RESUMEN
Hereditary hemochromatosis (HH) is a very common disorder characterized by iron overload and multi-organ damage. Several genes involved in iron metabolism have been implicated in the pathology of HH (refs. 1-4). We report that a mutation in the gene encoding Solute Carrier family 11, member A3 (SLC11A3), also known as ferroportin, is associated with autosomal dominant hemochromatosis.
Asunto(s)
Proteínas Portadoras/genética , Proteínas de Transporte de Catión , Hemocromatosis/genética , Mutación , Secuencia de Aminoácidos , Femenino , Ferritinas/sangre , Genes Dominantes , Ligamiento Genético , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Homología de Secuencia de Aminoácido , Transferrina/análisisRESUMEN
Sialic acid storage diseases (SASD, MIM 269920) are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or a slowly progressive adult form, which is prevalent in Finland (Salla disease). The main symptoms are hypotonia, cerebellar ataxia and mental retardation; visceromegaly and coarse features are also present in infantile cases. Progressive cerebellar atrophy and dysmyelination have been documented by magnetic resonance imaging (ref. 4). Enlarged lysosomes are seen on electron microscopic studies and patients excrete large amounts of free sialic acid in urine. A H+/anionic sugar symporter mechanism for sialic acid and glucuronic acid is impaired in lysosomal membranes from Salla and ISSD patients. The locus for Salla disease was assigned to a region of approximately 200 kb on chromosome 6q14-q15 in a linkage study using Finnish families. Salla disease and ISSD were further shown to be allelic disorders. A physical map with P1 and PAC clones was constructed to cover the 200-kb area flanked by the loci D6S280 and D6S1622, providing the basis for precise physical positioning of the gene. Here we describe a new gene, SLC17A5 (also known as AST), encoding a protein (sialin) with a predicted transport function that belongs to a family of anion/cation symporters (ACS). We found a homozygous SLC17A5 mutation (R39C) in five Finnish patients with Salla disease and six different SLC17A5 mutations in six ISSD patients of different ethnic origins. Our observations suggest that mutations in SLC17A5 are the primary cause of lysosomal sialic acid storage diseases.
Asunto(s)
Proteínas Portadoras/genética , Transporte Iónico/genética , Mutación , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Ácidos Siálicos/metabolismo , Adulto , Secuencia de Aminoácidos , Proteínas de Transporte de Anión , Secuencia de Bases , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Cartilla de ADN/genética , Femenino , Expresión Génica , Genes Recesivos , Humanos , Lactante , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Linaje , ARN Mensajero/genética , ARN Mensajero/metabolismo , Homología de Secuencia de Aminoácido , Distribución TisularAsunto(s)
Adenoma/complicaciones , Adenoma/patología , Neoplasias de los Conductos Biliares/complicaciones , Neoplasias de los Conductos Biliares/patología , Colangitis Esclerosante/etiología , Adenoma/cirugía , Anciano , Neoplasias de los Conductos Biliares/cirugía , Colangiopancreatografia Retrógrada Endoscópica , Colitis Ulcerosa/complicaciones , Hemorragia Gastrointestinal/complicaciones , Humanos , Cirrosis Hepática Biliar/complicaciones , Masculino , RecurrenciaRESUMEN
Bruton's tyrosine kinase (BTK) inhibitors are increasingly used in untreated and previously treated chronic lymphocytic leukaemia (CLL) patients. Invasive fungal infections (IFI) were rarely observed in patients treated for CLL in the pre-BTK era. In this article, we describe two patients with CLL who developed an IFI during treatment with the BTK inhibitor ibrutinib. The atypical presentation and the serious course of this complication are described.
