Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 98
Filtrar
Más filtros

Bases de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Brain ; 146(12): 5044-5059, 2023 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-38040034

RESUMEN

Xeroderma pigmentosum (XP) results from biallelic mutations in any of eight genes involved in DNA repair systems, thus defining eight different genotypes (XPA, XPB, XPC, XPD, XPE, XPF, XPG and XP variant or XPV). In addition to cutaneous and ophthalmological features, some patients present with XP neurological disease. It is unknown whether the different neurological signs and their progression differ among groups. Therefore, we aim to characterize the XP neurological disease and its evolution in the heterogeneous UK XP cohort. Patients with XP were followed in the UK National XP Service, from 2009 to 2021. Age of onset for different events was recorded. Cerebellar ataxia and additional neurological signs and symptoms were rated with the Scale for the Assessment and Rating of Ataxia (SARA), the Inventory of Non-Ataxia Signs (INAS) and the Activities of Daily Living questionnaire (ADL). Patients' mutations received scores based on their predicted effects. Data from available ancillary tests were collected. Ninety-three XP patients were recruited. Thirty-six (38.7%) reported neurological symptoms, especially in the XPA, XPD and XPG groups, with early-onset and late-onset forms, and typically appearing after cutaneous and ophthalmological symptoms. XPA, XPD and XPG patients showed higher SARA scores compared to XPC, XPE and XPV. SARA total scores significantly increased over time in XPD (0.91 points/year, 95% confidence interval: 0.61, 1.21) and XPA (0.63 points/year, 95% confidence interval: 0.38, 0.89). Hyporeflexia, hypopallesthaesia, upper motor neuron signs, chorea, dystonia, oculomotor signs and cognitive impairment were frequent findings in XPA, XPD and XPG. Cerebellar and global brain atrophy, axonal sensory and sensorimotor neuropathies, and sensorineural hearing loss were common findings in patients. Some XPC, XPE and XPV cases presented with abnormalities on examination and/or ancillary tests, suggesting underlying neurological involvement. More severe mutations were associated with a faster progression in SARA total score in XPA (0.40 points/year per 1-unit increase in severity score) and XPD (0.60 points/year per 1-unit increase), and in ADL total score in XPA (0.35 points/year per 1-unit increase). Symptomatic and asymptomatic forms of neurological disease are frequent in XP patients, and neurological symptoms can be an important cause of disability. Typically, the neurological disease will be preceded by cutaneous and ophthalmological features, and these should be actively searched in patients with idiopathic late-onset neurological syndromes. Scales assessing cerebellar function, especially walking and speech, and disability can show progression in some of the groups. Mutation severity can be used as a prognostic biomarker for stratification purposes in clinical trials.


Asunto(s)
Enfermedades del Sistema Nervioso Central , Xerodermia Pigmentosa , Humanos , Xerodermia Pigmentosa/complicaciones , Xerodermia Pigmentosa/genética , Xerodermia Pigmentosa/diagnóstico , Actividades Cotidianas , Estudios Prospectivos , Reparación del ADN , Mutación/genética
2.
Acta Neurochir (Wien) ; 165(6): 1615-1633, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36929449

RESUMEN

BACKGROUND: Diffuse hemispheric glioma, H3 G34-mutant, is a novel paediatric tumour type in the fifth edition of the WHO classification of CNS tumours associated with an invariably poor outcome. We present a comprehensive clinical, imaging and pathological review of this entity. METHODS: Patients with confirmed H3 G34R-mutant high-grade glioma were included in a single-centre retrospective cohort study and examined for clinical, radiological and histo-molecular data. RESULTS: Twelve patients were enrolled in the study - 7 males/5 females; the mean age was 17.5 years (10-57 years). Most patients presented with signs of raised intracranial pressure (8/12). The frontal lobe (60%) was the prevalent location, with a mixed cystic-nodular appearance (10/12) and presence of vascular flow voids coursing through/being encased by the mass (8/12), and all tumours showed cortical invasion. Nine patients had subtotal resection limited by functional margins, two patients underwent supra-total resection, and one patient had biopsy only. 5-ALA was administered to 6 patients, all of whom showed positive fluorescence. Histologically, the tumours showed a marked heterogeneity and aggressive spread along pre-existing brain structures and leptomeninges. In addition to the diagnostic H3 G34R/V mutation, pathogenic variants in TP53 and ATRX genes were found in most cases. Potential targetable mutations in PDGFRA and PIK3CA genes were detected in five cases. The MGMT promoter was highly methylated in half of the samples. Methylation profiling was a useful diagnostic tool and highlighted recurrent structural chromosome abnormalities, such as PDGFRA amplification, CDKN2A/B deletion, PTEN loss and various copy number changes in the cyclin D-CDK4/Rb pathway. Radiochemotherapy was the most common adjuvant treatment (9/12), and the average survival was 19.3 months. CONCLUSIONS: H3 G34R-mutant hemispheric glioma is a distinct entity with characteristic imaging and pathological features. Genomic landscaping of individual tumours can offer an opportunity to adapt individual therapies and improve patient management.


