RESUMO
OBJECTIVE: To derive an algorithm for genetic testing of patients with frontotemporal lobar degeneration (FTLD). METHODS: A literature search was performed to review the clinical and pathologic phenotypes and family history associated with each FTLD gene. RESULTS: Based on the literature review, an algorithm was developed to allow clinicians to use the clinical and neuroimaging phenotypes of the patient and the family history and autopsy information to decide whether or not genetic testing is warranted, and if so, the order for appropriate tests. CONCLUSIONS: Recent findings in genetics, pathology, and imaging allow clinicians to use the clinical presentation of the patient with FTLD to inform genetic testing decisions.
Assuntos
Algoritmos , Degeneração Lobar Frontotemporal/diagnóstico , Degeneração Lobar Frontotemporal/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Testes Genéticos/normas , Proteínas do Tecido Nervoso/genética , Adulto , Idoso , Análise Mutacional de DNA/métodos , Análise Mutacional de DNA/normas , Árvores de Decisões , Diagnóstico Diferencial , Feminino , Degeneração Lobar Frontotemporal/fisiopatologia , Testes Genéticos/economia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , FenótipoRESUMO
DCC (deleted in colorectal cancer), a receptor for the axon guidance cue netrin-1, is highly expressed by mesencephalic dopaminergic (DA) neurons during development; however, the contribution of DCC to DA development remains largely uncharacterized. DA neurons in ventral mesencephalic nuclei also express UNC5 homologue netrin receptors from late embryogenesis to adulthood, raising the possibility that DA axons could be attracted or repelled by netrins. Examining newborn dcc null mice, we report that loss of DCC function results in profound alterations of DA circuitry, including DA progenitor cell migration defects, reduced numbers of DA cells in midbrain nuclei, an anomalous DA ventral commissure, malformed DA innervation of the ventral striatum, and reduced DA innervation of the cerebral cortex. Caspase-3 activation was detected in inappropriately localized DA cells, consistent with apoptosis contributing to reduced cell numbers. Dcc heterozygous mice express reduced levels of DCC protein. Although less severely disrupted than dcc nulls, newborn and adult dcc heterozygotes also have fewer DA neurons in ventral mesenscephalic nuclei. Despite the reduced numbers of DA neurons, newborn dcc heterozygotes and nulls exhibit similar DA innervation density as wild-type littermates in the nucleus accumbens core, and adult dcc heterozygotes exhibit increased DA innervation in medial prefrontal cortex. A trend towards increased innervation of medial prefrontal cortex was detected in newborn dcc heterozygotes, but did not reach statistical significance, suggesting that the increase in adult heterozygotes results from enhanced DA arborization during postnatal development. Consistent with the hypothesis that DCC regulates DA axonal projections, disrupting DCC function in culture inhibits netrin-1 induced DA axon extension and axon branching. Furthermore, disrupting DCC function in isolated DA neurons grown as micro-island cultures reduces the number of autaptic synapses per cell. We conclude that DCC regulates appropriate precursor cell migration, axon guidance, and terminal arborization by DA neurons.
Assuntos
Axônios/fisiologia , Encéfalo/fisiologia , Dopamina/fisiologia , Neurônios/fisiologia , Receptores de Superfície Celular/fisiologia , Células-Tronco/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Animais Recém-Nascidos , Encéfalo/citologia , Movimento Celular , Células Cultivadas , Receptor DCC , Camundongos , Camundongos Knockout , Receptores de Superfície Celular/genética , Sinapses/fisiologia , Proteínas Supressoras de Tumor/genética , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Netrins are a family of secreted proteins that function as axon guidance cues during neural development. High levels of netrin-1 expressed by the embryonic ganglionic eminence, the precursor of the adult striatum, direct axons that pioneer the internal capsule. Here we describe netrin-1 expression by neurons distributed throughout the striatum of the adult mouse. Differences were detected in the number and type of neurons expressing netrin-1 in different regions of the striatum. Most neurons in the ventral striatum, including projection neurons and cholinergic interneurons, express netrin-1. In contrast, netrin-1 expression is largely limited to cholinergic interneurons in the dorsal striatum, and the proportion of cholinergic interneurons that express netrin-1 decreases along rostral-caudal and ventral-dorsal axes. Regional differences in expression in the adult striatum suggest that netrin-1 not only influences the development of striatal circuitry but may also participate in the maintenance and plasticity of connections in the adult brain.
Assuntos
Corpo Estriado/citologia , Expressão Gênica/fisiologia , Fatores de Crescimento Neural/metabolismo , Neurônios/classificação , Neurônios/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Colina O-Acetiltransferase/genética , Colina O-Acetiltransferase/metabolismo , Camundongos , Camundongos Transgênicos , Fatores de Crescimento Neural/genética , Proteínas do Tecido Nervoso/metabolismo , Netrina-1 , RNA Mensageiro/metabolismo , Proteínas Supressoras de Tumor/genética , beta-Galactosidase/genética , beta-Galactosidase/metabolismoRESUMO
Pedigrees from 269 patients with frontotemporal lobar degeneration (FTLD), including frontotemporal dementia (FTD), FTD with ALS (FTD/ALS), progressive nonfluent aphasia, semantic dementia (SD), corticobasal degeneration, and progressive supranuclear palsy were analyzed to determine the degree of heritability of these disorders. FTD/ALS was the most and SD the least heritable subtype. FTLD syndromes appear to have different etiologies and recurrence risks.
Assuntos
Demência/genética , Predisposição Genética para Doença/genética , Padrões de Herança/genética , Tauopatias/genética , Adulto , Idoso , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/genética , Afasia Primária Progressiva/genética , Transtornos Cromossômicos/genética , Estudos de Coortes , Saúde da Família , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Estudos Retrospectivos , Paralisia Supranuclear Progressiva/genética , Proteínas tau/genéticaRESUMO
Awareness of depression in the differential diagnosis of Alzheimer disease is essential for genetic counselors seeing patients at risk for early-onset familial Alzheimer disease (EOFAD). The genetic counselor is in a unique position to recognize depression as the cause of symptoms mimicking early-onset Alzheimer disease. While generating a family medical history, the counselor can evoke significant emotional history as well. Based on this information, appropriate referrals can be given for neurological and psychological evaluation. The counselor also serves to explain EOFAD and the benefits and limitations of genetic testing for each individual patient. Whether or not patients choose testing, they can benefit from correct diagnosis of troublesome, or even debilitating, symptoms that imitate symptoms of the feared hereditary disease.