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Infecciones Fúngicas Invasoras , Leucemia Linfocítica Crónica de Células B , Inhibidores de Proteínas Quinasas , Agammaglobulinemia Tirosina Quinasa , Humanos , Infecciones Fúngicas Invasoras/inducido químicamente , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , PirimidinasRESUMEN
Uncontrolled interferon γ (IFNγ)-mediated T-cell responses to commensal microbiota are a driver of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is crucial for controlling these T-cell responses, but the precise mechanism of inhibition remains unclear. A better understanding of how IL-10 exerts its suppressive function may allow identification of individuals with suboptimal IL-10 function among the heterogeneous population of IBD patients. Using cells from patients with an IL10RA deficiency or STAT3 mutations, we demonstrate that IL-10 signaling in monocyte-derived dendritic cells (moDCs), but not T cells, is essential for controlling IFNγ-secreting CD4+ T cells. Deficiency in IL-10 signaling dramatically increased IL-1ß release by moDCs. IL-1ß boosted IFNγ secretion by CD4+ T cells either directly or indirectly by stimulating moDCs to secrete IL-12. As predicted a signature of IL-10 dysfunction was observed in a subgroup of pediatric IBD patients having higher IL-1ß expression in activated immune cells and macroscopically affected intestinal tissue. In agreement, reduced IL10RA expression was detected in peripheral blood mononuclear cells and a subgroup of pediatric IBD patients exhibited diminished IL-10 responsiveness. Our data unveil an important mechanism by which IL-10 controls IFNγ-secreting CD4+ T cells in humans and identifies IL-1ß as a potential classifier for a subgroup of IBD patients.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Transducción de Señal , Adolescente , Comunicación Celular , Niño , Susceptibilidad a Enfermedades , Humanos , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/terapiaRESUMEN
BACKGROUND: Risk benefit strategies in managing inflammatory bowel diseases (IBD) are dependent upon understanding the risks of uncontrolled inflammation vs those of treatments. Malignancy and mortality in IBD have been associated with disease-related inflammation and immune suppression, but data are limited due to their rare occurrence. AIM: To identify and describe the most common causes of mortality, types of cancer and previous or current therapy among children and young adults with paediatric-onset IBD. METHODS: Information on paediatric-onset IBD patients diagnosed with malignancy or mortality was prospectively collected via a survey in 25 countries over a 42-month period. Patients were included if death or malignancy occurred after IBD diagnosis but before the age of 26 years. RESULTS: In total, 60 patients were identified including 43 malignancies and 26 fatal cases (9 due to cancer). Main causes of fatality were malignancies (n = 9), IBD or IBD-therapy related nonmalignant causes (n = 10; including 5 infections), and suicides (n = 3). Three cases, all fatal, of hepatosplenic T-cell lymphoma were identified, all were biologic-naïve but thiopurine-exposed. No other haematological malignancies were fatal. The 6 other fatal cancer cases included 3 colorectal adenocarcinomas and 3 cholangiocarcinomas (CCAs). Primary sclerosing cholangitis (PSC) was present in 5 (56%) fatal cancers (1 colorectal carcinoma, 3 CCAs and 1 hepatosplenic T-cell lymphoma). CONCLUSIONS: We report the largest number of paediatric-onset IBD patients with cancer and/or fatal outcomes to date. Malignancies followed by infections were the major causes of mortality. We identified PSC as a significant risk factor for cancer-associated mortality. Disease-related adenocarcinomas were a commoner cause of death than lymphomas.
Asunto(s)
Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/mortalidad , Neoplasias/complicaciones , Neoplasias/mortalidad , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Europa (Continente)/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Enfermedades Inflamatorias del Intestino/epidemiología , Masculino , Neoplasias/epidemiología , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Adulto JovenRESUMEN
We conducted anatomic dissections of macaque monkey orbits and made a quantitative assessment of the orbital geometry of the accessory lateral rectus muscle. Our results show that the expected effect of this muscle on rotations of the globe is to produce elevation and abduction. The abducting component could counteract nasal drifts, and thus our findings provide support for the hypothesis that this muscle could render monkeys resistant to the development of esodeviations. Dissections of the orbits from two naturally esotropic monkeys also are consistent with this hypothesis. The accessory lateral rectus muscle was absent in one of them and abnormally small in the other. Humans do not have an accessory lateral rectus muscle, and we speculate that the high prevalence of esodeviations in humans may be related to an evolutionary loss of this muscle system.