Asunto(s)
Neoplasias Encefálicas , Glioma , Masculino , Femenino , Humanos , Niño , Adolescente , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Histonas/genética , Estudios Retrospectivos , Glioma/diagnóstico por imagen , Glioma/genética , Glioma/metabolismo , Encéfalo/patología
3.
Br J Neurosurg ; 37(6): 1567-1571, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33050723

RESUMEN

INTRODUCTION: Inter-dural juxta-facet spinal cysts occur rarely. They form as part of the degenerative spinal disease process and can be misdiagnosed as synovial cysts or ganglion cysts. We report the case of a thoracic inter-dural juxta-facet spinal cyst causing acute compressive thoracic myelopathy. METHODS: The data was collected retrospectively from patient records. The literature review was performed in PubMed. RESULTS: We report a case of symptomatic inter-dural juxta-facet thoracic spinal cyst. The literature review showed a variety of different spinal cysts including arachnoid cyst, discal cyst, ganglion cyst, epidermoid cyst and synovial cysts. Micro-instability and repeated microtrauma associated with degenerative changes are most likely contributors to its formation. Asymptomatic cysts can show spontaneous resolution. When symptomatic, they can be managed with surgical excision with good patient outcome. CONCLUSION: Inter-dural spinal cysts can be diagnosed and surgically excised to produce excellent post-operative outcome. High pre-operative index of suspicion of this diagnosis together with good understanding of the intraoperative anatomy are essential to avoid inadvertent dural breach.


Asunto(s)
Quistes Aracnoideos , Compresión de la Médula Espinal , Quiste Sinovial , Humanos , Compresión de la Médula Espinal/diagnóstico por imagen , Compresión de la Médula Espinal/etiología , Compresión de la Médula Espinal/cirugía , Estudios Retrospectivos , Imagen por Resonancia Magnética , Quistes Aracnoideos/cirugía , Quiste Sinovial/complicaciones , Quiste Sinovial/diagnóstico por imagen , Quiste Sinovial/cirugía
4.
Pract Neurol ; 23(5): 441-445, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37460210

RESUMEN

Hypertrophic pachymeningitis is a rare disorder of the dura mater of the spine or brain. It can be caused by inflammatory, infective or neoplastic conditions or can be idiopathic. We report a man with hypertrophic pachymeningitis and bilateral chronic subdural haematoma caused by IgG4-related disease. We highlight the diagnostic challenges and discuss possible underlying mechanisms of subdural haematoma formation in inflammatory conditions. Isolated IgG4-related hypertrophic pachymeningitis with chronic subdural haematoma is very rare; previously reported cases have suggested a possible predilection for men in their sixth decade, presenting with headache as the dominant symptom. Given the rarity and complexity of the condition, it should be managed in a multidisciplinary team setting.


