are not generally available from human patients. We created a mouse model of one such condition, deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (HL), in liver (HLLKO mice). HL catalyses a reaction of ketone body synthesis and of leucine degradation. Chronic HL deficiency and acute crises each produced distinct abnormal liver acyl-CoA patterns, which would not be predictable from levels of urine organic acids and plasma acylcarnitines. In HLLKO hepatocytes, ketogenesis was undetectable. Carboxylation of [2-(14)C] pyruvate diminished following incubation of HLLKO hepatocytes with the leucine metabolite 2-ketoisocaproate (KIC). HLLKO mice also had suppression of the normal hyperglycemic response to a systemic pyruvate load, a measure of gluconeogenesis. Hyperammonemia and hypoglycemia, cardinal features of many inborn errors of acyl-CoA metabolism, occurred spontaneously in some HLLKO mice and were inducible by administering KIC. KIC loading also increased levels of several leucine-related acyl-CoAs and reduced acetyl-CoA levels. Ultrastructurally, hepatocyte mitochondria of KIC-treated HLLKO mice show marked swelling. KIC-induced hyperammonemia improved following administration of carglumate (N-carbamyl-L-glutamic acid), which substitutes for the product of an acetyl-CoA-dependent reaction essential for urea cycle function, demonstrating an acyl-CoA-related mechanism for this complication.


Assuntos
Acetilcoenzima A/metabolismo , Hiperamonemia/metabolismo , Hipoglicemia/metabolismo , Fígado/metabolismo , Acetilcoenzima A/genética , Acil Coenzima A/deficiência , Acil Coenzima A/genética , Animais , Dióxido de Carbono/metabolismo , Técnicas de Inativação de Genes , Ordem dos Genes , Marcação de Genes , Genes Letais , Gluconeogênese/genética , Hepatócitos/metabolismo , Humanos , Hiperamonemia/genética , Hiperamonemia/mortalidade , Hipoglicemia/genética , Hipoglicemia/mortalidade , Letargia , Leucina/metabolismo , Redes e Vias Metabólicas , Metaboloma , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Modelos Biológicos , Peroxissomos , Fenótipo , Ácido Pirúvico/metabolismo
7.
Pediatr Int ; 55(2): 237-40, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23679164

RESUMO

A 9-year-old boy died of rabies complications. We report the unusual combination between rabies, coronary dilatation on echocardiography and coronary vasculitis documented upon autopsy. In the search for the etiological agent of Kawasaki disease, we suggest that a viral infection with potential antigenic similarities to rabies virus should be entertained.


Assuntos
Aneurisma Coronário/etiologia , Vasos Coronários/patologia , Raiva/complicações , Vasculite/etiologia , Criança , Aneurisma Coronário/diagnóstico , Diagnóstico Diferencial , Evolução Fatal , Humanos , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Raiva/diagnóstico , Vasculite/diagnóstico
8.
Epilepsia ; 52(4): 728-37, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21320118

RESUMO

PURPOSE: The phenotypic and etiologic spectrum in adults with nodular heterotopias (NHs) has been well characterized. However, there are no large pediatric case series. We, therefore, wanted to review the clinical features of NHs in our population. METHODS: Hospital records of 31 patients with pathology or imaging-confirmed NHs were reviewed. Two-sided Fisher's exact t-test was used to assess associations between distribution of NHs and specific clinical features. KEY FINDINGS: NHs were distributed as follows: 8 (26%) unilateral focal subependymal, 3 (10%) unilateral diffuse subependymal, 5 (16%) bilateral focal subependymal, 12 (39%) bilateral diffuse subependymal, and 3 (10%) isolated subcortical. The phenotypic spectrum in our population differs from that described in adults. Significant morbidity and mortality are associated with presentation in childhood. Twenty-two of 31 patients (71%) died in the neonatal period or in childhood. Additional cerebral malformations were found in 80% and systemic malformations in 74%. The majority of patients had developmental delay, intellectual deficit, and intractable epilepsy. Patients with unilateral focal NHs were more likely to have ventriculomegaly (p = 0.027), and those with bilateral diffuse NHs more likely to have cerebellar abnormalities (p = 0.007). Isolated subcortical NHs were associated with multiple malformations (p = 0.049) and cardiac abnormalities (p = 0.027). Underlying etiology was heterogeneous and determined in only six cases (19%): del chr 1p36, del chr 15q11, pyruvate dehydrogenase deficiency, sialic acidosis type 1, Aicardi syndrome, and FLNA mutation. SIGNIFICANCE: NHs are present in childhood as part of multiple cerebral and systemic malformations; developmental delay and refractory seizures are the rule rather than the exception. Milder forms go unrecognized until seizure onset in adulthood.