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Músculos Oculomotores/anatomía & histología , Órbita/anatomía & histología , Estrabismo/patología , Animales , Movimientos Oculares , Macaca mulatta , Macaca nemestrina , Músculos Oculomotores/patología , Órbita/patologíaRESUMEN
The effects of postnatal monocular deprivation have been studied in macaque monkeys using behavioral perimetry field testing. The types of deprivation were: (1) early eyelid suture at 22-26 days after birth and then reverse suture at 10-13 months postnatally, (2) late eyelid suture beginning at 3 or 5 months postnatally and continued for 18 months, and (3) long-term occlusion by contact lenses. Response levels were normal for group 1 monkeys with some reduction in visual field extent. A reduced response level but no change in visual field extent was observed for the deprived eyes of group 2 monkeys. One monkey from group 3 that wore an occluder lens from birth to 19 months postnatally had no responses in any part of the visual field. Two other monkeys of group 3, whose occlusion started at 9 or 12 days of age and lasted for 2 years, had no responses to stimuli presented to the previously occluded eyes in their nasal visual fields and had reduced levels of response to stimuli presented in their temporal fields. The results indicate that the effects of monocular deprivation on macaque monkeys are affected by the start, length and type of deprivation. Some of these results are also consistent with a model of binocular competition in which the magnitude of the competition declines along a nasal-to-temporal gradient of visual field eccentricity. However, a mechanism that is independent of binocular competition is needed to account for the loss of responses to stimuli presented in the monocular visual segment.
Asunto(s)
Dominancia Cerebral/fisiología , Privación Sensorial/fisiología , Campos Visuales , Vías Visuales/fisiología , Animales , Atención/fisiología , Fijación Ocular , Macaca mulatta , Macaca nemestrina , Desempeño Psicomotor/fisiologíaRESUMEN
Mutations in coding exons or exon 10 5'-splice-site of the gene for microtubule-associated protein tau can cause chromosome 17-linked frontotemporal dementia and parkinsonism (FTDP-17). We sequenced the 11 coding exons plus exon-intron boundaries of the tau gene in 15 cases of progressive supranuclear palsy (PSP), and found no mutations in coding exons or exon ten 5'-splice sites. These data indicate that typical PSP is not associated with tau gene mutations similar to those causing FTDP-17. We also observed a +39deltaG base change in the intron following exon 4 in three out of 69 PSP cases (all three Italians), whereas it was not found in 150 Dutch controls and once in 112 Italian controls. The +39deltaG variant arose in the context of the PSP-associated tau H1 haplotype. Although a pathogenic role cannot be entirely excluded, +39deltaG is likely to be a rare polymorphism that may be in linkage disequilibrium with a biologically relevant locus inside or near to the tau gene.
Asunto(s)
Mutación/genética , Empalme del ARN/genética , Parálisis Supranuclear Progresiva/genética , Proteínas tau/genética , Anciano , Alelos , Análisis Mutacional de ADN , Exones/genética , Haplotipos , Humanos , Intrones/genética , Italia , Isoformas de ProteínasRESUMEN
In order to elucidate the type, size and depth of suppression scotomata in microstrabismus and small angle convergent strabismus, we performed binocular static perimetry in 14 subjects with strabismus and four normal observers. The strabismic cases had an objective angle of convergent squint between 1 and 8 deg, visual acuity between 0.1 and 1.25, and limited stereopsis. During testing the subjects fused pictures on two Friedmann visual field analyzers. Right and left eyes were studied separately under both monocular and binocular viewing conditions. In five strabismics a suppression scotoma was found in the squinting eye, with a diameter of 5-30 deg and a depth ranging from 4 to 14 dB. No suppression scotomata could be detected in the nine other subjects nor in the four normal observers. In conclusion, only 36% of subjects with strabismus were found to have a suppression scotoma. These scotomata were centered around the fixation point of the squinting eye, in some cases also encompassing the foveal area, and varying in depth and size.
