RESUMEN
BACKGROUND: The Arctic mutation (p.E693G/p.E22G)fs within the ß-amyloid (Aß) region of the ß-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimer's disease. Here we report the special character of Arctic AD neuropathology in four deceased patients. RESULTS: Aß deposition in the brains was wide-spread (Thal phase 5) and profuse. Virtually all parenchymal deposits were composed of non-fibrillar, Congo red negative Aß aggregates. Congo red only stained angiopathic vessels. Mass spectrometric analyses showed that Aß deposits contained variably truncated and modified wild type and mutated Aß species. In three of four Arctic AD brains, most cerebral cortical plaques appeared targetoid with centres containing C-terminally (beyond aa 40) and variably N-terminally truncated Aß surrounded by coronas immunopositive for Aßx-42. In the fourth patient plaque centres contained almost no Aß making the plaques ring-shaped. The architectural pattern of plaques also varied between different anatomic regions. Tau pathology corresponded to Braak stage VI, and appeared mainly as delicate neuropil threads (NT) enriched within Aß plaques. Dystrophic neurites were scarce, while neurofibrillary tangles were relatively common. Neuronal perikarya within the Aß plaques appeared relatively intact. CONCLUSIONS: In Arctic AD brain differentially truncated abundant Aß is deposited in plaques of variable numbers and shapes in different regions of the brain (including exceptional targetoid plaques in neocortex). The extracellular non-fibrillar Aß does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular Aß oligomers are more neurotoxic than extracellular Aß deposits. However, the enrichment of NTs within plaques suggests some degree of intra-plaque axonal damage including accumulation of hp-tau, which may impair axoplasmic transport, and thereby contribute to synaptic loss. Finally, similarly as the cotton wool plaques in AD resulting from exon 9 deletion in the presenilin-1 gene, the Arctic plaques induced only modest glial and inflammatory tissue reaction.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Encéfalo/metabolismo , Mutación , Anciano , Enfermedad de Alzheimer/patología , Encéfalo/patología , Familia , Humanos , Persona de Mediana Edad , Linaje , Suecia , Población Blanca/genéticaRESUMEN
Sporadic inclusion-body myositis (s-IBM) is a myopathy that is characterized by progressive weakness and muscle pathology demonstrating inflammation and rimmed vacuoles. In addition, similar to the pathology observed in the brains of patients with Alzheimer's disease, the deposition of beta-amyloid and phosphorylated tau proteins in muscle fibers has been reported. These shared pathologic features have prompted hypotheses suggesting a shared etiology of these two conditions. We report a case of a 73-year-old woman initially diagnosed with s-IBM who later developed Alzheimer's disease.
RESUMEN
OBJECTIVE: To describe the Alzheimer disease (AD)-like clinical and pathological features, including marked neurofibrillary tangle (NFT) pathology, of a familial prion disease due to a rare nonsense mutation of the prion gene (PRNP). METHODS: Longitudinal clinical assessments were available for the proband and her mother. After death, both underwent neuropathological evaluation. PRNP was sequenced after failure to find immunopositive Aß deposits in the proband and the documentation of prion protein (PrP) immunopositive pathology. RESULTS: The proband presented at age 42 years with a 3-year history of progressive short-term memory impairment and depression. Neuropsychological testing found impaired memory performance, with relatively preserved attention and construction. She was diagnosed with AD and died at age 47 years. Neuropathologic evaluation revealed extensive limbic and neocortical NFT formation and neuritic plaques consistent with a Braak stage of VI. The NFTs were immunopositive, with multiple tau antibodies, and electron microscopy revealed paired helical filaments. However, the neuritic plaques were immunonegative for Aß, whereas immunostaining for PrP was positive. The mother of the proband had a similar presentation, including depression, and had been diagnosed clinically and pathologically as AD. Reevaluation of her brain tissue confirmed similar tau and PrP immunostaining findings. Genetic analysis revealed that both the proband and her mother had a rare PRNP mutation (Q160X) that resulted in the production of truncated PrP. INTERPRETATION: We suggest that PRNP mutations that result in a truncation of PrP lead to a prolonged clinical course consistent with a clinical diagnosis of AD and severe AD-like NFTs.