Asunto(s)
Hematoma Subdural Crónico , Meningitis , Masculino , Humanos , Inmunoglobulina G , Hematoma Subdural Crónico/complicaciones , Hematoma Subdural Crónico/diagnóstico por imagen , Meningitis/complicaciones , Meningitis/diagnóstico por imagen , Hipertrofia/complicaciones , Hipertrofia/diagnóstico , Duramadre/diagnóstico por imagen , Imagen por Resonancia Magnética/efectos adversos
5.
Am J Med Genet A ; 188(9): 2783-2789, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35616428

RESUMEN

Biallelic pathogenic variants in phosphopantothenoylcysteine synthetase, PPCS, are a rare cause of a severe early-onset dilated cardiomyopathy with high morbidity and mortality. To date, only five individuals with PPCS-mutations have been reported. Here, we report a female infant who presented in the neonatal period with hypotonia, a necrotizing myopathy with intermittent rhabdomyolysis and other extracardiac manifestations before developing a progressive and ultimately fatal dilated cardiomyopathy. Gene agnostic trio genome sequencing revealed two rare variants in the PPCS [MIM: 609853] in trans, a previously reported pathogenic c.320_334del p. (Pro107_Ala111del) variant, and a c.613-3C>G intronic variant of uncertain significance. Functional studies confirmed the likely pathogenicity of this variant. Our case provides clinical and histopathological evidence for an associated neuromuscular phenotype not previously recognized and expands the evolving phenotypic spectrum of PPCS-related disorders. We also performed a literature search of all previously published cases and summarize the common features.


Asunto(s)
Cardiomiopatía Dilatada , Cardiomiopatía Dilatada/genética , Femenino , Humanos , Mutación
6.
BMC Neurol ; 22(1): 500, 2022 Dec 23.
Artículo en Inglés | MEDLINE | ID: mdl-36564732

RESUMEN

BACKGROUND: Amyloid-ß-related angiitis (ABRA) is a rare complication of cerebral amyloid angiopathy, characterized by amyloid-ß deposition in the leptomeningeal and cortical vessels with associated angiodestructive granulomatous inflammation. The clinical presentation is variable, including subacute cognitive decline, behavioural changes, headaches, seizures and focal neurological deficits, which may mimic other conditions. Here, we present a case with fatal thrombolysis-related haemorrhage associated with ABRA in a middle-aged patient. CASE PRESENTATION: A 55-year-old man was admitted to hospital with sudden onset left-sided cheek, arm and hand sensory loss, blurred vision, and worsening headache, with a National Institutes of Health Stroke Scale (NIHSS) score of 3. An acute CT head scan showed no contraindications, and therefore the decision was made to give intravenous thrombolysis. Post-thrombolysis, he showed rapid deterioration with visual disturbances, headache and confusion, and a repeat CT head scan confirmed several areas of intracerebral haemorrhage. No benefit from surgical intervention was expected, and the patient died four days after the first presentation. Neuropathological examination found acute ischemic infarcts of three to five days duration in the basal ganglia, insular cortex and occipital lobe, correlating with the initial clinical symptoms. There were also extensive recent intracerebral haemorrhages most likely secondary to thrombolysis. Furthermore, the histological examination revealed severe cerebral amyloid angiopathy associated with granulomatous inflammatory reaction, consistent with ABRA. CONCLUSIONS: Presentation of ABRA in a middle-aged patient highlighted the difficulties in recognition and management of this rare condition. There is emerging evidence that patients with CAA may have increased risk of fatal intracerebral haemorrhages following thrombolysis. This may be further increased by a coexisting CAA-related inflammatory vasculopathy which is potentially treatable with steroid therapy if early diagnosis is made.


Asunto(s)
Angiopatía Amiloide Cerebral , Vasculitis , Masculino , Persona de Mediana Edad , Humanos , Péptidos beta-Amiloides , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/diagnóstico por imagen , Angiopatía Amiloide Cerebral/tratamiento farmacológico , Vasculitis/complicaciones , Vasculitis/tratamiento farmacológico , Terapia Trombolítica/efectos adversos , Cefalea/complicaciones
7.
Br J Neurosurg ; : 1-6, 2022 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-35379054

