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1.
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
2.
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
3.
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
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.
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
6.
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
7.
Can J Diabetes ; 47(6): 473-481.e1, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37059389

RESUMO

OBJECTIVES: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in people with type 1 diabetes (PWT1D). We assessed cardiovascular risk factors and pharmacologic treatment in a large Canadian cohort of PWT1D. METHODS: This cross-sectional study used data from adult PWT1D in the BETTER registry (n=974). CVD risk factor status, diabetes complications, and treatments (used as proxy for blood pressure and dyslipidemia) were self-reported through online questionnaires. Objective data were available for a subgroup of PWT1D (23%, n=224). RESULTS: Participants were adults (43.9±14.8 years) with a diabetes duration of 23.3±15.2 years; 34.8% reported glycated hemoglobin (A1C) levels of ≤7%, 67.2% reported a very high cardiovascular risk, and 27.2% reported at least 3 CVD risk factors. Most participants received care for CVD in accordance with the Diabetes Canada Clinical Practice Guidelines (DC-CPG), with a median recommended pharmacologic treatment score of 75.0%. However, 3 subgroups of participants with lower adherence (<70%) to DC-CPG were identified: 1) those with microvascular complications and receiving a statin (60.8%, 208 of 342) or renin-angiotensin axis nephroprotective therapy (52.6%, 180 of 342); 2) those aged ≥40 years and receiving statin therapy (67.1%, 369 of 550); and 3) those aged ≥30 years with a diabetes duration of ≥15 years and receiving statin therapy (58.9%, 344 of 584). Among a subgroup of participants with recent laboratory results, only 24.5% of PWT1D (26 of 106) achieved both A1C and low-density lipoprotein cholesterol targets. CONCLUSIONS: Most PWT1D received recommended pharmacologic cardiovascular protection, but specific subgroups required special attention. Target achievement for key risk factors remains suboptimal.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 1 , Inibidores de Hidroximetilglutaril-CoA Redutases , Adulto , Humanos , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Estudos Transversais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Fatores de Risco , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hemoglobinas Glicadas , Canadá/epidemiologia , Fatores de Risco de Doenças Cardíacas
8.
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
9.
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
10.
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
11.
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 , Chlorocebus aethiops , 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
12.
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
13.
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
14.
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
15.
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
16.
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
17.
J Neuropathol Exp Neurol ; 61(9): 747-59, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12230321

RESUMO

Pelizaeus-Merzbacher disease (PMD) can now be defined as an X-linked recessive leukodystrophy that is caused by a mutation in the proteolipid protein (PLP) gene on chromosome Xq22. The most common mutation is gene duplication followed in frequency by missense mutations, insertions, and deletions. The clinical spectrum ranges from severe neonatal cases to relatively benign adult forms and X-linked recessive spastic paraplegia type 2. The lack of PLP is accompanied by deficits in the other myelin proteins of the central nervous system, including myelin basic protein, myelin-associated glycoprotein, and cyclic nucleotide phosphodiesterase. Surprisingly, the total absence of PLP due to gene deletion or a null allele causes a relatively benign form of PMD. Abnormal PLP is thought to impair protein trafficking and to induce apoptosis in oligodendroglia. Immunocytochemistry with specific antibodies reveals the PLP deficiency and insufficient generation of myelin sheaths with the remaining proteins. Both excessive biosynthesis of PLP, as in gene duplications, or conformational change of the protein, as in missense mutations, are detrimental to myelination. Several naturally occurring and transgenic animal models with PLP gene mutations or deletions have contributed to our understanding of dysmyelination in PMD and the general knowledge of myelination and myelin repair.


Assuntos
Proteína Proteolipídica de Mielina/genética , Doença de Pelizaeus-Merzbacher/patologia , Doença de Pelizaeus-Merzbacher/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Duplicação Gênica , Genes Recessivos , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Camundongos , Mutação , Bainha de Mielina/metabolismo , Doença de Pelizaeus-Merzbacher/diagnóstico , Fenótipo , Ratos , Deleção de Sequência , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Cromossomo X/genética
18.
J Neuropathol Exp Neurol ; 61(10): 849-56, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12387451

RESUMO

Molecular, genetic, and pharmacological studies have shown that neprilysin (also called NEP) catabolizes amyloid beta peptides (A beta) in healthy conditions. However, in Alzheimer disease (AD), A beta accumulates forming senile plaques in brain parenchyma and amyloid deposition around blood vessels. In this study, we tested at cellular level the relationship between neprilysin and A beta in human healthy and AD brain. Our results provided evidence for declining levels of neprilysin in AD brains as compared to healthy controls in parallel with increasing deposition of A beta. In hippocampus of AD individuals we observed a significant down-regulation of neprilysin expression in pyramidal neurons, consistent with the possibility that neprilysin controls the level of A beta accumulation and plaque formation in this area. In the cortex and leptomeninges, neprilysin was expressed in the smooth muscle cells of blood vessels. In sections from AD patients we observed a clear inverse relationship between neprilysin and A beta peptide levels in the vasculature, implicating neprilysin in cerebral amyloid angiopathy.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Angiopatia Amiloide Cerebral/enzimologia , Circulação Cerebrovascular/fisiologia , Regulação Enzimológica da Expressão Gênica , Músculo Liso Vascular/patologia , Neprilisina/genética , Doença de Alzheimer/enzimologia , Encéfalo/irrigação sanguínea , Encéfalo/enzimologia , Primers do DNA , Hipocampo/irrigação sanguínea , Hipocampo/enzimologia , Hipocampo/patologia , Humanos , Músculo Liso Vascular/enzimologia , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , Transcrição Gênica
20.
Can J Neurol Sci ; 31(3): 363-7, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15376481

RESUMO

OBJECTIVE: Frontotemporal dementia is a neurodegenerative disease affecting mostly the frontal and/or temporal lobes, with neuronal loss and intraneuronal and/or intraglial inclusions composed of hyperphosphorylated microtubule-associated protein tau and ubiquitin. Missense and splice site mutations in the TAU gene have been identified in approximately 15% of all frontotemporal dementia cases. In this study, we evaluated the involvement of mutations in the TAU gene in development of frontotemporal dementia phenotype in patients of French or English Canadian origins. METHODS: Fourteen patients with frontotemporal dementia phenotype and 98 normal controls were recruited for the study. The TAU gene was screened by sequencing and denaturing high performance liquid chromatography. RESULTS: No mutations, except some new polymorphisms, were detected in the TAU gene of these patients. One polymorphism, however, may play a role in pathogenesis. CONCLUSION: Our results agree with previous work suggesting that mutations in this gene are not a frequent cause of the frontotemporal dementia phenotype in Canadian patients.


Assuntos
Demência/genética , Polimorfismo Genético , Proteínas tau/genética , Canadá , Éxons , Humanos , Mutação , Fenótipo
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