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1.
Acta Neurol Scand ; 138(4): 278-283, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29749055

RESUMEN

INTRODUCTION: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), previously known as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) or pigmentary orthochromatic leukodystrophy (POLD), is the most frequent non-vascular adult-onset leukoencephalopathy. It is caused by autosomal dominant mutations in CSF1R gene. Recently, also autosomal recessive mutations in AARS2 gene were found to be the cause of an adult-onset leukodystrophy with axonal spheroids. Our aim was to achieve a genetic diagnosis in a cohort of CSF1R-negative patients, performing a sequence analysis of AARS2 gene. MATERIAL AND METHODS: AARS2 sequencing was performed in 38 CSF1R-negative patients with clinical and magnetic resonance imaging (MRI) findings of adult-onset leukoencephalopathy. RESULTS: Three patients carrying AARS2 compound heterozygous mutations have been found. All patients were female with ovarian failure and leukoencephalopathy. In 2 patients, MRI findings were consistent with previous reports while the third patient showed focal white matter (WM) lesions in the centrum semiovale and the corpus callosum in the absence of extensive involvement and rarefaction of the WM. MRI spectroscopy showed the presence of increased lactate in 2 patients, thus linking AARS2-related leukoencephalopathy with other mitochondrial leukoencephalopathies with high levels of cerebral lactate. CONCLUSION: We recommend screening for mutations in AARS2 gene in CSF1R-negative patients, also in the absence of a clear family history and peculiar MRI findings. Our results also suggest that findings of conventional MRI and MR spectroscopy may be useful in prompting the genetic screening.


Asunto(s)
Alanina-ARNt Ligasa/genética , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/genética , Imagen por Resonancia Magnética/métodos , Mutación/genética , Enfermedades del Ovario/diagnóstico por imagen , Enfermedades del Ovario/genética , Adulto , Anciano , Anciano de 80 o más Años , Cuerpo Calloso/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuroimagen/métodos
2.
Acta Neurol Scand ; 136(6): 668-671, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28608406

RESUMEN

OBJECTIVES: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease caused by NOTCH3 gene mutations. CADASIL women are frequently considered at high risk of systemic vascular events during pregnancy and often prescribed with antithrombotic drugs. This decision is not evidence-based considering the lack of data about pregnancy outcome in CADASIL. We describe our experience on pregnancy in CADASIL patients. MATERIALS AND METHODS: We reviewed records of 50 CADASIL females followed in our center, and we collected prospective information in six patients for a total of 93 pregnancies. RESULTS: No woman had the disease onset or suffered from cerebral vascular ischemic events during pregnancy. Sixteen miscarriages (17.2%) were recorded. There were 72 vaginal births, and five cesarean sections. Considering the six patients followed prospectively (for a total of eight pregnancies), data on fetal growth and newborns weight were in line with those from the general population. Considering gestational complications, we recorded mild proteinuria without hypertension in one patient and hyperinsulinemia and pre-eclampsia in another affected by a known nephropathy. Antithrombotic drugs were used in three patients, in one for an unrelated coexisting prothrombotic condition. CONCLUSIONS: CADASIL does not seem to be associated with an unfavorable outcome of pregnancy either for women and fetuses. Patients and treating physicians should be reassured that pregnancy can be safely initiated in CADASIL, as there is no evidence to support a specific preventive antithrombotic treatment during pregnancy in CADASIL. Larger studies are needed to definitively confirm these conclusions.


Asunto(s)
CADASIL/epidemiología , Complicaciones del Embarazo/epidemiología , Adulto , Peso al Nacer , CADASIL/diagnóstico , CADASIL/terapia , Femenino , Humanos , Recién Nacido , Masculino , Embarazo , Complicaciones del Embarazo/diagnóstico , Complicaciones del Embarazo/terapia , Resultado del Embarazo
3.
Acta Neurol Scand ; 131(1): 30-6, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25109394

