RESUMO
In 1982, Rickard & Williams stated that immunity to larval taeniid cestodes could be divided into two different phases: the establishment phase, operating against oncospheres, and the established phase, operating against established metacestodes in the tissues. These concepts were largely based on experimental and veterinary data. As a result of subsequent research combined with clinical data, we can consider that, for metacestodes of Echinococcus spp, a single established phase is probably too simple a concept. These parasites show developmental changes in different hosts over time, the most significant being growth, fertility and degeneration. Recent clinical cyst classifications (WHO/IWGE) have highlighted that all hydatid cysts are morphologically not the same. This is important for treatment but fails to completely address variation in the host/parasite response and the understanding of parasite survival. This review attempts to relate the immunological and developmental data obtained from experimental, veterinary and medical studies to update our understanding of established immunity against E. granulosus. It proposes that a single 'Established' phase for E. granulosus could be subdivided into four additional phases: maturing; stable; unstable and degenerative. Combining this type of information with existing cyst classification systems could significantly benefit our understanding of the parasites immunobiology.
Assuntos
Equinococose/imunologia , Equinococose/parasitologia , Echinococcus granulosus/crescimento & desenvolvimento , Echinococcus granulosus/imunologia , Animais , Echinococcus granulosus/citologia , Echinococcus granulosus/fisiologia , Humanos , ImunidadeRESUMO
The prevalence of the digenean Plagiorchis sp. was investigated in a natural wood mouse population (Apodemus sylvaticus) in a periaquatic environment. Classical identification was complemented with the use of molecular differentiation to determine prevalence and verify species identity. Use of the complete ITS1-5.8S rDNA-ITS2 and partial 28S rDNA gene sequences have confirmed that the species reported at this location was Plagiorchis elegans and not Plagiorchis muris as reported previously. This underlines the difficulties in identification of these morphologically similar parasites. Plagiorchis elegans is typically a gastrointestinal parasite of avian species but has also been reported from small mammal populations. Although the occurrence of this digenean in A. sylvaticus in the UK is rare, in the area immediately surrounding Malham Tarn, Yorkshire, it had a high prevalence (23%) and a mean worm burden of 26.6 ± 61.5. The distribution of P. elegans followed a typically overdispersed pattern and both mouse age-group and sex were determined to be two main factors associated with prevalence. Male mice harboured the majority of worms, carrying 688 of 717 recovered during the study, and had a higher prevalence of 32.4% in comparison to only 8.7% in the small intestine of female mice. A higher prevalence of 43% was also observed in adult mice compared to 14% for young adults. No infection was observed in juvenile mice. These significant differences are likely to be due to differences in the foraging behaviour between the sexes and age cohorts of wood mice.
Assuntos
Murinae/parasitologia , Doenças dos Roedores/epidemiologia , Doenças dos Roedores/parasitologia , Trematódeos/classificação , Trematódeos/isolamento & purificação , Infecções por Trematódeos/veterinária , Fatores Etários , Animais , Sequência de Bases , DNA de Helmintos/química , DNA de Helmintos/genética , DNA Ribossômico/química , DNA Ribossômico/genética , DNA Espaçador Ribossômico/química , DNA Espaçador Ribossômico/genética , Feminino , Masculino , Camundongos , Dados de Sequência Molecular , Prevalência , RNA Ribossômico 28S/genética , RNA Ribossômico 5,8S/genética , Análise de Sequência de DNA , Fatores Sexuais , Trematódeos/genética , Infecções por Trematódeos/epidemiologia , Infecções por Trematódeos/parasitologia , Reino UnidoRESUMO
Hereditary demyelinating peripheral neuropathies consist of a heterogeneous group of genetic disorders that includes hereditary neuropathy with liability to pressure palsies (HNPP), Charcot-Marie-Tooth disease (CMT), Dejerine-Sottas syndrome (DSS), and congenital hypomyelination (CH). The clinical classification of these neuropathies into discrete categories can sometimes be difficult because there can be both clinical and pathologic variation and overlap between these disorders. We have identified five novel mutations in the myelin protein zero (MPZ) gene, encoding the major structural protein (P0) of peripheral nerve myelin, in patients with either CMT1B, DSS, or CH. This finding suggests that these disorders may not be distinct pathophysiologic entities, but rather represent a spectrum of related "myelinopathies" due to an underlying defect in myelination. Furthermore, we hypothesize the differences in clinical severity seen with mutations in MPZ are related to the type of mutation and its subsequent effect on protein function (i.e., loss of function versus dominant negative).