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Codón sin Sentido , Ovillos Neurofibrilares/genética , Ovillos Neurofibrilares/patología , Enfermedades por Prión/genética , Priones/genética , Proteínas tau/genética , Adulto , Anciano , Enfermedad de Alzheimer/diagnóstico , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/patología , Femenino , Glutamina , Humanos , Trastornos de la Memoria/genética , Trastornos de la Memoria/patología , Memoria a Corto Plazo , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fenotipo , Enfermedades por Prión/patología , Enfermedades por Prión/psicología , Proteínas Priónicas , Priones/metabolismo , Tirosina , Proteínas tau/metabolismoRESUMEN
Kikuchi-Fujimoto disease is a self-limited benign condition of unknown etiology characterized by cervical lymphadenopathy, fever, and leucopenia. An autoimmune hypothesis has been suggested and an association with systemic lupus erythematosus, Sjogren's disease, and antiphospholipid syndrome has been noted. We report a 27-year-old male who presented for evaluation of weakness and he was diagnosed with seropositive generalized myasthenia gravis and underwent a thymectomy. He was stable until five months post-thymectomy, when he developed a high fever associated with nontender cervical lymphadenopathy, chills, and night sweats. Histopathology of a cervical lymph gland biopsy was compatible with Kikuchi-Fujimoto lymphadenitis. He improved spontaneously and was asymptomatic at the followup six months later. Our case expands the association of Kikuchi-Fujimoto disease with autoimmune disorders to include myasthenia gravis.
RESUMEN
Rosai-Dorfman disease is a rare benign idiopathic histioproliferative disorder usually manifesting as massive painless adenopathy. Extranodal involvement of the Central Nervous System (CNS) mimicking a skull base meningioma is rare. A 42-year-old male presented with painless, progressive left visual loss of 4 months duration. Clinically, he had a left ptosis, proptosis and ophthalmoplegia. Magnetic Resonance Imaging (MRI) of the brain with gadolinium revealed a destructive lesion of the left orbital apex, middle cranial fossa and cavernous sinus. He was treated with corticosteroids and underwent debulking. Pathology showed inflammatory infiltrate in the absence of an infectious agent, emperipolesis and a positive S100 stain was consistent with Rosai-Dorfman disease. As there was no improvement following steroids and debulking, he underwent radiation therapy with significant improvement of his symptoms. Although a rare entity, Rosai-Dorfman disease should be considered in the differential of a skull base lesion.
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Histiocitosis Sinusal/patología , Enfermedades Orbitales/patología , Adulto , Antineoplásicos Hormonales/uso terapéutico , Terapia Combinada , Dexametasona/uso terapéutico , Diabetes Mellitus Tipo 2 , Diagnóstico Diferencial , Histiocitosis Sinusal/terapia , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Neoplasias Meníngeas/patología , Meningioma/patología , Enfermedades Orbitales/cirugía , Neoplasias Orbitales/patología , Radioterapia , Proteínas S100/metabolismo , Neoplasias de la Base del Cráneo/patología , Tomografía Computarizada por Rayos XRESUMEN
The authors report the de novo occurrence and treatment of an arteriovenous lesion within an anaplastic oligodendroglioma in a patient with previously unremarkable brain imaging. Intracranial arteriovenous malformations (AVMs) are believed to be congenitally acquired lesions, and their association with brain neoplasms is extremely rare. Diagnostic imaging revealed a mass lesion with large arteriovenous shunts and a vascular nidus mimicking a true AVM. Histological and immunohistochemical testing showed an anaplastic oligodendroglioma mixed with an AVM. The clinical, radiological, and operative data are reviewed, as are the histopathological findings. To the authors' knowledge this is the first case of de novo occurrence of an arteriovenous lesion with large shunts and a vascular nidus within an anaplastic oligodendroglioma.