RESUMEN

OBJECTIVES: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by NOTCH3 mutations. There are no clinical and neuroimaging findings pathognomonic of the disease. The aim of this paper was to provide a description of a group of NOTCH3-negative patients with a phenotype closely resembling that of CADASIL. MATERIALS AND METHODS: We performed NOTCH3 analysis (exons 2-23) in 117 probands because of a clinician's suspicion of CADASIL. The CADASIL scale, a recently developed tool that allows to better select patients for NOTCH3 analysis, was retrospectively applied to NOTCH3-negative patients; the patient subgroup that scored higher than the screening cutoff for CADASIL was defined as CADASIL-like. RESULTS: Thirty-four CADASIL-like patients (mean age at onset 57.8 years [52.1-63.4], 50% males) were identified. Compared with 25 patients with CADASIL for clinical, familial, and neuroimaging features, only the following variables were significantly (α level <0.05) different in frequency between patients with CADASIL and CADASIL-like patients: a positive family history for stroke at age ≤ 60 years, more frequent in patients with CADASIL, and hypertension, more frequent in CADASIL-like patients. CONCLUSIONS: Our experience highlights the growing number of patients presenting with a high suspicion of a cerebral small vessel disease with an autosomal dominant pattern of inheritance and a phenotype closely similar to that of CADASIL but without NOTCH3 mutations. This group remains to be characterized from the genetic point of view. The role of other genes or NOTCH3 alterations on exons other than 2-23 or introns has to be further assessed.


Asunto(s)
CADASIL/complicaciones , CADASIL/genética , CADASIL/patología , Edad de Inicio , Encéfalo/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Fenotipo , Receptor Notch3 , Receptores Notch/genética , Estudios Retrospectivos
4.
Eur J Neurol ; 21(1): 65-71, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-23869710

RESUMEN

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease that may lead to disability and whose phenotype modulators are still unknown. METHODS: In the MIcrovascular LEukoencephalopathy Study (MILES), we assessed the influence of vascular risk factors and the effect of different cognitive domains (memory, psychomotor speed and executive functions) performances on functional abilities in CADASIL in comparison with age-related leukoencephalopathy (ARL). RESULTS: We evaluated 51 CADASIL patients (mean age 50.3 ± 13.8 years, 47.1% males) and 68 ARL patients (70.6 ± 7.4 years, 58.8% males). Considering vascular risk factors, after adjustment for age, CADASIL patients had higher mean BMI values than ARL patients. Stroke history frequency was similar in the two groups. After adjustment for age, more CADASIL patients were disabled (impaired on ≥ 2 items of the Instrumental Activities of Daily Living scale) in comparison with ARL patients, and CADASIL patients had worse functional performances evaluated with the Disability Assessment for Dementia (DAD) scale. In CADASIL patients, hypertension was related to both DAD score and disability. The cognitive profile of CADASIL and ARL patients was similar, but on a stepwise linear regression analysis functional performances were mainly associated with the memory index (ß = -0.418, P < 0.003) in CADASIL patients and the executive function index (ß = -0.321, P = 0.028) in ARL. CONCLUSIONS: This study suggests that hypertension may contribute to functional impairment in CADASIL and that memory impairment has a large influence on functional decline in contrast with that observed in a sample of subjects with ARL.


Asunto(s)
CADASIL/complicaciones , CADASIL/psicología , Hipertensión/complicaciones , Anciano , Trastornos del Conocimiento/etiología , Femenino , Humanos , Leucoencefalopatías/complicaciones , Leucoencefalopatías/psicología , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fenotipo , Factores de Riesgo
6.
Neurol Sci ; 34(1): 79-83, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22274816

RESUMEN

Late-onset Krabbe disease may have variable misleading clinical manifestations and be a puzzling problem for physicians. We report clinical and peripheral nerve studies of three patients with adult-onset Krabbe disease. Two cases had a predominantly spastic paraparesis; in one case, the symptoms mimicked a cerebrovascular disorder. Predominantly, demyelinating neuropathy was observed in one case and axonal neuropathy in two cases. In all cases, no typical intracytoplasmic inclusions were found. These observations suggest that peripheral neuropathy in adult-onset Krabbe disease has variable clinical and pathological characteristics, different from those described in the classic form.