Assuntos
Doença de Charcot-Marie-Tooth/genética , Doenças Desmielinizantes/genética , Neuropatia Hereditária Motora e Sensorial/genética , Proteína P0 da Mielina/genética , Adulto , Doença de Charcot-Marie-Tooth/diagnóstico , Clonagem Molecular , Estudos de Coortes , Cristalografia , Análise Mutacional de DNA , Doenças Desmielinizantes/congênito , Doenças Desmielinizantes/diagnóstico , Feminino , Genótipo , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Humanos , Masculino , Microscopia Eletrônica , Proteína P0 da Mielina/química , Fenótipo , Mutação Puntual/fisiologia , Conformação Proteica , Nervo Sural/ultraestruturaRESUMO
Periventricular heterotopia (PH) occurs when collections of neurons lay along the lateral ventricles or just beneath. Human Filamin A gene (FLNA) mutations are associated with classical X-linked bilateral periventricular nodular heterotopia (PNH), featuring contiguous heterotopic nodules, mega cisterna magna, cardiovascular malformations and epilepsy. FLNA encodes an F-actin-binding cytoplasmic phosphoprotein and is involved in early brain neurogenesis and neuronal migration. A rare, recessive form of bilateral PNH with microcephaly and severe delay is associated with mutations of the ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2) gene, required for vesicle and membrane trafficking from the trans-Golgi. However, PH is a heterogeneous disorder. We studied clinical and brain MRI of 182 patients with PH and, based on its anatomic distribution and associated birth defects, identified 15 subtypes. Classical bilateral PNH represented the largest group (98 patients: 54%). The 14 additional phenotypes (84 patients: 46%) included PNH with Ehlers-Danlos syndrome (EDS), temporo-occipital PNH with hippocampal malformation and cerebellar hypoplasia, PNH with fronto-perisylvian or temporo-occipital polymicrogyria, posterior PNH with hydrocephalus, PNH with microcephaly, PNH with frontonasal dysplasia, PNH with limb abnormalities, PNH with fragile-X syndrome, PNH with ambiguous genitalia, micronodular PH, unilateral PNH, laminar ribbon-like and linear PH. We performed mutation analysis of FLNA in 120 patients, of whom 72 (60%) had classical bilateral PNH and 48 (40%) other PH phenotypes, and identified 25 mutations in 40 individuals. Sixteen mutations had not been reported previously. Mutations were found in 35 patients with classical bilateral PNH, in three with PNH with EDS and in two with unilateral PNH. Twenty one mutations were nonsense and frame-shift and four missense. The high prevalence of mutations causing protein truncations confirms that loss of function is the major cause of the disorder. FLNA mutations were found in 100% of familial cases with X-linked PNH (10 families: 8 with classical bilateral PNH, 1 with EDS and 1 with unilateral PH) and in 26% of sporadic patients with classical bilateral PNH. Overall, mutations occurred in 49% of individuals with classical bilateral PNH irrespective of their being familial or sporadic. However, the chances of finding a mutation were exceedingly gender biased with 93% of mutations occurring in females and 7% in males. The probability of finding FLNA mutations in other phenotypes was 4% but was limited to the minor variants of PNH with EDS and unilateral PNH. Statistical analysis considering all 42 mutations described so far identifies a hotspot region for PNH in the actin-binding domain (P < 0.05).