Assuntos
Córtex Cerebral/patologia , Heterotopia Nodular Periventricular/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Comorbidade , Feminino , Humanos , Lactente , Masculino , Heterotopia Nodular Periventricular/etiologia , Heterotopia Nodular Periventricular/mortalidade , Adulto Jovem
9.
J Child Neurol ; 26(4): 510-7, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21233460

RESUMO

Galloway-Mowat syndrome is a rare condition that is likely hereditary though the underlying offending gene has not been identified, and is characterized by microcephaly and severe nephrotic syndrome culminating in childhood death. Some of the reported cases have abnormalities in neuronal migration and intractable seizures, but many of the described cases focus on the renal pathology and emphasize a diversity of clinical and pathological features. The case described herein includes a thorough neuropathological description, and when the neuroradiology and neuropathology of the previously published cases is scrutinized, a fairly consistent clinical and neuropathological phenotype emerges.


Assuntos
Encéfalo/patologia , Epilepsia/complicações , Microcefalia/complicações , Morte Celular/fisiologia , Epilepsia/patologia , Hérnia Hiatal/complicações , Hérnia Hiatal/patologia , Humanos , Lactente , Masculino , Microcefalia/patologia , Nefrose/complicações , Nefrose/patologia
10.
J Med Genet ; 48(3): 183-9, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21266382

RESUMO

BACKGROUND: The natural history of all known patients with French-Canadian Leigh disease (Saguenay-Lac-St-Jean cytochrome c oxidase deficiency, MIM220111, SLSJ-COX), the largest known cohort of patients with a genetically homogeneous, nuclear encoded congenital lactic acidosis, was studied. RESULTS: 55 of 56 patients were homozygous for the A354V mutation in LRPPRC. One was a genetic compound (A354V/C1277Xdel8). Clinical features included developmental delay, failure to thrive, characteristic facial appearance and, in 90% of patients, acute crises that have not previously been detailed, either metabolic (fulminant lactic acidosis) and/or neurological (Leigh syndrome and/or stroke-like episodes). Survival ranged from 5 days to >30 years. 46/56 patients (82%) died, at a median age of 1.6 years. Of 73 crises, 38 (52%) were fatal. The immediate causes of death were multiple organ failure and/or Leigh disease. Major predictors of mortality during crises (p<0.005) were hyperglycaemia, hepatic cytolysis, and altered consciousness at admission. Compared to a group of SURF1-deficient Leigh syndrome patients assembled from the literature, SLSJ-COX is distinct by the occurrence of metabolic crises, leading to earlier and higher mortality (p=0.001). CONCLUSION: SLSJ-COX is clinically distinct, with acute fatal acidotic crises on a backdrop of chronic moderate developmental delay and hyperlactataemia. Leigh syndrome is common. Stroke-like episodes can occur. The Leigh syndrome of SLSJ-COX differs from that of SURF1-related COX deficiency. SLSJ-COX has a different spectrum of associated abnormalities, acidotic crises being particularly suggestive of LRPPRC related Leigh syndrome. Even among A354V homozygotes, pronounced differences in survival and severity occur, showing that other genetic and/or environmental factors can influence outcome.