RESUMEN

Glomangiomyomatosis is an extremely rare variant of glomus tumours. We describe the first known case of paravertebral glomangiomyomatosis in the literature to cause spinal cord compression. A 45-year old female patient presented with sudden onset of left leg pain and progressive weakness in left-sided hip flexion. An MRI spine revealed a large, lobulated, heterogeneous mass cantered on the left L2/3 foramen, mimicking a dumbbell nerve sheath tumour. The mass was invading the psoas muscle and displayed evidence of recent haemorrhage. The patient underwent debulking of the lesion via a left retroperitoneal approach. Surgery was uneventful, with clinical improvement and resolution of leg pain post-operatively. Histopathology of the tumour revealed delineated glomus-like cells and foci of spindled shaped cells resembling myoid differentiation. Immuno-histochemical features of the tumour confirmed the diagnosis of glomangiomyomatosis. The patient continued under close follow up, representing 18 months later with clinical and radiological progression of the disease with similar symptoms of leg pain but no weakness. Follow up MRI revealed progression of the intraspinal and paraspinal components of the tumour with thecal compression. A posterior approach was utilized in order to decompress the intraspinal component, which again was uneventful, and improved the patient's symptoms. This is the first known case of paravertebral glomangiomyomatosis in the literature and this rare entity should be considered in the differential diagnosis of nerve sheath tumours due to risk of progression and recurrence.

8.
Clin Endocrinol (Oxf) ; 94(3): 413-423, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33340135

RESUMEN

OBJECTIVE: To report the clinical presentation, management and outcomes of young patients with prolactinomas (<20 years) and conduct a systematic review and meta-analysis. PATIENTS AND DESIGN: Clinical, biochemical and radiological data (1996-2018) were collected from our centre. A systematic review and meta-analysis of published literature (1994-2019) on prolactinoma (age <20 years) were conducted. Both random and fixed effects meta-analysis were used to pool outcomes across studies. RESULTS 1 CASE SERIES: Twenty-two patients (14 females) were identified; median age at diagnosis 15.7 years (range 13-19); 12 patients (6 females) had a macroprolactinoma. Seven patients (macroprolactinoma-6) had associated pituitary hormone deficiencies at presentation. Five patients (4 males) underwent surgical resection due to poor response to cabergoline or apoplexy. Patients undergoing surgery had larger tumours (p < .02) and higher serum prolactin concentration (p < .005). All patients with macroprolactinoma >20 mm required surgical intervention. RESULTS 2 SYSTEMATIC REVIEW AND META-ANALYSIS: We selected 11 studies according to strict inclusion criteria describing 275 patients. Macroprolactinoma was more common in girls (78.7% [95% CI 70.5-85.9]) than boys and was more frequent than microprolactinoma (56.6% [95% CI 48.4-64.5]). In males, only 6/57 (10.5%) of tumours were microprolactinoma as compared to 102/198 (51.5%) microprolactinoma in females (risk difference -0.460; [95% CI -0.563 to -0.357]; p < .001). Surgery was first-line therapy in 18.9% patients, with another 15.4% requiring it as a second line (overall 31.3%). CONCLUSIONS: Macroprolactinoma, particularly if >20 mm, usually requires multimodal therapy including surgical intervention. While overall prolactinomas in <20 years age group are more common in females, the proportion of macroprolactinoma vs microprolactinoma is greater in males, particularly for large invasive tumours. Microprolactinoma is a rare diagnosis in adolescent males.


Asunto(s)
Neoplasias Hipofisarias , Prolactinoma , Adolescente , Adulto , Factores de Edad , Cabergolina , Agonistas de Dopamina , Femenino , Humanos , Masculino , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/terapia , Prolactina , Prolactinoma/patología , Prolactinoma/terapia , Adulto Joven
9.
Acta Neuropathol ; 141(3): 431-453, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33449170

RESUMEN

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.