Assuntos
Encéfalo/anormalidades , Proteínas Contráteis/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas dos Microfilamentos/genética , Mutação , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Ehlers-Danlos/genética , Feminino , Filaminas , Síndrome do Cromossomo X Frágil/genética , Genótipo , Humanos , Hidrocefalia/genética , Deformidades Congênitas dos Membros/genética , Imageamento por Ressonância Magnética/métodos , Masculino , Microcefalia/genética , Pessoa de Meia-Idade , Linhagem , FenótipoRESUMO
BACKGROUND: Human autosomal recessive primary microcephaly (MCPH) is a heterogeneous disorder with at least six genetic loci (MCPH1-6), with MCPH5, caused by ASPM mutation, being the most common. Despite the high prevalence of epilepsy in microcephaly patients, microcephaly with frequent seizures has been excluded from the ascertainment of MCPH. Here, we report a pedigree with multiple affected individuals with microcephaly and seizures. OBJECTIVE: To identify the gene responsible for microcephaly and seizures in this pedigree. METHODS: Clinical assessments of three patients and brain MRIs of two patients were obtained. Genome-wide linkage screen with 10 k SNP microarray, fine mapping with microsatellite markers, and mutational analysis of the genomic DNA were performed on the pedigree. RESULTS: We found that the family was linked to the MCPH5 locus on chromosome 1q31.2-q32.1. We screened ASPM and identified a previously unreported nonsense mutation that introduced a premature stop codon in exon 18 of the ASPM gene. CONCLUSIONS: We thus expand the clinical spectrum of ASPM mutations by showing that they can occur in patients with seizures and that the history of seizures alone should not necessarily preclude the diagnosis of primary microcephaly.
Assuntos
Microcefalia/genética , Mutação , Proteínas do Tecido Nervoso/genética , Convulsões/genética , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Consanguinidade , Análise Mutacional de DNA , Família , Feminino , Humanos , Masculino , Linhagem , Arábia SauditaRESUMO
To further characterize the clinical, radiographic and chondro-osseous morphologic changes in the Desbuquois syndrome, 7 patients from three sibships are described. They all had prenatal onset severe rhizomelic and mesomelic shortness with marked joint laxity and marked micrognathia. Radiographic changes were distinct, consisting of a supernumerary ossification center between the proximal phalanx of the index finger and the second metacarpal, and variable thumb changes. The femoral necks showed enlargement of the lesser trochanter with metaphyseal breaking, producing a characteristic "monkey wrench" (Swedish key) appearance. Growth plate cartilage showed dilated cisterns of rough endoplasmic reticulum in reserve zone chondrocytes. Three of the 7 cases were diagnosed prenatally by second trimester ultrasound and one case by fetoscopy. This syndrome exhibits significant phenotypic variability and must be differentiated from the Catel-Manzke syndrome which exhibits similar radiographic changes in the hands.
Assuntos
Osso e Ossos/anormalidades , Nanismo/patologia , Instabilidade Articular/patologia , Adolescente , Pré-Escolar , Nanismo/diagnóstico por imagem , Feminino , Lâmina de Crescimento/patologia , Humanos , Corpos de Inclusão/patologia , Lactente , Instabilidade Articular/diagnóstico por imagem , Masculino , Radiografia , SíndromeAssuntos
Agenesia do Corpo Caloso , Encefalopatias/patologia , Ventrículos Cerebrais , Coristoma/patologia , Núcleos da Linha Média do Tálamo , Encefalopatias/genética , Coristoma/genética , Feminino , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase ReversaAssuntos
Anormalidades Múltiplas/genética , Deficiência Intelectual/patologia , Proteínas de Membrana/genética , Microcefalia/patologia , Mutação , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Animais , Sequência de Bases , Cerebelo/metabolismo , Criança , Pré-Escolar , DNA/química , DNA/genética , Análise Mutacional de DNA , Anormalidades do Olho , Face/anormalidades , Feminino , Mutação da Fase de Leitura , França , Genótipo , Humanos , Hibridização In Situ , Japão , Masculino , Camundongos , Mutação de Sentido Incorreto , Omã , Linhagem , Fenótipo , Arábia Saudita , Deleção de Sequência , Síndrome , Proteínas de Transporte VesicularRESUMO