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Fístula Arteriovenosa/diagnóstico , Fístula Arteriovenosa/terapia , Neoplasias Encefálicas/irrigación sanguínea , Embolización Terapéutica/métodos , Malformaciones Arteriovenosas Intracraneales/diagnóstico , Oligodendroglioma/irrigación sanguínea , Fístula Arteriovenosa/cirugía , Diagnóstico Diferencial , Resultado Fatal , Femenino , Humanos , Persona de Mediana EdadRESUMEN
BACKGROUND: A majority of mutations within the beta-amyloid region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral hemorrhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra-beta-amyloid mutation to date causing the more typical clinical picture of Alzheimer disease. OBJECTIVE: To describe features of 1 Swedish and 1 American family with the previously reported Arctic APP mutation. DESIGN, SETTING, AND PARTICIPANTS: Affected and nonaffected carriers of the Arctic APP mutation from the Swedish and American families were investigated clinically. In addition, 1 brain from each family was investigated neuropathologically. RESULTS: The clinical picture, with age at disease onset in the sixth to seventh decade of life and dysfunction in multiple cognitive areas, is indicative of Alzheimer disease and similar to the phenotype for other Alzheimer disease APP mutations. Several affected mutation carriers displayed general brain atrophy and reduced blood flow of the parietal lobe as demonstrated by magnetic resonance imaging and single-photon emission computed tomography. One Swedish case and 1 American case with the Arctic APP mutation came to autopsy, and both showed no signs of hemorrhage but revealed severe congophilic angiopathy, region-specific neurofibrillary tangle pathological findings, and abundant amyloid plaques. Intriguingly, most plaques from both of these cases had a characteristic ringlike character. CONCLUSIONS: Overall, our findings corroborate that the Arctic APP mutation causes a clinical and neuropathological picture compatible with Alzheimer disease.
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Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Encéfalo/patología , Receptores de Superficie Celular/genética , Factores de Edad , Edad de Inicio , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/patología , Atrofia , Niño , Electroencefalografía , Femenino , Tamización de Portadores Genéticos , Genotipo , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Examen Neurológico , Pruebas Neuropsicológicas , Lóbulo Parietal/irrigación sanguínea , Lóbulo Parietal/patología , Linaje , Fenotipo , Placa Amiloide/patología , Nexinas de Proteasas , Flujo Sanguíneo Regional/fisiología , Suecia , Tomografía Computarizada de Emisión de Fotón Único , Estados UnidosRESUMEN
AIM: Neuropathological examination of both individuals in a monozygotic (MZ) twin pair with Alzheimer's disease (AD) is rare, especially in the molecular genetic era. We had the opportunity to assess the concordance and discordance of clinical presentation and neuropathology in three MZ twin pairs with AD. METHODS: The MZ twins were identified and characterised by the University of Washington Alzheimer's Disease Research Center. We reviewed the available clinical and neuropathological records for all six cases looking specifically for concordance and discordance of clinical phenotype, neuritic amyloid plaques (NP), neurofibrillary tangles (NFT) and Lewy related pathology (LRP). RESULTS: Discordance in age of onset for developing AD in the MZ twins varied from 4 to 18 years. Clinical presentations also differed between twins. One twin presented with a dementia with Lewy Body clinical syndrome while the other presented with typical clinical AD. Neuropathology within the MZ twin pairs was concordant for NP and NFT, regardless of duration of disease, and was discordant for LRP. This difference was most marked in the late onset AD twin pair. One pair was found to have a mutation in presenilin-1 (PS1) (A79V) with remarkably late onset in a family member. CONCLUSIONS: MZ twins with AD can vary considerably in age of onset, presentation and disease duration. The concordance of NP and NFT pathological change and the discordance of LRP support the concept that, in AD, the former are primarily under genetic control whereas the latter (LRP) is more influenced by disease duration and environmental factors. The A79V mutation in PS1 can be associated with very late onset of dementia.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Gemelos Monocigóticos/genética , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico , Infarto Cerebral/complicaciones , Infarto Cerebral/diagnóstico , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Mutación , Ovillos Neurofibrilares/genética , Ovillos Neurofibrilares/patología , Enfermedad de Parkinson/complicaciones , Linaje , Placa Amiloide/genética , Placa Amiloide/patologíaRESUMEN