Asunto(s)
Leucodistrofia de Células Globoides/complicaciones , Enfermedades del Sistema Nervioso Periférico/etiología , Adulto , Biopsia , Encéfalo/patología , Trastornos del Conocimiento/etiología , Femenino , Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/patología , Galactosilceramidasa/genética , Humanos , Leucodistrofia de Células Globoides/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Examen Neurológico , Nervios Periféricos/patología , Enfermedades del Sistema Nervioso Periférico/patología
7.
Int J Neurosci ; 121(4): 201-8, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21244301

RESUMEN

Wernicke encephalopathy (WE) is a neurological emergency due to thiamine deficiency. We aimed to identify clinical course and causes of diagnostic delay or failure of WE in a group of patients who underwent surgery for gastrointestinal tumors. A retrospective review of clinical, laboratory, neuroimaging, and therapeutic features of 10 patients with WE following abdominal surgery for cancer was carried out. Four patients died; in these subjects, diagnosis was delayed and supplementation of vitamin was absent or likely inadequate. Diagnostic delay or failure was also related to the coexistence of several medical complications at presentation masking typical symptoms of WE. In the surviving patients, outcome was influenced by promptness and type of therapy. Postoperative abdominal bleeding and number of subsequent operations may also had an effect. Postsurgical patients with gastrointestinal tumors may develop a subtle WE. The number of subsequent operations and the severity of postoperative complications may increase the risk of unrecognized WE. The disease should be suspected in postsurgical patients who have unexpected mental status changes, even under prophylactic treatment with vitamins. We suggest that prophylaxis with high doses of thiamine should be undertaken in patients with gastrointestinal tumors before surgery.


Asunto(s)
Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Neoplasias Gastrointestinales/cirugía , Tracto Gastrointestinal/cirugía , Deficiencia de Tiamina/diagnóstico , Deficiencia de Tiamina/etiología , Encefalopatía de Wernicke/diagnóstico , Encefalopatía de Wernicke/etiología , Anciano , Errores Diagnósticos/prevención & control , Procedimientos Quirúrgicos del Sistema Digestivo/métodos , Femenino , Tracto Gastrointestinal/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Cuidados Preoperatorios/métodos , Cuidados Preoperatorios/normas , Estudios Retrospectivos , Medición de Riesgo/métodos
8.
J Neurol Neurosurg Psychiatry ; 81(11): 1189-93, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20972203

RESUMEN

OBJECTIVE: To quantify total and regional brain damage in subjects with cerebrotendinous xanthomatosis (CTX) using MR based quantitative measures. BACKGROUND: CTX is a rare inherited disorder characterised by progressive neurological impairment. Appropriate therapy can slow disease progression. Measures of brain volume changes have been used in several neurological disorders due to their value in assessing disease outcome and monitoring patients' evolution. METHODS: 24 CTX patients underwent conventional MRI to measure total and regional brain volumes. In five CTX patients who started therapy at baseline, clinical and MRI examinations were repeated after 2 years. Clinical disability, overall cognitive performance and cerebellar function were evaluated using the modified Rankin Scale (RS), Mini Mental Status Examination (MMSE) and cerebellar functional system score (CB-FSS). RESULTS: Measures of normalised brain, cortical and cerebellar volumes were lower in CTX patients than in healthy controls (p<0.01). Instead, there were no differences in normalised white matter volumes between the two groups (p=0.1). At regional analysis, a significant volume decrease was found in each cortical region (p<0.01 for all regions). Normalised cortical volumes correlated closely with age (r=-0.9, p<0.0001), RS (r=-0.65, p<0.001) and MMSE (r=-0.60, p<0.01). Normalised cerebellar volumes correlated closely with CB-FSS scores (r=-0.58, p<0.01). In the five CTX patients followed over time, the annual brain volume decrease was -1.1 ± 0.2%. CONCLUSIONS: Cortical volume, rather than white matter volume, is diffusely decreased in CTX patients and correlates closely with the patient's clinical status. These data provide evidence for the presence of clinically relevant neuronal-axonal damage in the brains of CTX patients.