BACKGROUND: Multiple lines of evidence have suggested that developmental dyslexia may be associated with abnormalities of neuronal migration or axonal connectivity. In patients with periventricular nodular heterotopia--a rare genetic brain malformation characterized by misplaced nodules of gray matter along the lateral ventricles--a specific and unexpected reading disability is present, despite normal intelligence. We sought to investigate the cognitive and structural brain bases of this phenomenon. METHODS: Ten adult subjects with heterotopia, 10 with dyslexia, and 10 normal controls were evaluated, using a battery of neuropsychometric measures. White matter integrity and fiber tract organization were examined in six heterotopia subjects, using diffusion tensor imaging methods. RESULTS: Subjects with heterotopia and those with developmental dyslexia shared a common behavioral profile, with specific deficits in reading fluency. Individuals with dyslexia seemed to have a more prominent phonological impairment than heterotopia subjects. Periventricular nodular heterotopia was associated with specific, focal disruptions in white matter microstructure and organization in the vicinity of gray matter nodules. The degree of white matter integrity correlated with reading fluency in this population. CONCLUSIONS: We demonstrate that a genetic disorder of gray matter heterotopia shares behavioral characteristics with developmental dyslexia, and that focal white matter defects in this disorder may serve as the structural brain basis of this phenomenon. Our findings represent a potential model for the use of developmental brain malformations in the investigation of abnormal cognitive function.
Assuntos
Encéfalo/anormalidades , Dislexia/patologia , Malformações do Desenvolvimento Cortical do Grupo II/patologia , Vias Neurais/anormalidades , Heterotopia Nodular Periventricular/patologia , Adulto , Dislexia/etiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical do Grupo II/complicações , Fibras Nervosas Mielinizadas/patologia , Heterotopia Nodular Periventricular/complicações , LeituraRESUMO
OBJECTIVE: To define the behavioral profile of periventricular nodular heterotopia (PNH), a malformation of cortical development that is associated with seizures but reportedly normal intelligence, and to correlate the results with anatomic and clinical features of this disorder. METHODS: Ten consecutive subjects with PNH, all with epilepsy and at least two periventricular nodules, were studied with structural MRI and neuropsychological testing. Behavioral results were statistically analyzed for correlation with other features of PNH. RESULTS: Eight of 10 subjects had deficits in reading skills despite normal intelligence. Processing speed and executive function were also impaired in some subjects. More marked reading difficulties were seen in subjects with more widely distributed heterotopia. There was no correlation between reading skills and epilepsy severity or antiepileptic medication use. CONCLUSION: The neuronal migration disorder of periventricular nodular heterotopia is associated with an impairment in reading skills despite the presence of normal intelligence.
Assuntos
Córtex Cerebral/anormalidades , Dislexia/diagnóstico , Dislexia/psicologia , Malformações do Sistema Nervoso/psicologia , Adolescente , Adulto , Movimento Celular/fisiologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Coristoma/patologia , Coristoma/fisiopatologia , Coristoma/psicologia , Dislexia/fisiopatologia , Epilepsia/etiologia , Epilepsia/patologia , Epilepsia/fisiopatologia , Feminino , Humanos , Inteligência/fisiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Malformações do Sistema Nervoso/patologia , Malformações do Sistema Nervoso/fisiopatologia , Neurônios/fisiologia , Testes Neuropsicológicos , Valor Preditivo dos TestesRESUMO
OBJECTIVE: To define the clinical, radiologic, and genetic features of periventricular heterotopia (PH) with Ehlers-Danlos syndrome (EDS). METHODS: Exonic sequencing and single stranded conformational polymorphism (SSCP) analysis was performed on affected individuals. Linkage analysis using microsatellite markers on the X-chromosome was performed on a single pedigree. Western blotting evaluated for loss of filamin A (FLNA) protein and Southern blotting assessed for any potential chromosome rearrangement in this region. RESULTS: The authors report two familial cases and nine additional sporadic cases of the EDS-variant form of PH, which is characterized by nodular brain heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular PH, indistinguishable from PH due to FLNA mutations. Exonic sequencing or SSCP analyses of FLNA revealed a 2762 delG single base pair deletion in one affected female. Another affected female harbored a C116 single point mutation, resulting in an A39G change. A third affected female had a 4147 delG single base pair deletion. One pedigree with no detectable exonic mutation demonstrated positive linkage to the FLNA locus Xq28, an affected individual in this family also had no detectable FLNA protein, but no chromosomal rearrangement was detected. CONCLUSION: These results suggest that the Ehlers-Danlos variant of periventricular heterotopia (PH), in part, represents an overlapping syndrome with X-linked dominant PH due to filamin A mutations.