Asunto(s)
Conectina/genética , Miotonía Congénita/diagnóstico , Miotonía Congénita/genética , Miotonía Congénita/patología , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación Missense , Adulto Joven
10.
Pediatr Hematol Oncol ; 38(8): 707-721, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33900873

RESUMEN

High grade gliomas (HGG) have a dismal prognosis with survival rates of 15-35%. Approximately 10-12% of pediatric HGG occur in young children and their molecular biology and clinical outcomes differ from those arising at older ages. We report on four children aged <5 years newly diagnosed with non-brainstem HGG between 2011 and 2018 who were treated with surgery and BBSFOP chemotherapy. Two died of tumor progression. The other two are still alive without radiotherapy at 3.8 and 3.9 years from diagnosis: one of whom remains disease-free off treatment; and the other one, whose tumor harbored a KCTD16:NTRK2 fusion, went on to receive larotrectinib. Additionally we review the general management, outcomes and latest updates in molecular biology and targeted therapies for young children with HGG. Infant gliomas can be stratified in molecular subgroups with clinically actionable oncogenic drivers. Chemotherapy-based strategies can avoid or delay the need for radiotherapy in young children with HGG. Harnessing the potential of NTRK, ALK, ROS1 and MET inhibitors offers the opportunity to optimize the therapeutic armamentarium to improve current outcomes for these children.


Asunto(s)
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Preescolar , Glioma/genética , Glioma/terapia , Humanos , Lactante
11.
Acta Neuropathol ; 139(2): 277-286, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31732806

RESUMEN

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40 years (range 15-61 years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2 bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48 months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.


Asunto(s)
Neoplasias Encefálicas/genética , Mutación/genética , Glándula Pineal , Tumor Rabdoide/genética , Tumor Rabdoide/patología , Proteína SMARCB1/genética , Adolescente , Adulto , Factores de Edad , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tumor Rabdoide/mortalidad , Tasa de Supervivencia , Adulto Joven
12.
J Inherit Metab Dis ; 43(5): 1002-1013, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32187699

RESUMEN

In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings.


Asunto(s)
Glucanos/metabolismo , Enfermedad del Almacenamiento de Glucógeno/genética , Enfermedad del Almacenamiento de Glucógeno/metabolismo , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/genética , Niño , Preescolar , Femenino , Humanos , Inflamación/patología , Masculino , Músculo Esquelético/patología , Enfermedades Musculares/patología , Reinfección/patología
13.
Pediatr Blood Cancer ; 67(7): e28407, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32426927

RESUMEN

Little is known about pseudoprogression in brain tumours other than gliomas. A 9-year-old male child with a pineal teratoma/germinoma underwent surgical resection followed by adjuvant chemo-radiotherapy. The magnetic resonance imaging scan 4 months post-radiotherapy showed a contrast-enhancing lesion within the surgical cavity suspicious of recurrence. These radiological findings subsequently resolved without any specific intervention. The child continues in remission 2 years post-treatment. This case illustrates the occurrence of pseudoprogression post-radiotherapy in intracranial GCT and highlights an unmet need for greater implementation of functional imaging techniques in paediatric neuro-oncology to avoid undue discontinuation of effective treatments or inappropriate enrolment in clinical trials.


Asunto(s)
Imagen por Resonancia Magnética/métodos , Imagen Molecular/métodos , Neoplasias de Células Germinales y Embrionarias/patología , Pinealoma/patología , Radioterapia Adyuvante/métodos , Teratoma/patología , Niño , Progresión de la Enfermedad , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/diagnóstico por imagen , Neoplasias de Células Germinales y Embrionarias/radioterapia , Pinealoma/diagnóstico por imagen , Pinealoma/radioterapia , Pronóstico , Teratoma/diagnóstico por imagen , Teratoma/radioterapia
14.
Br J Neurosurg ; 34(5): 537-542, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31079493

RESUMEN

We describe the case of a 65-year-old lady who presented with mutism and a right hemiparesis. Imaging showed a severe spontaneous tension pneumocephalus. The cause was diagnosed as Ecchordosis physaliphora (EP). EP is a rare cystic congenital hamartomatous benign notochordal tumor (BNCT) arising from an ectopic notochordal remnant. To the authors' knowledge, this is the first case of EP to be described in the literature which presented with a life-threatening but treatable condition of severe tension pneumocephalus.