Asunto(s)
Cerebelo/patología , Corteza Cerebral/patología , Imagen por Resonancia Magnética , Xantomatosis Cerebrotendinosa/patología , Adolescente , Adulto , Atrofia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Fibras Nerviosas Mielínicas/patología , Neuronas/patología , Pruebas Neuropsicológicas , Adulto Joven
11.
Eur J Neurol ; 17(10): 1259-62, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20402754

RESUMEN

BACKGROUND AND PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease, because of sterol 27-hydroxylase deficiency. Clinical manifestations of CTX are tendon xanthomas, juvenile cataracts, osteoporosis, diarrhoea and multiple progressive neurological dysfunctions. More than 300 patients with CTX have been reported to date worldwide and about fifty different mutations identified in CYP27A1 gene. This study describes the clinical and laboratory findings of seven new patients. METHODS: We report the molecular and clinical characterization of seven new Italian patients with CTX carrying four novel mutations. RESULTS: We identified four novel mutations located in different exons, in particular in the region of exons 2-5 of the CYP27A1 gene. Phenotypical expression did not differ from classical CTX presentation except for absence of tendon xanthomas in two patients.


Asunto(s)
Colestanotriol 26-Monooxigenasa/deficiencia , Colestanotriol 26-Monooxigenasa/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Xantomatosis Cerebrotendinosa/enzimología , Xantomatosis Cerebrotendinosa/genética , Adolescente , Adulto , Femenino , Humanos , Italia , Masculino , Xantomatosis Cerebrotendinosa/diagnóstico , Adulto Joven
12.
J Neurol Neurosurg Psychiatry ; 80(1): 41-7, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18829627

RESUMEN

OBJECTIVE: To assess, by using quantitative MRI metrics, structural and metabolic brain abnormalities in subjects with preclinical cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). BACKGROUND: Brain MRI abnormalities have been occasionally reported in preclinical CADASIL subjects. However, very little is known as to when the brain tissue damage starts to accumulate, what brain regions are primarily involved and whether the brain damage is significant in subjects who have no overt clinical manifestations of the disease. METHODS: Twelve subjects (mean age 40 years; range 26-55 years; males/females 6/6) with genetically proven CADASIL and no clinical signs of the disease underwent conventional MRI and proton MR spectroscopic imaging ((1)H-MRSI) to measure white matter (WM) lesion volume (LV), global and regional cerebral volumes, and WM levels of N-acetylaspartate (NAA) normalised to creatine (Cr). MR values were compared with those of 13 age- and sex-matched healthy controls. RESULTS: All preclinical CADASIL showed WM lesions (range 0.2 to 26 cm(3)). They were mostly distributed in the frontal and parietal regions, with the highest probability in the corona radiata. On (1)H-MRSI examination, NAA/Cr values were lower in preclinical CADASIL than in HC, particularly in the corona radiata (p<0.01). Normalised brain and cortical volumes were also lower in preclinical CADASIL than in HC (p<0.01), particularly in the frontal cortex. CONCLUSIONS: The pathological process occurring in CADASIL leads to damage of WM and neocortex much before the evidence of clinical symptoms. At this preclinical stage, this seems to take place prevalently in the frontal brain region.


Asunto(s)
CADASIL/metabolismo , CADASIL/patología , Infarto Cerebral/metabolismo , Infarto Cerebral/patología , Imagen por Resonancia Magnética , Adulto , Factores de Edad , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Creatina/metabolismo , Femenino , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Protones
13.
Mult Scler Relat Disord ; 27: 294-297, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30448470

RESUMEN

BACKGROUND: Peak width of skeletonized mean diffusivity (PSMD) is a novel and fully automated, MRI biomarker, which has shown clinical relevance in cerebral small vessel diseases (SVD). We aimed here to assess PSMD levels across the brain of patients with multiple sclerosis (MS), in comparison to normal controls (NC) and patients with CADASIL, a genetically defined form of severe SVD. METHODS: We assessed PSMD in relapsing-remitting (RR) MS patients (n = 47) in comparison to age-matched CADASIL patients (n = 25) and NC (n = 28). Diffusion Tensor Imaging data were acquired on 1.5T MR clinical scanner to automatically compute PSMD through "skeletonization" of WM tracts and diffusion histograms. RESULTS: RRMS had lower WM lesion volume (LV) than CADASIL (8.6 ±â€¯8.2 vs 24.4 ±â€¯17.4 cm3, p < 0.001). After correction for LV, PSMD values in MS were higher than in CADASIL patients (adjusted mean values: 4.5 vs 3.9 × 10-4 mm2/s, p = 0.03) and in both patient groups were higher than in NC (2.8 ±â€¯0.3 × 10-4 mm2/s, p < 0.001). PSMD values correlated with LV in both patient groups (r = 0.8, p < 0.001 in MS; r = 0.6, p = 0.002 in CADASIL). CONCLUSIONS: In both patient groups, PSMD was higher than in NC and closely correlated with LV, suggesting sensitivity in assessing brain tissue damage in these disorders. In MS patients, PSMD levels were higher than in CADASIL patients, despite the lower LV. This might be related to more severe normal-appearing WM abnormalities occurring in the MS brains. This novel, fully automated, MRI metric may represent a useful marker for a robust quantification of the diffuse WM tissue damage in MS.


Asunto(s)
Imagen de Difusión por Resonancia Magnética/métodos , Interpretación de Imagen Asistida por Computador , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/patología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto , Biomarcadores , Imagen de Difusión Tensora , Femenino , Humanos , Masculino , Persona de Mediana Edad
14.
J Neurol Neurosurg Psychiatry ; 79(1): 82-5, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17634216

RESUMEN

OBJECTIVE: Neuropathological descriptions of the brain in Friedreich's ataxia (FRDA) were obtained before availability of the current molecular genetic tests for this disease. Voxel-based morphometry (VBM) enables an unbiased whole-brain quantitative analysis of differences in gray matter (GM) and white matter (WM) volume. METHODS: Using VBM, we assessed the brain structural damage in 22 patients with genetically confirmed FRDA and 25 healthy controls. The results were correlated with the disease duration and the severity of the patients' clinical deficits--evaluated using the International Cerebellar Ataxia Rating Scale and Inherited Ataxia Clinical Rating Scale. RESULTS: In patients with FRDA, VBM showed a symmetrical volume loss in dorsal medulla, infero-medial portions of the cerebellar hemispheres, the rostral vermis and in the dentate region. No volume loss in cerebral hemispheres was observed. The atrophy of the cerebellum and medulla correlated with the severity of the clinical deficit and disease duration. CONCLUSIONS: In patients with FRDA, significant GM and WM loss was observed only in the cerebellum and dorsal medulla. These structural changes correlate with the severity of the clinical deficit and disease duration.


Asunto(s)
Encéfalo/anatomía & histología , Encéfalo/fisiopatología , Ataxia de Friedreich/diagnóstico , Ataxia de Friedreich/fisiopatología , Adolescente , Adulto , Anciano , Alelos , Atrofia/patología , Atrofia/fisiopatología , Cerebelo/patología , Cerebelo/fisiopatología , Giro Dentado/patología , Giro Dentado/fisiopatología , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Ataxia de Friedreich/genética , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Factores de Tiempo
15.
Eur J Neurol ; 15(11): 1252-5, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18803653

RESUMEN

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be considered a useful model of pure subcortical vascular dementia (SVD) because it occurs in young adults, unlikely to have concomitant age- and Alzheimer's disease (AD)-related pathology. In patients with CADASIL we evaluated the cerebrospinal fluid (CSF) levels of beta-amyloid 1-42 (Abeta42), total tau protein (t-tau) and phosphorylated tau protein (p-tau), which are well-accepted biomarkers of AD. METHODS: The CSF Abeta42, t-tau and p-tau levels were determined with Innotest beta-amyloid 1-42, Innotest hTAU-Ag and Innotest Phospho-tau 181p sandwich enzyme-linked immunoassay, in 10 CADASIL patients and 17 healthy age-matched subjects. A case-control statistical analysis was carried out. RESULTS: CSF Abeta42 levels were significantly lower in CADASIL patients than in controls, whereas CSF t-tau and p-tau levels did not differ between the two groups. CONCLUSIONS: The pattern found in CADASIL patients is similar to that reported in those with sporadic SVD, suggesting that decreased CSF Abeta42 might be related to the subcortical vascular lesions in the white matter.


Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/líquido cefalorraquídeo , CADASIL/líquido cefalorraquídeo , CADASIL/complicaciones , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/análisis , Biomarcadores/análisis , Biomarcadores/líquido cefalorraquídeo , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , CADASIL/fisiopatología , Comorbilidad , Humanos , Persona de Mediana Edad , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Fragmentos de Péptidos/análisis , Fosforilación , Placa Amiloide/metabolismo , Placa Amiloide/patología , Valor Predictivo de las Pruebas , Proteínas tau/análisis
16.
J Neurol Sci ; 271(1-2): 211-3, 2008 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-18538791

RESUMEN

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary form of small vessel disease in which the pons may show lacunar infarcts and leukoaraiosis. Acute pure vestibular syndrome may be due to caudal pontine lesions and is probably underestimated. We describe a case of CADASIL with acute vestibular syndrome mimicking peripheral vestibulopathy, and evidence of focal infarction in the ponto-medullary junction at gadolinium-enhanced MRI including diffusion-weighted imaging, involving the area of the right vestibular nucleus and root entry zone of the ipsilateral vestibular nerve bundle. In CADASIL, both focal brainstem lesions and leukoaraiosis may parallel supratentorial white matter changes and may be related to poor outcome. Their actual extent should be evaluated in longitudinal studies that might predict clinical outcome and progression of disability.


Asunto(s)
CADASIL/complicaciones , Infarto Cerebral/complicaciones , Enfermedades Vestibulares/complicaciones , Adulto , CADASIL/patología , Infarto Cerebral/patología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Enfermedades Vestibulares/patología
17.
Eur J Neurol ; 15(11): 1216-21, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18803652

RESUMEN

BACKGROUND AND PURPOSE: Although sudden death (SD) accounts for numerous cases of premature mortality in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the risk factors responsible for this dramatic event remain unclear. We sought possible differences in the QT variability index (QTVI) -- a well-known index of temporal dispersion in myocardial repolarization strongly associated with the risk of SD -- between a group of patients with CADASIL and healthy controls. METHODS: A total of 13 patients with CADASIL and 13 healthy volunteers underwent a 5-min electrocardiogram recording to calculate the QTVI. All the patients also underwent a clinical assessment, including functional status by Rankin score, and a magnetic resonance imaging (MRI) brain scan for quantitative analysis of T2-weighted (T2-W) and T1-weighted (T1-W) lesion volume (LV). RESULTS: Short-term QT-interval analysis showed significantly higher QTVI (P = 0.029) in patients than in controls. In patients, notwithstanding the limitations of the small sample size, QTVI also well correlated with T1-W LV (r = 0.747, P = 0.003) and T2-W LV (r = 0.731, P = 0.005). CONCLUSION: Because patients with CADASIL have increased temporal cardiac repolarization variability as assessed by QTVI, this mechanism could underlie these patients' risk of SD. Whether this easily assessed, non-invasive marker could be used to stratify the risk of malignant ventricular arrhythmias in patients with CADASIL and, possibly, to guide their therapeutic management warrants confirmation from larger prospective studies.


Asunto(s)
Arritmias Cardíacas/etiología , CADASIL/complicaciones , Muerte Súbita Cardíaca/etiología , Adulto , Anciano , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatología , Encéfalo/irrigación sanguínea , Encéfalo/patología , Encéfalo/fisiopatología , Arterias Cerebrales/patología , Electrocardiografía , Femenino , Sistema de Conducción Cardíaco/fisiopatología , Frecuencia Cardíaca/fisiología , Ventrículos Cardíacos/inervación , Ventrículos Cardíacos/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Proyectos Piloto , Valor Predictivo de las Pruebas
18.
J Neurol Sci ; 272(1-2): 106-9, 2008 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-18603265

RESUMEN

We sequenced all genes of mitochondrial tRNAs of a patient with chronic progressive external ophthalmoplegia with 5% ragged red fibres and 15% COX-negative fibres but without macrorearrangements of mitochondrial DNA (mtDNA). Direct sequencing showed a novel heteroplasmic G>A substitution in position 12316 of tRNA(Leu(CUN)) gene. This change destroys a highly conserved G-C base coupling in tRNA TpsiC branch. By RFLP analysis we could demonstrate different degrees of heteroplasmy in different patient's tissues. This alteration, absent in a population of 110 patients with different encephalomyopathies, can be considered pathogenic: it is the tenth tRNA(Leu(CUN)) pathogenic mutation described up to date.