BACKGROUND: The origin and significance of Lewy bodies and neurites (Lewy body pathology [LBP]) in Alzheimer disease (AD) are poorly understood. OBJECTIVE: To examine LBP in the brainstem, limbic cortex, and neocortex of a large number of familial AD cases with mutations in 2 presenilin (PSEN) genes. METHODS: Twenty-five familial AD cases with 9 known PSEN 1 mutations and 14 familial AD cases with a single PSEN 2 mutation (N141I) were examined for LBP using alpha-synuclein immunohistochemistry and sampling of multiple brainstem and cortical regions. RESULTS: The amygdala was the most vulnerable site for LBP. In fact, virtually all (24 [96%] of 25 cases) of the PSEN 1 mutation cases had LBP in the amygdala. The PSEN 1 mutation cases also had more frequent LBP in the amygdala and neocortex than those with the PSEN 2 mutation. However, within families with a single mutation of either PSEN 1 or PSEN 2, there was frequent variability of the LBP. CONCLUSION: These findings suggest that there are genetic influences on the presence of LBP in familial AD as demonstrated by the differences between PSEN 1 and PSEN 2 mutation cases.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Cuerpos de Lewy/patología , Adulto , Anciano , Anciano de 80 o más Años , Apolipoproteínas E/genética , Encéfalo/metabolismo , Encéfalo/patología , Femenino , Genotipo , Humanos , Inmunohistoquímica/métodos , Cuerpos de Lewy/genética , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación , Neuritas/patología , Pruebas Neuropsicológicas/estadística & datos numéricos , Presenilina-1 , Presenilina-2 , alfa-Sinucleína/metabolismoRESUMEN
Neuropathological (np) relative frequency estimates of dementia may be biased if the autopsied subjects are not representative of all dementia subjects within a target population. We identified characteristics that differed between autopsied and non-autopsied subjects from an incident-based dementia case series and compared autopsy-based estimates of the relative frequency of np diagnoses before and after adjusting for potential selection bias. Clinically demented subjects who were autopsied (n = 206), had died but were not autopsied (n = 271), were still alive (n = 71), or had dropped out of the study (n = 82) were included. Compared with non-autopsied subjects, autopsied subjects were more likely to be Caucasian, educated beyond high school, and married. They also tended to have a lower baseline Mini-Mental State Examination score and were more likely to have a clinical diagnosis of Alzheimer disease (AD) than non-autopsied subjects. Neuropathological AD with Lewy bodies (LB) had the largest crude relative frequency estimate at 38% of the autopsy sample, followed by 25% for AD with vascular lesions, 13% for pure AD, 13% for LB (with or without vascular lesions), and 8% for pure vascular pathologies. Adjustment for potential sources of selection bias had little effect on relative frequency estimates, suggesting that np diagnoses in the autopsied subjects provide reasonable dementia relative frequency estimates among all clinically demented cases in this series.
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Demencia/epidemiología , Demencia/patología , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Autopsia , Distribución de Chi-Cuadrado , Femenino , Humanos , Incidencia , Masculino , Sistema de Registros/estadística & datos numéricos , Sesgo de SelecciónRESUMEN
Several kindreds of Volga German (VG) ancestry have a single PS2 mutation that causes an autosomal dominant form of Alzheimer's disease (AD). These families show a wide range in age-at-onset, which suggests the existence of modifying factors other than the PS2 mutation. To examine evidence for a genetic basis of variation in onset age, we performed a Bayesian oligogenic segregation and linkage analysis on nine VG families confirmed to have at least one affected PS2 carrier. This analysis simultaneously estimated the effects of APOE and PS2 and the number and effects of additional loci affecting AD age-at-onset. In addition, a family effect accounted for shared environmental effects. This analysis approach has the advantage of full use of the complete pedigree structure, as well as use of information on unsampled individuals with phenotypic data. These analyses provide evidence that APOE plays a small, but significant, role in modifying the age-at-onset in these VG families. The effects estimated for the APOE epsilon3 and epsilon4 genotypes were consistent with those estimated in previous analysis of late-onset AD families, with evidence for a dose-dependent relationship between number of epsilon4 alleles and age-at-onset. We estimated an approximately 83% posterior probability of at least one modifier locus in addition to APOE, and that the fraction of the variance in age-at-onset attributable to PS2, APOE, other loci, and family effects is approximately 70, approximately 2, approximately 6.5, and approximately 8.5%, respectively. These results provide evidence that APOE and other loci modify onset in AD caused by PS2 mutation.