Assuntos
Deficiência de Citocromo-c Oxidase/genética , Doença de Leigh/genética , Mutação , Proteínas de Neoplasias/genética , Acidose Láctica/genética , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Homozigoto , Humanos , Lactente , Doença de Leigh/metabolismo , Modelos Logísticos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteínas de Neoplasias/metabolismo , Fenótipo , Estudos Retrospectivos , Adulto Jovem
11.
J Otolaryngol Head Neck Surg ; 39(3): 236-43, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20470667

RESUMO

OBJECTIVE: To identify and to compare the protective effect of intratympanic injections of N-acetylcysteine (NAC) or methylprednisolone to prevent cisplatin-induced ototoxicity, to investigate inner ear protection using an electron microscope and to evaluate the effect of 4% NAC on the middle ear. DESIGN: Experimental study. SETTING: Basic ear research center at Sainte-Justine hospital. METHODS: Ten Hartley guinea pigs were divided into two groups, according to the product used intratympanically (4% NAC or 62.5 mg/mL methylprednisolone) in one ear. The other ear was left as control. Cisplatin was administered intraperitoneally (3 mg/kg), once a week for 5 weeks. MAIN OUTCOME MEASURES: Auditory evoked brainstem responses were used to test hearing. The inner ear was screened using an electron microscope. RESULTS: Significant threshold shift was seen on all tested frequencies of both groups. This difference is clinically and statistically significant in the methylprednisolone group. The NAC-treated group had a lower threshold shift than the methylprednisolone group in both ears. Electron microscope studies showed in all untreated-NAC ears severe lesion of the inner and outer hair cells with complete degeneration of steriocilia, whereas in NAC-treated ears we noted a nuclear and cytoplasmic membrane preservation with some preservation of steriocila. Also, 4% intratympanic NAC produces an external auditory canal and middle ear inflammatory reaction. CONCLUSIONS: Intratympanic injections of methylprednisolone failed to demonstrate efficacy in protecting cisplatin ototoxicity whereas 4% NAC showed a partial protection. The safety of intratympanic injections should be investigated in further studies, as possible systemic shift of the locally administered treatment is suspected.


Assuntos
Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/efeitos adversos , Antivirais/farmacologia , Antivirais/uso terapêutico , Cisplatino/efeitos adversos , Transtornos da Audição/induzido quimicamente , Transtornos da Audição/prevenção & controle , Metilprednisolona/farmacologia , Metilprednisolona/uso terapêutico , Membrana Timpânica/efeitos dos fármacos , Acetilcisteína/administração & dosagem , Animais , Anti-Inflamatórios/administração & dosagem , Antivirais/administração & dosagem , Modelos Animais de Doenças , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Cobaias , Transtornos da Audição/diagnóstico , Injeções , Metilprednisolona/administração & dosagem , Índice de Gravidade de Doença , Resultado do Tratamento
12.
Am J Hum Genet ; 86(2): 213-21, 2010 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-20096397

RESUMO

The recently described human anion channel Anoctamin (ANO) protein family comprises at least ten members, many of which have been shown to correspond to calcium-activated chloride channels. To date, the only reported human mutations in this family of genes are dominant mutations in ANO5 (TMEM16E, GDD1) in the rare skeletal disorder gnathodiaphyseal dysplasia. We have identified recessive mutations in ANO5 that result in a proximal limb-girdle muscular dystrophy (LGMD2L) in three French Canadian families and in a distal non-dysferlin Miyoshi myopathy (MMD3) in Dutch and Finnish families. These mutations consist of a splice site, one base pair duplication shared by French Canadian and Dutch cases, and two missense mutations. The splice site and the duplication mutations introduce premature-termination codons and consequently trigger nonsense-mediated mRNA decay, suggesting an underlining loss-of-function mechanism. The LGMD2L phenotype is characterized by proximal weakness, with prominent asymmetrical quadriceps femoris and biceps brachii atrophy. The MMD3 phenotype is associated with distal weakness, of calf muscles in particular. With the use of electron microscopy, multifocal sarcolemmal lesions were observed in both phenotypes. The phenotypic heterogeneity associated with ANO5 mutations is reminiscent of that observed with Dysferlin (DYSF) mutations that can cause both LGMD2B and Miyoshi myopathy (MMD1). In one MMD3-affected individual, defective membrane repair was documented on fibroblasts by membrane-resealing ability assays, as observed in dysferlinopathies. Though the function of the ANO5 protein is still unknown, its putative calcium-activated chloride channel function may lead to important insights into the role of deficient skeletal muscle membrane repair in muscular dystrophies.


Assuntos
Canais de Cloreto/genética , Genes Recessivos/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação/genética , Adulto , Idoso , Anoctaminas , Sequência de Bases , Canadá , Canais de Cloreto/química , Códon sem Sentido/genética , Cicloeximida/farmacologia , Análise Mutacional de DNA , Disferlina , Família , Feminino , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteínas Musculares/genética , Músculos/efeitos dos fármacos , Músculos/patologia , Músculos/ultraestrutura , Distrofia Muscular do Cíngulo dos Membros/patologia , Linhagem
13.
Eur J Neurosci ; 30(9): 1823-30, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19863653

RESUMO

Evidence suggests that the genes involved in brain lipid homeostasis are of particular relevance for Alzheimer's disease (AD) etiology. Among these genes, that encoding paraoxonase 1 (PON1) has gained newfound interest from a public health perspective, as recent studies have suggested that PON1 L55M and Q192R genetic variants might affect individual susceptibility to environmental events, such as exposure to cholinesterase inhibitors. Cholinesterase inhibitor therapy being the treatment of choice for patients with mild to moderate AD, we sought to answer two main questions: (i) are these genetic variants associated with increased AD risk, earlier age of onset/death, or shorter AD duration; and (ii) do they affect the neuropathological hallmarks of AD? This genetic study used a large cohort of clinical and autopsy-confirmed AD cases and age-matched, cognitively intact controls from the Douglas Hospital Brain Bank, Quebec, Canada (n = 1066). The evidence presented here suggests multiple gender-specific effects of PON1 polymorphisms on AD etiopathology. The L55M Met allele exerts an AD risk-enhancing effect only in men (P < 0.001), whereas both men and women carrying the M55M/Q192Q genotype exhibit increased survival (2.5 years, P < 0.05) and later age of onset (1.5 years, P < 0.05). These genetic variants are also individually and significantly associated, sometimes in opposite directions for both genders, with beta-amyloid levels (P < 0.001), senile plaque accumulation (P < 0.001) and choline acetyltransferase activity (P < 0.05) in, respectively, two of two, five of six, and three of six brain areas. These results suggest an involvement of the PON1 gene in AD etiopathology and responses to treatment.


Assuntos
Doença de Alzheimer , Arildialquilfosfatase/genética , Variação Genética , Polimorfismo de Nucleotídeo Único , Idoso , Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Encéfalo/patologia , Colina O-Acetiltransferase/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Masculino
15.
Carcinogenesis ; 30(7): 1089-96, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19359592

RESUMO

Met, the receptor for hepatocyte growth factor (HGF), is a receptor tyrosine kinase that has recently emerged as an important contributor to human neoplasia. In physiological and pathological conditions, Met triggers various cellular functions related to cell proliferation, cell migration and the inhibition of apoptosis, and also regulates a genetic program leading to coagulation. Since medulloblastomas (MBs) express high levels of tissue factor (TF), the main initiator of blood coagulation, we therefore examined the link between Met and TF expression in these pediatric tumors. We observed that stimulation of the MB cell line DAOY with HGF led to a marked increase of TF expression and procoagulant activity, in agreement with analysis of clinical MB tumor specimens, in which tumors expressing high levels of Met also showed high levels of TF. The HGF-dependent increase in TF expression and activity required Src family kinases and led to the translocation of TF to actin-rich structures at the cell periphery, suggesting a role of the protein in cell migration. Accordingly, addition of physiological concentrations of the TF activator factor VIIa (FVII) to HGF-stimulated DAOY cells promoted a marked increase in the migratory potential of these cells. Overall, these results suggest that HGF-induced activation of the Met receptor results in TF expression by MB cells and that this event probably contribute to tumor proliferation by enabling the formation of a provisional fibrin matrix. In addition, TF-mediated non-hemostatic functions, such as migration toward FVIIa, may also play a central role in MB aggressiveness.