Asunto(s)
Estrabismo/fisiopatología , Visión Binocular/fisiología , Campos Visuales/fisiología , Adulto , Esotropía/fisiopatología , Femenino , Humanos , Masculino , Escotoma/etiología , Estrabismo/complicaciones , Visión Monocular/fisiología , Pruebas del Campo VisualRESUMEN
PURPOSE: To determine the optimal stimulus duration as well as the most appropriate luminance profile to elicit suppression in small-angle convergent strabismus. METHODS: In 10 subjects with small-angle convergent strabismus, using a device allowing binocular viewing and peripheral fusion, we determined what the optimal stimulus would be to elicit suppression. Three control subjects were also included in the study. Stimuli were shown randomly in the central 3 degrees of the visual field of either eye. Stimulus durations were varied in seven steps from 50 to 1000 ms and three luminance-time profiles were used: square wave, triangle and half-sinus, thus yielding 21 different stimuli. The peak light intensity was the same for all stimuli. RESULTS: Suppression, defined as the difference in the threshold sensitivities under monocular vs. binocular viewing, was found with our test device in five of the ten subjects, and ranged between 3 and 33 dB. Suppression was deepest with triangular or half-sinusoidal stimuli of 400 ms duration. Square wave stimuli elicited the smallest amount of suppression. CONCLUSION: Stimuli with a gradual increment and decrement, like triangular or half-sinusoidal stimuli, with a duration of 400 ms are the most effective to elicit suppression
Asunto(s)
Convergencia Ocular , Estimulación Luminosa/métodos , Estrabismo/fisiopatología , Adolescente , Adulto , Humanos , Persona de Mediana Edad , Visión Binocular , Visión MonocularRESUMEN
A 40-year-old man developed cortical blindness during cyclosporin treatment shortly after an allogeneic bone marrow transplantation for chronic myeloid leukaemia. At that time the patient had a therapeutic cyclosporin blood level (226 ng/ml), but a low serum magnesium level and a marginally decreased serum cholesterol level. In addition the patient had hypertension, headache and paraesthesia in the oral, palmar and plantar areas. Vision was fully recovered after discontinuation of the cyclosporin treatment and correction of the hypomagnesaemia. Eighteen cases of cortical blindness during cyclosporin treatment are now known in the literature. Hypomagnesaemia appears to be implicated in the pathogenesis.
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Ceguera/inducido químicamente , Ciclosporinas/efectos adversos , Adulto , Ceguera/fisiopatología , Trasplante de Médula Ósea , Encéfalo/metabolismo , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Deficiencia de Magnesio/inducido químicamente , Deficiencia de Magnesio/complicaciones , Imagen por Resonancia Magnética , Masculino , Campos VisualesRESUMEN
A novel mutation, C118T, in exon 2 of the acid alpha-glucosidase gene has been found in an infant with glycogen storage disease type II. This mutation is predicted to result in protein truncation. The phenotype was that of the severe infantile form of the disorder with lack of motor development, but with eye regard, social smile and vocalization. The parents were heterozygous for C118T and belong to an Islamic community opposed to termination of pregnancy. As the C118T mutation results in the loss of one of two AvaI sites present in an informative PCR product, reliable premarriage carrier detection became possible and was acceptable to the members of this extended family.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , alfa-Glucosidasas/genética , Bronconeumonía/etiología , ADN/análisis , Análisis Mutacional de ADN , Cartilla de ADN , Ecocardiografía , Resultado Fatal , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/psicología , Heterocigoto , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Mutación , Pakistán , EmbarazoRESUMEN
We performed a retrospective study on 45 patients admitted to the Rotterdam Eye Hospital and the Ophthalmic Department of the Academic Medical Center in Amsterdam with pseudophakic endophthalmitis. Vitreous loss during cataract extraction was associated with a significantly increased risk of postoperative endophthalmitis when compared with uncomplicated cataract extraction (p < 0.0001). The incidence of pseudophakic endophthalmitis in diabetic patients was not significantly higher as compared to non-diabetic patients. Vitrectomy in the treatment of postoperative endophthalmitis did not improve the final visual acuity, probably because of selection bias. Methicillin and cephazolin, used intravitreally against gram-positive organisms, failed to provide a good coverage for endophthalmitis due to Staphylococcus epidermidis.