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Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Proteínas de la Membrana/genética , Mutación , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Teorema de Bayes , Cromosomas Humanos Par 1/genética , Salud de la Familia , Femenino , Ligamiento Genético , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Linaje , Presenilina-2 , Sitios de Carácter Cuantitativo/genéticaRESUMEN
OBJECTIVES: To investigate whether clinical and neuropathological differences exist between Alzheimer's disease (AD) cases with and without vascular lesions neuropathologically diagnosed using Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. DESIGN: Descriptive observational study. SETTING: A community-based registry that identified incident dementia cases. PARTICIPANTS: Of the 124 subjects with available clinical and neuropathological assessments, 30 had AD lesions alone, and 18 had AD with vascular lesions. Patients with other neuropathological findings were excluded. MEASUREMENTS: Dependent measures included demographic, clinical, and neuropathological characteristics. Neuropathological diagnoses were made using the CERAD criteria and Braak and Braak staging. RESULTS: Of the 124 autopsied cases, 85 cases were diagnosed with neuropathological AD. Of these, 30 had pathology consistent with "pure" AD, whereas 18 had AD pathology with significant vascular lesions (AD/V). There were no differences in age, sex, or education between groups. AD/V cases had higher baseline and final Mini-Mental State Examination (MMSE) scores than pure AD cases, but after adjusting for education, differences in MMSE scores were not statistically significant. The AD/V group had significantly lower Braak staging than the pure AD group, after adjusting for education and final MMSE scores. CONCLUSION: In this comparison study of AD cases with and without vascular lesions, AD/V cases had less severe AD pathology than those with AD alone, indicating that cerebrovascular disease likely contributes to the severity of cognitive impairment in those with AD. Controlling for vascular risk factors in patients with AD may have a significant effect on severity of dementia.
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Enfermedad de Alzheimer/complicaciones , Trastornos Cerebrovasculares/complicaciones , Cognición , Demencia Vascular/complicaciones , Evaluación Geriátrica , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/fisiopatología , Estudios de Casos y Controles , Trastornos Cerebrovasculares/diagnóstico , Trastornos Cerebrovasculares/epidemiología , Trastornos Cerebrovasculares/fisiopatología , Comorbilidad , Demencia Vascular/diagnóstico , Demencia Vascular/epidemiología , Demencia Vascular/fisiopatología , Escolaridad , Femenino , Humanos , Masculino , Escala del Estado Mental , Pruebas Neuropsicológicas , Sistema de Registros , Factores de Riesgo , Índice de Severidad de la Enfermedad , Washingtón/epidemiologíaRESUMEN
Late-onset familial Alzheimer disease (LOFAD) is a genetically heterogeneous and complex disease for which only one locus, APOE, has been definitively identified. Difficulties in identifying additional loci are likely to stem from inadequate linkage analysis methods. Nonparametric methods suffer from low power because of limited use of the data, and traditional parametric methods suffer from limitations in the complexity of the genetic model that can be feasibly used in analysis. Alternative methods that have recently been developed include Bayesian Markov chain-Monte Carlo methods. These methods allow multipoint linkage analysis under oligogenic trait models in pedigrees of arbitrary size; at the same time, they allow for inclusion of covariates in the analysis. We applied this approach to an analysis of LOFAD on five chromosomes with previous reports of linkage. We identified strong evidence of a second LOFAD gene on chromosome 19p13.2, which is distinct from APOE on 19q. We also obtained weak evidence of linkage to chromosome 10 at the same location as a previous report of linkage but found no evidence for linkage of LOFAD age-at-onset loci to chromosomes 9, 12, or 21.