Assuntos
Neoplasias Encefálicas/metabolismo , Movimento Celular/fisiologia , Fator VII/metabolismo , Meduloblastoma/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Tromboplastina/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Meduloblastoma/patologia
16.
J Child Neurol ; 24(6): 758-62, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19264734

RESUMO

We report a child presenting with severe demyelinating myelitis complicated with critical illness polyneuropathy. This previously healthy 8-month-old boy presented with acute superior limb weakness, absent tendon reflexes, and respiratory failure. Spinal magnetic resonance imaging showed an extensive cervical demyelinating lesion. Spinal cord trauma was suspected and high doses of dexamethasone were administered. Electromyography and nerve conduction studies showed absence of compound muscle action potentials and sural nerve sensory action potential, which was suggestive of a severe Guillain-Barré syndrome. However, intravenous immunoglobulins did not induce any improvement. Afterward, sural nerve biopsy showed a mild neuropathy, but muscle biopsy revealed abnormalities compatible with severe critical illness myopathy. After 5 months of evolution without improvement, the patient died following withdrawal of life support therapy. This case highlights the possible occurrence of critical illness polyneuromyopathy when treatment with corticosteroids are used in patients with acute demyelinating myelitis.


Assuntos
Mielite Transversa/complicações , Polineuropatias/complicações , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Eletromiografia , Evolução Fatal , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Masculino , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Músculo Esquelético/ultraestrutura , Mielite Transversa/tratamento farmacológico , Mielite Transversa/fisiopatologia , Condução Nervosa , Polineuropatias/fisiopatologia , Medula Espinal/patologia , Nervo Sural/patologia , Nervo Sural/fisiopatologia
17.
J Clin Endocrinol Metab ; 94(1): 197-203, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18957494

RESUMO

CONTEXT: Thyroid transcription factor 1 (TITF1/NKX2.1) is expressed in the thyroid, lung, ventral forebrain, and pituitary. In the lung, TITF1/NKX2.1 activates the expression of genes critical for lung development and function. Titf/Nkx2.1(-/-) mice have pituitary and thyroid aplasia but also impairment of pulmonary branching. Humans with heterozygous TITF1/NKX2.1 mutations present with various combinations of primary hypothyroidism, respiratory distress, and neurological disorders. OBJECTIVE: The objective of the study was to report clinical and molecular studies of the first patient with lethal neonatal respiratory distress from a novel heterozygous TITF1/NKX2.1 mutation. PARTICIPANT: This girl, the first child of healthy nonconsanguineous French-Canadian parents, was born at 41 wk. Birth weight was 3,460 g and Apgar scores were normal. Soon after birth, she developed acute respiratory failure with pulmonary hypertension. At neonatal screening on the second day of life, TSH was 31 mU/liter (N <15) and total T(4) 245 nmol/liter (N = 120-350). Despite mechanical ventilation, thyroxine, surfactant, and pulmonary vasodilators, the patient died on the 40th day. RESULTS: Histopathology revealed pulmonary tissue with low alveolar counts. The thyroid was normal. Sequencing of the patient's lymphocyte DNA revealed a novel heterozygous TITF1/NKX2.1 mutation (I207F). This mutation was not found in either parent. In vitro, the mutant TITF-1 had reduced DNA binding and transactivation capacity. CONCLUSION: This is the first reported case of a heterozygous TITF1/NKX2.1 mutation leading to neonatal death from respiratory failure. The association of severe unexplained respiratory distress in a term neonate with mild primary hypothyroidism is the clue that led to the diagnosis.