Asunto(s)
ADN Mitocondrial/genética , Mutación , Oftalmoplejía Externa Progresiva Crónica/genética , ARN de Transferencia de Leucina/genética , Análisis Mutacional de ADN , Femenino , Humanos , Persona de Mediana Edad , Músculo Esquelético/patología , Oftalmoplejía Externa Progresiva Crónica/patología
19.
AJNR Am J Neuroradiol ; 39(3): 427-434, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29348134

RESUMEN

BACKGROUND AND PURPOSE: Mitochondrial neurogastrointestinal encephalopathy is a rare disorder due to recessive mutations in the thymidine phosphorylase gene, encoding thymidine phosphorylase protein required for mitochondrial DNA replication. Clinical manifestations include gastrointestinal dysmotility and diffuse asymptomatic leukoencephalopathy. This study aimed to elucidate the mechanisms underlying brain leukoencephalopathy in patients with mitochondrial neurogastrointestinal encephalopathy by correlating multimodal neuroradiologic features to postmortem pathology. MATERIALS AND METHODS: Seven patients underwent brain MR imaging, including single-voxel proton MR spectroscopy and diffusion imaging. Absolute concentrations of metabolites calculated by acquiring unsuppressed water spectra at multiple TEs, along with diffusion metrics based on the tensor model, were compared with those of healthy controls using unpaired t tests in multiple white matters regions. Brain postmortem histologic, immunohistochemical, and molecular analyses were performed in 1 patient. RESULTS: All patients showed bilateral and nearly symmetric cerebral white matter hyperintensities on T2-weighted images, extending to the cerebellar white matter and brain stem in 4. White matter, N-acetylaspartate, creatine, and choline concentrations were significantly reduced compared with those in controls, with a prominent increase in the radial water diffusivity component. At postmortem examination, severe fibrosis of brain vessel smooth muscle was evident, along with mitochondrial DNA replication depletion in brain and vascular smooth-muscle and endothelial cells, without neuronal loss, myelin damage, or gliosis. Prominent periependymal cytochrome C oxidase deficiency was also observed. CONCLUSIONS: Vascular functional and histologic alterations account for leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy. Thymidine toxicity and mitochondrial DNA replication depletion may induce microangiopathy and blood-brain-barrier dysfunction, leading to increased water content in the white matter. Periependymal cytochrome C oxidase deficiency could explain prominent periventricular impairment.


Asunto(s)
Enfermedades de los Pequeños Vasos Cerebrales/patología , Leucoencefalopatías/patología , Mitocondrias/patología , Encefalomiopatías Mitocondriales/patología , Adulto , Encéfalo/metabolismo , Encéfalo/patología , Enfermedades de los Pequeños Vasos Cerebrales/etiología , Enfermedades de los Pequeños Vasos Cerebrales/metabolismo , Imagen de Difusión por Resonancia Magnética , Femenino , Humanos , Leucoencefalopatías/etiología , Leucoencefalopatías/metabolismo , Masculino , Mitocondrias/metabolismo , Encefalomiopatías Mitocondriales/complicaciones , Encefalomiopatías Mitocondriales/metabolismo
20.
AJNR Am J Neuroradiol ; 28(3): 486-8, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17353317

RESUMEN

SUMMARY: Morphometry and spectroscopy were performed in 3 patients with fragile X-associated tremor/ataxia syndrome (FXTAS). The brain stem and cerebellum were atrophic and satisfied criteria for olivopontocerebellar atrophy in 2 patients. However, the vermis was relatively spared and the basis pontis maintained its oval shape. The only spectroscopic abnormality was a decrease of the pontine N-acetylaspartate/creatine ratio in 1 patient. Atrophy and metabolic changes in FXTAS differ to some extent from those of olivopontocerebellar atrophy.


Asunto(s)
Ataxia/patología , Tronco Encefálico/patología , Cerebelo/patología , Síndrome del Cromosoma X Frágil/patología , Espectroscopía de Resonancia Magnética , Temblor/patología , Anciano , Ataxia/etiología , Diagnóstico Diferencial , Síndrome del Cromosoma X Frágil/complicaciones , Humanos , Masculino , Protones , Temblor/etiología
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