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Enfermedad de Alzheimer/genética , Cromosomas Humanos Par 19/ultraestructura , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Teorema de Bayes , Mapeo Cromosómico , Cromosomas Humanos Par 10/ultraestructura , Cromosomas Humanos Par 12/ultraestructura , Cromosomas Humanos Par 21/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Salud de la Familia , Ligamiento Genético , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Persona de Mediana Edad , Método de Montecarlo , Sitios de Carácter CuantitativoRESUMEN
We report a nonepisodic autosomal dominant (AD) spinocerebellar ataxia (SCA) not caused by a nucleotide repeat expansion that is, to our knowledge, the first such SCA. The AD SCAs currently comprise a group of > or =16 genetically distinct neurodegenerative conditions, all characterized by progressive incoordination of gait and limbs and by speech and eye-movement disturbances. Six of the nine SCAs for which the genes are known result from CAG expansions that encode polyglutamine tracts. Noncoding CAG, CTG, and ATTCT expansions are responsible for three other SCAs. Approximately 30% of families with SCA do not have linkage to the known loci. We recently mapped the locus for an AD SCA in a family (AT08) to chromosome 19q13.4-qter. A particularly compelling candidate gene, PRKCG, encodes protein kinase C gamma (PKC gamma), a member of a family of serine/threonine kinases. The entire coding region of PRKCG was sequenced in an affected member of family AT08 and in a group of 39 unrelated patients with ataxia not attributable to trinucleotide expansions. Three different nonconservative missense mutations in highly conserved residues in C1, the cysteine-rich region of the protein, were found in family AT08, another familial case, and a sporadic case. The mutations cosegregated with disease in both families. Structural modeling predicts that two of these amino acid substitutions would severely abrogate the zinc-binding or phorbol ester-binding capabilities of the protein. Immunohistochemical studies on cerebellar tissue from an affected member of family AT08 demonstrated reduced staining for both PKC gamma and ataxin 1 in Purkinje cells, whereas staining for calbindin was preserved. These results strongly support a new mechanism for neuronal cell dysfunction and death in hereditary ataxias and suggest that there may be a common pathway for PKC gamma-related and polyglutamine-related neurodegeneration.
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Mutación Missense , Polimorfismo Genético , Proteína Quinasa C/genética , Ataxias Espinocerebelosas/genética , Secuencia de Aminoácidos , Secuencia Conservada , Femenino , Genes Dominantes , Humanos , Isoenzimas/química , Isoenzimas/genética , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Linaje , Conformación Proteica , Proteína Quinasa C/química , Valores de Referencia , Alineación de Secuencia , Homología de Secuencia de AminoácidoRESUMEN
BACKGROUND: The autosomal dominant spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders. Although molecular genetic studies have so far implicated 16 loci in the etiology of these diseases, approximately 30% of families with SCAs remain unlinked. OBJECTIVES: To report the location of a gene causing a "pure" autosomal dominant cerebellar ataxia in one family and to describe the clinical phenotype. PATIENTS: We have identified a 4-generation American family of English and Dutch ethnicity with a pure cerebellar ataxia displaying an autosomal dominant pattern of inheritance. The disease typically has its onset in the third and fourth decades of life, shows no evidence of anticipation, progresses slowly, and does not appear to decrease life expectancy. Clinical DNA testing excluded SCA1, 2, 3, 6, 7, and 8. METHODS: A genome-wide linkage analysis at a 10 centimorgan (cM) level was performed with samples from 26 family members (11 affected, 10 clinically unaffected at risk, and 5 spouses). RESULTS: Assuming 90% penetrance, we found suggestive evidence of linkage to chromosome 19, with a lod score of 2.49 for D19S571. More detailed mapping in this region provided a maximum 2-point lod score of 2.57 at theta = 0 for D19S254 and a maximum multipoint lod score of 4.72 at D19S926. By haplotype construction a 22-cM critical region from D19S601 to the q telomere was defined. CONCLUSIONS: We have mapped a gene for an autosomal dominant SCA to chromosome 19q13.4-qter in one family. The critical region overlaps with the locus for SCA14, a disease described in a single Japanese family and characterized by axial myoclonus. Myoclonus was not seen in the family we studied, but it remains possible that the 2 disorders are allelic variants.
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Cromosomas Humanos Par 19 , Ligamiento Genético , Adolescente , Adulto , Niño , Mapeo Cromosómico , Femenino , Genes Dominantes , Humanos , Masculino , Persona de Mediana Edad , Linaje , Ataxias EspinocerebelosasRESUMEN
BACKGROUND: Hippocampal sclerosis (HS) is a neuropathologic finding characterized by neuronal loss and gliosis in the CA-1 and subiculum of the hippocampus. Previous studies of HS have shown that this is a common postmortem finding in elderly subjects with dementia. However, these studies were from selected samples and therefore are not necessarily representative of patients seen in the general medical community. OBJECTIVES: To examine the clinical and pathologic characteristics of HS in a community-based case series of dementia and to compare these characteristics with those observed in subjects with Alzheimer disease (AD) from the same study sample. METHODS: One hundred thirty-four autopsy cases were available from a community-based registry of dementia. Sixteen cases (12%) had a postmortem diagnosis of HS. Thirty-two comparison control cases with a neuropathologic diagnosis of AD were selected from the same files. Each case of HS was reviewed for HS neuropathologic features, including severity, distribution, and additional pathologic processes. Blinded review of clinical characteristics for the HS and control groups was performed to assess risk factors. RESULTS: There was a wide range of severity and distribution of HS lesions between cases and substantial variability in lesion severity and age within individual cases. Serial neuropsychologic and behavioral assessments revealed similar clinical features and rates of dementia progression between HS and AD groups. Of all neuropsychologic tests performed at enrollment, only enhanced performance on Trails A differentiated the HS from the AD group (64 seconds, 0 errors vs 114 seconds, 0.6 errors; P< or = .05). The number of AD cases with at least 1 apolipoprotein epsilon 4 allele was significantly greater than the HS cases (61% vs 31%; chi(2) = 3.81, P< or = .05). Although medical record review indicated higher frequencies of clinical stroke and neuroradiologic white matter abnormalities in the HS group, risk factors for vascular disease and neuropathologic evidence of cerebrovascular disease did not differ between the groups. CONCLUSIONS: Our results suggest that HS is a frequent pathologic finding in community-based dementia. Individuals with HS have similar initial symptoms and rates of dementia progression to those with AD and therefore are frequently misclassified as having AD. Our clinical and pathologic findings suggest that HS has characteristics of a progressive disorder although the underlying cause remains elusive.
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Enfermedad de Alzheimer/patología , Demencia/patología , Hipocampo/patología , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Apolipoproteínas E/genética , Demencia/genética , Demencia/psicología , Femenino , Genotipo , Humanos , Masculino , Registros Médicos , Pruebas Neuropsicológicas , Sistema de Registros , Estudios Retrospectivos , Esclerosis , Índice de Severidad de la EnfermedadRESUMEN
The cdc2/cyclin B1 kinase is absent from neurons that are terminally differentiated. However, unscheduled activation of Cdc2/cyclin B and accumulation of mitotic phosphoepitopes have been described in degenerating neurons of Alzheimer's disease (AD), and their appearance precedes hallmark lesion formation. In cycling cells the timing of cdc2 activation and onset of mitosis are determined by the Wee1 tyrosine kinase. We therefore investigated the Wee1 kinase in human brain. Surprisingly, we have found that the enzyme is constitutively active in neurons of normal brain. Consistent with its behavior in M phase, Wee1 in AD has decreased activity, becomes MPM-2 immunoreactive, and is redistributed from its normally nuclear domain to the cytoplasm of affected neurons. These data suggest that Wee1 functions in normal postmitotic neurons, but is altered in AD so as to promote activation of Cdc2/cyclin B1. Thus, Wee1 is yet another mitotic regulator that participates in the AD neurodegenerative process.
RESUMEN
En un períodod de 8 años, una mujer de 41 años desarrolló 3 meningiomas angioblásticos con metástasis a la región retroauricular y al hígado. Uno de los tumores intracraneales se derarrolló en un sitio de excisión previa después de una extirpación aparentemente completa. La paciente fue sometida a hepatectomía izquierda por una metástasis de 9 cm de diámetro y estuvo asintomática por 18 meses cuando volvió a presentar metástasis en el cuello y mediastino. Falleció con la enfermedad tumoral dos años después de la lobectomia hepática