Assuntos
Hipotireoidismo/genética , Mutação , Proteínas Nucleares/genética , Insuficiência Respiratória/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Células COS , DNA/metabolismo , Feminino , Heterozigoto , Humanos , Imuno-Histoquímica , Recém-Nascido , Dados de Sequência Molecular , Proteínas Nucleares/química , Análise de Sequência de DNA , Fator Nuclear 1 de Tireoide , Fatores de Transcrição/química , Ativação Transcricional
18.
Pediatr Res ; 64(4): 364-9, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18552707

RESUMO

Children with hypoplastic left heart syndrome (HLHS) have an increased prevalence of central nervous system (CNS) abnormalities. The extent to which this problem is due to CNS maldevelopment, prenatal ischemia, postnatal chronic cyanosis and/or multiple exposures to cardiopulmonary bypass is unknown. To better understand the etiology of CNS abnormalities in HLHS, we evaluated 68 neonates with HLHS; in 28 cases, both fetal ultrasound and echocardiogram data were available to assess head size, head growth and aortic valve anatomy (atresia or stenosis). In addition, we evaluated neuropathology in 11 electively aborted HLHS fetuses. The mean head circumference percentile in HLHS neonates was significantly smaller than HLHS fetuses (22 +/- 2% versus 40 +/- 4%, p < 0.001). A significant decrease in head growth, defined as a 50% reduction in head circumference percentile, was observed in half (14/28) of HLHS fetuses and nearly a quarter (6/28) were already growth restricted (

Assuntos
Valva Aórtica/patologia , Cabeça/embriologia , Síndrome do Coração Esquerdo Hipoplásico/complicações , Cefalometria , Ecocardiografia , Cabeça/diagnóstico por imagem , Humanos , Síndrome do Coração Esquerdo Hipoplásico/patologia , Recém-Nascido , Ohio
19.
Pediatr Neurol ; 38(4): 261-6, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18358405

RESUMO

Congenital axonal neuropathy associated with encephalopathy appears to be very rare. Only a few cases have been reported in the literature. In the last 25 years, we have seen seven patients affected by congenital axonal neuropathy with encephalopathy. Biopsies of their sural nerves revealed axonal atrophy and loss of large-diameter nerve fibers. All of these patients presented at birth or soon thereafter with hypotonia associated with distal weakness and diffuse areflexia. Central nervous system manifestations included microcephaly, seizures, and developmental delay. Outcomes were poor. Four children died before age 3 years from respiratory insufficiency or aspiration pneumonia. The three surviving patients manifested severe developmental delay. In our most recent patient, Western-blot analysis of snap-frozen specimens of the temporal and cerebellar cortex demonstrated an absence or marked decrease of microtubule-associated protein types 1A and 2, compared with age-matched control subjects. Calloso-splenial hypogenesis and neurofilament swellings were also documented in the deep white matter and adjacent cortex. The absence or hypo-expression of central nervous system microtubule-associated proteins has never been reported in congenital neuropathies, and may represent a new clinicopathologic entity.


Assuntos
Axônios , Encefalopatias/congênito , Doenças do Sistema Nervoso Periférico/congênito , Encefalopatias/diagnóstico , Encefalopatias/metabolismo , Canadá , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Condução Nervosa/fisiologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/metabolismo , Prognóstico , Estudos Retrospectivos
20.
J Child Neurol ; 22(11): 1301-4, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18006961

RESUMO

We report a male term newborn with genetically confirmed spinal muscular atrophy type 0, presenting with arthrogryposis and severe generalized weakness and requiring ventilatory support. Muscle biopsy revealed fibers with central nuclei resembling myotubes and negative myotubularin immunohistochemical staining compared with a control muscle biopsy. The absence of myotubularin associated with survival motor neuron protein deficiency suggests that survival motor neuron protein may have a role in muscle fiber maturation and myotubularin expression. Studying the pathology of this rare and lethal neonatal form of spinal muscular atrophy may further our understanding of spinal muscular atrophy pathogenesis.


Assuntos
Atrofia Muscular Espinal/patologia , Miopatias Congênitas Estruturais/diagnóstico , Humanos , Recém-Nascido , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Atrofia Muscular Espinal/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo
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