Asunto(s)
Enfermedades del Sistema Nervioso Central , Hamartoma , Neumocéfalo , Anciano , Femenino , Humanos , Notocorda , Neumocéfalo/diagnóstico por imagen , Neumocéfalo/etiología , Neumocéfalo/cirugía
15.
J Neural Transm (Vienna) ; 126(3): 327-337, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30730007

RESUMEN

Early detection and accurate diagnosis of neurodegenerative disorders may provide better epidemiological data, closer monitoring of disease progression and enable more specialised intervention. We analysed the clinical records and pathology of brain donations from 180 patients from two Brains for Dementia Research cohorts to determine the agreement between in-life clinical diagnosis and post-mortem pathological results. Clinical diagnosis was extracted from medical records and cases assigned into broad clinical groups; control, Alzheimer's disease (AD), vascular dementia (CVD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and combined diseases. Pathology was assessed blindly, and cases categorised into; control, intermediate AD, severe AD, CVD, AD and CVD combined, DLB, AD and DLB combined and frontotemporal lobar degeneration (FTLD), according to the major contributing pathologies. In more than a third of cases clinical diagnosis was different from final neuropathological diagnosis. The majority of AD, DLB and control clinical groups matched the pathological diagnosis; however, thirty-five percent of clinical AD cases showed additional prominent CVD or DLB pathology which had not been diagnosed clinically and twenty-five percent of clinical control cases were found to have intermediate Tau pathology (modified Braak stage III-IV) or CVD. CVD and AD + CVD clinical groups showed an average of only thirty-two percent pathological correlation, the majority actually having no CVD, and fifty-three percent of pathologically identified FTLD cases had been incorrectly clinically diagnosed. Our results underlie the importance of neuropathological confirmation of clinical diagnosis. The relatively low accuracy of clinical diagnosis demonstrates the need for standardised and validated diagnostic assessment procedures.


Asunto(s)
Demencia/diagnóstico , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/patología , Neurología/normas , Patología Clínica/normas , Demencia/etiología , Demencia/patología , Humanos , Enfermedades Neurodegenerativas/complicaciones , Reproducibilidad de los Resultados
16.
Neuropathology ; 39(2): 135-140, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30847986

RESUMEN

Sporadic prion diseases are fatal neurodegenerative disorders characterized clinically by rapidly progressive dementia and myoclonus. Variably protease-sensitive prionopathy (VPSPr) is a recently identified sporadic human prion disorder that may present with a lengthy atypical clinical history. Here, we describe a case of VPSPr in a patient with a long history of suspected frontotemporal dementia (FTD). A 61-year-old man presented with speech difficulties, including naming objects and constructing multipart sentences, while there was no difficulty in comprehension. Movement abnormalities included slightly jerky pursuit, minor dysmetria of saccades and brisk reflexes. There was no family history of dementia. Later he developed swallowing difficulties and the possibility of FTD with motor neuron disease was suspected. He died at the age of 71 and his brain was donated to the London Neurodegenerative Diseases Brain Bank. The brain (1004 g) showed mild to moderate atrophy, predominantly in the frontal lobe. Histology revealed moderate spongiform microvacuolation mostly affecting the frontal and parietal cortices, but also present focally in the basal ganglia and the cerebellum. Only mild Alzheimer pathology was found by extensive immunohistochemistry, in keeping with BrainNet Europe stage II. Trans-activation response DNA-binding protein 43 kDa and α-synuclein immunostains were negative. Immunostaining for prion protein (PrP) showed granular/synaptic positivity in a patchy distribution, mainly within the deeper cortex, and also revealed microplaques in the cerebellum and basal ganglia. Western blotting confirmed a low molecular weight protease-resistant PrP band with a faint ladder-like pattern in the absence of types 1 and 2 isoforms. These features are diagnostic of VPSPr. VPSPr can mimic various neurodegenerative conditions; diagnosis requires both PrP immunohistochemistry and Western blotting. The presence of patchy spongiform change in the absence of other neurodegenerative pathology should raise suspicion of VPSPr, even in elderly patients with a lengthy clinical history.