Asunto(s)
Extracción de Catarata/efectos adversos , Endoftalmitis/etiología , Infecciones Bacterianas del Ojo/etiología , Lentes Intraoculares/efectos adversos , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Endoftalmitis/tratamiento farmacológico , Infecciones Bacterianas del Ojo/tratamiento farmacológico , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , VitrectomíaRESUMEN
BACKGROUND: Although there have been a number of studies on the size of the suppression scotoma in divergent strabismus, there have been no reports on the full extent (i.e. size as well as depth) of this scotoma. METHODS: Binocular static perimetry was used to measure suppression scotomas in five patients with primary divergent strabismus and ten patients with consecutive divergent strabismus. Four control subjects were also included in the study. With two modified Friedmann visual field analysers, we measured the visual field of both eyes under monocular and binocular viewing conditions. The objective angle of squint ranged from 3 degrees to 25 degrees. Best corrected visual acuity was at least 0.4, but mostly 1.0 in both eyes. RESULTS: All subjects had normal visual fields for each eye under monocular viewing conditions. In 12 of the 15 subjects, we found a large area of suppression encompassing the projection of the fixation point as well as that of the fovea in the non-fixating eye under binocular viewing conditions. In 2 of these 12 patients, one with primary and one with consecutive divergent strabismus, the area of suppression was located nasally to the position of the fovea in the field of the non-fixating eye (nasal hemisuppression). In another two patients with divergent squint combined with vertical deviation, a small fixation-point suppression scotoma was found. The depth of suppression ranged from 3 dB to 16 dB. In one subject only, no suppression was found. CONCLUSIONS: Our findings indicate that the shape of the suppression scotoma is not related to the origin of divergent strabismus or to the angle of squint. Our results also indicate that the critical age for the development of suppression in divergent squint might be up to 14 years.
Asunto(s)
Exotropía/fisiopatología , Campos Visuales/fisiología , Adolescente , Adulto , Factores de Edad , Exotropía/complicaciones , Femenino , Fijación Ocular/fisiología , Humanos , Masculino , Persona de Mediana Edad , Escotoma/etiología , Escotoma/fisiopatología , Visión Binocular/fisiología , Pruebas del Campo VisualRESUMEN
Mutations in the gene for the microtubule-associated protein tau are associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In this study we compared the presence of the P301L mutated tau protein from brain material of patients with that of the normal 4-repeat, using polyclonal antibodies specific for the P301L point mutation and its normal counterpart. We determined the relative ratio of mutated versus normal tau protein in the sarkosyl-soluble and -insoluble protein fractions from several brain regions. Although mutated and normal tau proteins are both present in the sarkosyl-insoluble deposits, quantitative analysis showed that the mutated protein is the major component. In the sarkosyl-soluble fraction of frontal and temporal cortex the overall ratio of 3-repeat versus 4-repeat tau isoforms is unchanged but there is a dramatic depletion of mutant tau protein. Furthermore, we observed an increase in tau-immunoreactive cleavage products with the P301L antibody, suggesting that the mutant protein is partly resistant to degradation and this is confirmed by pulse-chase experiments. This is the first direct evidence using patient material that shows a selective aggregation of mutant tau protein resulting in sarkosyl-insoluble deposits and the specific depletion of mutated tau protein in the soluble fraction.
Asunto(s)
Corteza Cerebral/metabolismo , Demencia/genética , Proteínas Asociadas a Microtúbulos/genética , Trastornos Parkinsonianos/genética , Proteínas tau/genética , Anciano , Sustitución de Aminoácidos , Animales , Anticuerpos , Células COS , Cromosomas Humanos Par 17 , Demencia/metabolismo , Humanos , Inmunohistoquímica , Proteínas Asociadas a Microtúbulos/inmunología , Persona de Mediana Edad , Células PC12 , Trastornos Parkinsonianos/metabolismo , Mutación Puntual , Corteza Prefrontal/metabolismo , Conejos , Ratas , Proteínas tau/inmunologíaRESUMEN
From 1983 to 1992, 134 patients were treated for clinically suspected endophthalmitis. 61% of this endophthalmitis population consisted of cases that were referred to our clinic. In this nine year period antibiotic treatment was carried out according to three consecutively used guidelines. These three treatment schemes differed in antibiotic spectrum and mode of antibiotic delivery. In 68 patients we performed vitrectomy on account of clinical deterioration under antibiotic treatment. We did not find significant differences in visual outcome between the three treatment groups. The incidence of endophthalmitis following cataract or vitreous surgery did not change throughout the study period. There was however a dramatic decrease in incidence of post-traumatic endophthalmitis following the introduction of a prophylactic antibiotic treatment scheme consisting of fortified gentamicin and cefazolin eyedrops, and intravenously and subconjunctivally administered gentamicin, cefazolin, and clindamycin. In 55 of 68 cases in which vitrectomy was performed in conjunction with intravitreal antibiotics, a vitreous or anterior chamber specimen was cultured. 36 patients had a positive culture result. In the group with positive culture result 42% had better visual acuity in the post-treatment period than before treatment. In the group with a sterile culture result 79% had better vision after treatment.
Asunto(s)
Endoftalmitis/fisiopatología , Endoftalmitis/terapia , Infecciones del Ojo/fisiopatología , Infecciones del Ojo/terapia , Agudeza Visual , Antibacterianos/uso terapéutico , Extracción de Catarata/efectos adversos , Endoftalmitis/etiología , Lesiones Oculares/complicaciones , Humanos , Incidencia , Lentes Intraoculares/efectos adversos , Países Bajos , Premedicación , Resultado del TratamientoRESUMEN
Several mutations in the tau gene have been found in families with hereditary frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 (FTDP-17). This study is the first attempt to correlate genotype and phenotype in six families with FTDP-17 with mutations in the tau gene (deltaK280, G272V, P301L, and R406W). We have investigated tau pathology in 1 P301L and 1 R406W patient. The R406W family showed a significantly higher age at onset (59.2 +/- 5.5 years) and longer duration of illness (12.7 +/- 1.5 years) than the families with the other mutations. The six families showed considerable variation in clinical presentation, but none of them had early parkinsonism. Mutism developed significantly later in the R406W family than in the other families. Frontotemporal atrophy on neuroimaging in the R406W family was less severe than in the P301L and deltaK280 families. The P301L brain contained many pretangles in the frontal and temporal cortex, and the dentate gyrus of hippocampus, showing three tau bands (64, 68, and 72 kd) of extracted tau from the frontal cortex. The presence of many neurofibrillary tangles, many diffuse and classic neuritic plaques in the temporal and parietal cortex, and the hippocampus of the same P301L brain correlated with the presence of four sarkosyl-insoluble (60, 64, 68, and 72 kd) tau bands. The coexistence of characteristic P301L and Alzheimer pathology in the same brain needs further explanation. The R406W brain showed abundant neurofibrillary tangles in several brain regions, and four tau bands (60, 64, 68, and 72 kd) of extracted tau from these regions. The slower progression of the disease in the R406W family might be explained by the microtubule-binding properties of the mutant protein.
Asunto(s)
Demencia/genética , Lóbulo Frontal , Mutación/genética , Lóbulo Temporal , Proteínas tau/genética , Adulto , Anciano , Demencia/patología , Femenino , Lóbulo Frontal/patología , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Lóbulo Temporal/patología , Proteínas tau/análisisRESUMEN
Recently, mutations in the tau gene on chromosome 17 were found causative for autosomal dominantly inherited frontotemporal dementia and parkinsonism (FTDP-17). We describe a family carrying a missense mutation at nucleotide 1137 C --> T, resulting in the amino acid substitution P301S. Methods of investigations include clinical, electrophysiological, and imaging techniques. This kindred presents with a novel phenotype characterized by an early onset of rapidly progressive frontotemporal dementia and parkinsonism in combination with epileptic seizures. We define the dopaminergic deficits as being predominantly presynaptic by the use of single-photon emission computed tomography with a dopamine transporter ligand. The association of this early-onset phenotype with P301S mutation is not entirely consistent with current criteria for the diagnosis of frontotemporal dementias and may encourage the search for tau mutations in diseases similar but not identical to FTDP-17. Also, the change from proline to serine suggests that this mutation might contribute to tau hyperphosphorylation.