Assuntos
Encéfalo/anormalidades , Proteínas Contráteis/deficiência , Síndrome de Ehlers-Danlos/genética , Proteínas dos Microfilamentos/deficiência , Mutação Puntual , Deleção de Sequência , Adolescente , Adulto , Substituição de Aminoácidos , Criança , Cromossomos Humanos X/genética , Proteínas Contráteis/genética , Proteínas Contráteis/fisiologia , Análise Mutacional de DNA , Síndrome de Ehlers-Danlos/patologia , Epilepsia/etiologia , Éxons/genética , Feminino , Filaminas , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/fisiologia , Repetições de Microssatélites , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Polimorfismo Conformacional de Fita SimplesRESUMO
OBJECTIVE: To describe a novel form of pontocerebellar hypoplasia (PCH) and map its genetic locus. BACKGROUND: PCH is a heterogeneous group of disorders that are characterized by abnormally small cerebellum and brainstem. Autosomal recessive inheritance has been implied in many cases, but no genetic loci have been mapped to date. METHODS: The authors studied a consanguineous family from the Sultanate of Oman with three siblings with a novel form of PCH. The authors performed clinical studies and linkage analysis of this pedigree. RESULTS: The clinical features of the affected children include developmental delay, progressive microcephaly with brachycephaly, seizures during the first year of life, hypotonia with hyperreflexia, short stature, and optic atrophy. Imaging studies showed a small pons and cerebellum, prominent sulci and lateral ventricles, and decreased cerebral white matter volume. A lack of dyskinesias distinguishes this pedigree from PCH type 2. Genetic studies of this family revealed evidence of significant linkage to chromosome 7q11-21 (maximum multipoint lod score 3.23). CONCLUSIONS: This pedigree represents a novel form of autosomal recessive PCH, which the authors propose to call cerebellar atrophy with progressive microcephaly (CLAM). This disorder maps to chromosome 7q11-21, and this locus was named CLAM. This report represents the first identification of a genetic locus for PCH.
Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Cromossomos Humanos Par 7/genética , Ponte/anormalidades , Mapeamento Cromossômico , Consanguinidade , Epilepsia/genética , Evolução Fatal , Genes Recessivos , Genótipo , Humanos , Deficiência Intelectual/genética , Escore Lod , Microcefalia/genética , Doenças Musculoesqueléticas/genética , Omã , LinhagemRESUMO
BACKGROUND: Syndromes of bilateral symmetric polymicrogyria include an autosomal recessive form of bilateral frontoparietal polymicrogyria (BFPP), in which the malformation is most severe rostrally. The authors describe a new syndrome they have termed "bilateral generalized polymicrogyria" (BGP), in which the malformation occurs in a generalized distribution but is often most severe in the perisylvian regions. METHODS: Patients with bilateral polymicrogyria were identified from multiple medical centers worldwide. The diagnosis of BGP was based on findings from conventional spin echo MRI and, in one case, postmortem neuropathologic findings. Genetic analysis was performed for those patients from consanguineous pedigrees and those with multiple affected siblings to rule out linkage to the BFPP locus on chromosome 16q. RESULTS: Twelve patients were identified with BGP. Clinical features included cognitive and motor delay as well as seizures. Some specific features characteristic of other known bilateral polymicrogyria syndromes, such as pseudobulbar palsy and dysconjugate gaze, were not commonly seen in these patients. Radiologically, polymicrogyria appeared widespread but was often most severe in the perisylvian regions. Pathologic examination in one case revealed a diffusely thin and excessively folded cerebral cortex lacking normal six-layered architecture. Seven patients subjected to genetic analysis did not demonstrate linkage to the BFPP locus. CONCLUSIONS: BGP is a distinct syndrome of cortical malformation. Several features allow BGP to be distinguished from other disorders on the growing list of bilateral symmetric polymicrogyria syndromes.
Assuntos
Córtex Cerebral/anormalidades , Deficiências do Desenvolvimento/etiologia , Deficiência Intelectual/etiologia , Anormalidades Múltiplas/genética , Ventrículos Cerebrais/anormalidades , Criança , Pré-Escolar , Cromossomos Humanos Par 16/genética , Consanguinidade , Deficiências do Desenvolvimento/genética , Epilepsias Parciais/etiologia , Epilepsias Parciais/genética , Evolução Fatal , Feminino , Genes Recessivos , Heterogeneidade Genética , Humanos , Lactente , Deficiência Intelectual/genética , Imageamento por Ressonância Magnética , Masculino , Repetições de Microssatélites , Malformações do Sistema Nervoso/classificação , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Doenças Neuromusculares/genética , Fenótipo , Quadriplegia/genética , SíndromeRESUMO
BACKGROUND: Familial periventricular heterotopia (PH) represents a disorder of neuronal migration resulting in multiple gray matter nodules along the lateral ventricular walls. Prior studies have shown that mutations in the filamin A (FLNA) gene can cause PH through an X-linked dominant inheritance pattern. OBJECTIVE: To classify cortical malformation syndromes associated with PH. METHODS: Analyses using microsatellite markers directed toward genomic regions of FLNA and to a highly homologous autosomal gene, FLNB, were performed on two pedigrees to evaluate for linkage with either filamin gene. RESULTS: Two consanguineous pedigrees with PH that suggest an autosomal recessive inheritance pattern are reported. MRI of the brain revealed periventricular nodules of cerebral gray matter intensity, typical for PH. Seizures or developmental delay appeared to be a common presenting feature. Microsatellite analysis suggested no linkage to FLNA or FLNB. CONCLUSIONS: Autosomal recessive PH is another syndromic migrational disorder, distinct from X-linked dominant PH. Further classification of these different syndromes will provide an approach for genetic evaluation.
Assuntos
Encefalopatias/genética , Ventrículos Cerebrais/anormalidades , Coristoma/genética , Adulto , Idoso , Encefalopatias/complicações , Encefalopatias/diagnóstico , Movimento Celular/genética , Pré-Escolar , Coristoma/complicações , Coristoma/diagnóstico , Cromossomos Humanos Par 3/genética , Cromossomos Humanos X/genética , Consanguinidade , Proteínas Contráteis/genética , Deficiências do Desenvolvimento/genética , Eletroencefalografia , Feminino , Filaminas , Genes Recessivos , Ligação Genética , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Proteínas dos Microfilamentos/genética , Repetições de Microssatélites , Pessoa de Meia-Idade , Linhagem , Convulsões/genética , Turquia/etnologia , Iêmen/etnologiaRESUMO
Periventricular heterotopia (PH) is characterized by neuronal nodules along the lateral ventricles. Whereas mutations in X-linked FLNA cause such cortical malformations, the authors report two cases of PH localizing to chromosome 5p. Both subjects have complex partial seizures. MRI demonstrated bilateral nodular PH, with subcortical heterotopia or focal gliosis. FISH identified a duplication of 5p15.1 [46,XX,dup(5)(p15.1p15.1)] and a trisomy of 5p15.33 [46,XY,der(14)t(5;14)(p15.33;p11.2) mat]. These findings suggest a new PH locus along the telomeric end of chromosome 5p.