Asunto(s)
Encéfalo/patología , Demencia Frontotemporal/patología , Enfermedades por Prión/patología , Anciano , Encéfalo/metabolismo , Diagnóstico Diferencial , Endopeptidasa K/administración & dosificación , Demencia Frontotemporal/metabolismo , Humanos , Masculino , Enfermedades por Prión/metabolismo , Proteínas Priónicas/metabolismo
18.
Pediatr Nephrol ; 33(3): 439-446, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29032433

RESUMEN

BACKGROUND: A 7-month-old male infant was admitted because he was suffering from nephrotic syndrome, along with encephalomyopathy, hypertrophic cardiomyopathy, clinically suspected deafness and retinitis pigmentosa, and an elevated serum lactate level. METHODS: Coenzyme Q10 supplementation was started because of the clinical suspicion of primary CoQ10 deficiency. Despite intensive efforts, he passed away 4 weeks after admission. RESULTS: The results of genetic tests, available postmortem, explored two hitherto undescribed mutations in the PDSS2 gene. Both were located within the polyprenyl synthetase domain. Clinical exome sequencing revealed a heterozygous missense mutation in exon 3, and our in-house joint-analysis algorithm detected a heterozygous large 2923-bp deletion that affected the 5 prime end of exon 8. Other causative defects in the CoQ10 and infantile nephrosis-related genes examined were not found. A postmortem histological, immunohistochemical, and electron microscopic evaluation of the glomeruli revealed collapsing-sclerosing lesions consistent with diffuse mesangial sclerosis. The extrarenal alterations included hypertrophic cardiomyopathy and diffuse alveolar damage. A histological evaluation of the central nervous system and skeletal muscles did not demonstrate any obvious abnormality. CONCLUSIONS: Until now, the clinical features and the mutational status of 6 patients with a PDSS2 gene defect have been reported in the English literature. Here, we describe for the first time detailed kidney morphology features in a patient with nephrotic syndrome carrying mutations in the PDSS2 gene.


Asunto(s)
Transferasas Alquil y Aril/genética , Ataxia/genética , Riñón/patología , Enfermedades Mitocondriales/genética , Debilidad Muscular/genética , Síndrome Nefrótico/genética , Esclerosis/genética , Ubiquinona/deficiencia , Ataxia/complicaciones , Autopsia , Resultado Fatal , Pruebas Genéticas/métodos , Humanos , Lactante , Masculino , Enfermedades Mitocondriales/complicaciones , Debilidad Muscular/complicaciones , Mutación , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/etiología , Esclerosis/complicaciones , Ubiquinona/análogos & derivados , Ubiquinona/genética , Ubiquinona/uso terapéutico
19.
Childs Nerv Syst ; 34(12): 2519-2523, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30062591

RESUMEN

INTRODUCTION: Arachnoid cysts (ACs) account for a small proportion of all intracranial lesions. They are often incidental but can become symptomatic and even cause a threat to life. Symptoms are usually due to direct compression of neural elements and/or raised intracranial pressure. CASE REPORT: We report the case of an infant with an enlarging posterior fossa arachnoid cyst (PFAC) causing torticollis and gastro-oesophageal reflux (GOR), the combination of which had been previously unreported in this context. Endoscopic fenestration and cyst decompression were followed by complete resolution of the symptoms. We discuss the possible mechanisms of torticollis and GOR in this context.


Asunto(s)
Quistes Aracnoideos/complicaciones , Reflujo Gastroesofágico/etiología , Tortícolis/etiología , Quistes Aracnoideos/cirugía , Fosa Craneal Posterior/patología , Descompresión Quirúrgica , Humanos , Hidrocefalia/etiología , Lactante , Complicaciones Posoperatorias/etiología
20.
Brain ; 139(Pt 3): 765-81, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26917586

RESUMEN

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.


Asunto(s)
Agenesia del Cuerpo Calloso/diagnóstico , Agenesia del Cuerpo Calloso/genética , Autofagia/genética , Catarata/diagnóstico , Catarata/genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Proteínas/genética , Agenesia del Cuerpo Calloso/complicaciones , Animales , Proteínas Relacionadas con la Autofagia , Catarata/complicaciones , Preescolar , Estudios Transversales , Drosophila melanogaster , Femenino , Hipocampo/patología , Humanos , Proteínas de Membrana de los Lisosomas , Masculino , Mutación/genética , Trastornos del Neurodesarrollo/complicaciones , Estudios Retrospectivos , Proteínas de Transporte Vesicular
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA