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1.
Parkinsonism Relat Disord ; 123: 106069, 2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38493523

RESUMEN

Corticobasal syndrome is generally considered to be a sporadic condition. There are familial and isolated genetic cases, associated with GRN, MAPT, c9orf72 or PNRP variants. Some reports implicate other genes: LRRK2, CHMP2B, GBA, CYP27A1, PSEN1, APP, TARDBP and TBK1. Here, we report a case of a patient carrying a SQSTM1 Pro392Leu variant. We report a 57-year-old right-handed-woman with a history of progressive speech impairment, marked right side rigidity and bradykinesia, with rest tremor and stimulus sensitive myoclonus. She had predominantly right-sided apraxia. She had right side agraphestesia and astereognosis. MRI showed asymmetrical left frontotemporoparietal atrophy. DaTSCAN showed predominantly left involvement, PiB-PET was negative. CSF NfL was of 9356.5pg/mL. She carried a heterozygous variant P392L in SQSTM1. This case report expands the spectrum of phenotypes associated with SQSTM1 pathogenic variants. It also expands the list of genes associated with corticobasal syndrome, supporting the involvement of the ubiquitin-proteasome system in this condition.

2.
Alzheimers Res Ther ; 16(1): 66, 2024 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-38539243

RESUMEN

BACKGROUND: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. METHODS: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. RESULTS: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. CONCLUSIONS: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.


Asunto(s)
Demencia Frontotemporal , Masculino , Humanos , Femenino , Progranulinas/genética , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Péptidos y Proteínas de Señalización Intercelular/genética , Virulencia , Mutación/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética
3.
Acta Neurol Belg ; 124(1): 49-54, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37392320

RESUMEN

BACKGROUND: Familial cerebral cavernous malformations (FCCM) is a rare autosomal dominant disease, characterized by vascular malformations that can lead to macro and microhemorrhages. The neurocognitive impact of FCCM is still underrecognized. METHODS: We report the clinical, neurocognitive, imaging and genetic data of a three generation family with FCCM. RESULTS: A 63-year-old man (proband) had progressive memory impairment since the last year. Neurologic exam was unremarkable. Brain MRI showed multiple large cavernomas (mainly in the pons, left temporal, and right temporo-parietal) and scattered microhemorrhages. Neuropsychological assessment mainly revealed left frontal and right temporo-parietal dysfunction. A 41-year-old daughter, presented with headache, vertigo and memory complaints in the last 2 years. Neurological examination revealed left central facial paralysis. Brain MRI showed two small right parietal and internal capsule cavernomas, as well as microhemorrhages. Neuropsychological assessment showed moderate temporal neocortical left dysfunction. A 34-year-old daughter had recurrent headache and memory complaints, with unremarkable neurological exam. Brain MRI revealed two large cavernomas (left fronto-orbitary and inferior temporal), with few microhemorrhages. Neuropsychological assessment was normal. A granddaughter had mild headaches and a small right cerebellar cavernoma, without microhemorrhages. Neuropsychological assessment showed mild temporal neocortical left dysfunction. A nonsense variant, c.55C > T; p.R19* generating a premature stop codon in CCM2 gene shared by all affected family members was identified. CONCLUSIONS: Neuropsychological evaluation showed that memory complaints and cognitive impairment could be an important unrecognized finding in FCCM. Its pathophysiological mechanisms are still unknown but the role of recurrent microhemorrhages could provide an interesting hypothesis.


Asunto(s)
Hemangioma Cavernoso del Sistema Nervioso Central , Masculino , Humanos , Persona de Mediana Edad , Adulto , Hemangioma Cavernoso del Sistema Nervioso Central/complicaciones , Hemangioma Cavernoso del Sistema Nervioso Central/diagnóstico por imagen , Proteína KRIT1/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas Proto-Oncogénicas/genética , Linaje , Imagen por Resonancia Magnética , Cefalea
4.
Eur J Med Chem ; 261: 115837, 2023 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-37837673

RESUMEN

The aggregation of wild-type transthyretin (TTR) and over 130 genetic TTR variants underlies a group of lethal disorders named TTR amyloidosis (ATTR). TTR chemical chaperones are molecules that hold great promise to modify the course of ATTR progression. In previous studies, we combined rational design and molecular dynamics simulations to generate a series of TTR selective kinetic stabilizers displaying exceptionally high affinities. In an effort to endorse the previously developed molecules with optimal pharmacokinetic properties, we conducted structural design optimization, leading to the development of PITB. PITB binds with high affinity to TTR, effectively inhibiting tetramer dissociation and aggregation of both the wild-type protein and the two most prevalent disease-associated TTR variants. Importantly, PITB selectively binds and stabilizes TTR in plasma, outperforming tolcapone, a drug currently undergoing clinical trials for ATTR. Pharmacokinetic studies conducted on mice confirmed that PITB exhibits encouraging pharmacokinetic properties, as originally intended. Furthermore, PITB demonstrates excellent oral bioavailability and lack of toxicity. These combined attributes position PITB as a lead compound for future clinical trials as a disease-modifying therapy for ATTR.


Asunto(s)
Neuropatías Amiloides Familiares , Prealbúmina , Ratones , Animales , Prealbúmina/metabolismo , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/metabolismo , Tolcapona/uso terapéutico , Simulación de Dinámica Molecular
6.
Int J Mol Sci ; 25(1)2023 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-38203682

RESUMEN

In Portugal, heterozygous loss-of-function mutations in the progranulin (GRN) gene account for approximately half of the genetic mediated forms of frontotemporal dementia (FTD). GRN mutations reported thus far cause FTD through a haploinsufficiency disease mechanism. Herein, we aim to unveil the GRN mutation spectrum, investigated in 257 FTD patients and 19 family members from the central/north region of Portugal using sequencing methods. Seven different pathogenic variants were identified in 46 subjects including 40 patients (16%) and 6 relatives (32%). bvFTD was the most common clinical presentation among the GRN mutation patients, who showed a global pattern of moderate-to-severe frontotemporoparietal deficits in the neuropsychological evaluation. Interestingly, two mutations were novel (p.Thr238Profs*18, p.Leu354Profs*16), and five were previously described, although three of them only in the Portuguese population, suggesting a population-specific GRN mutational spectrum. The subjects harboring a GRN mutation showed a significant reduction in serum PGRN levels, supporting the pathogenic nature of these variants. This work broadens the mutation spectrum of GRN and the identification of the underlying GRN mutations provided an accurate genetic counselling and allowed the enrolment of subjects with GRN mutations (both asymptomatic and symptomatic) in ongoing clinical trials, which is essential to test new drugs for the disease.


Asunto(s)
Demencia Frontotemporal , Enfermedad de Pick , Humanos , Demencia Frontotemporal/genética , Mutación , Portugal , Progranulinas/genética
7.
J Med Chem ; 65(21): 14673-14691, 2022 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-36306808

RESUMEN

Transthyretin amyloidosis (ATTR) is a group of fatal diseases described by the misfolding and amyloid deposition of transthyretin (TTR). Discovering small molecules that bind and stabilize the TTR tetramer, preventing its dissociation and subsequent aggregation, is a therapeutic strategy for these pathologies. Departing from the crystal structure of TTR in complex with tolcapone, a potent binder in clinical trials for ATTR, we combined rational design and molecular dynamics (MD) simulations to generate a series of novel halogenated kinetic stabilizers. Among them, M-23 displays one of the highest affinities for TTR described so far. The TTR/M-23 crystal structure confirmed the formation of unprecedented protein-ligand contacts, as predicted by MD simulations, leading to an enhanced tetramer stability both in vitro and in whole serum. We demonstrate that MD-assisted design of TTR ligands constitutes a new avenue for discovering molecules that, like M-23, hold the potential to become highly potent drugs to treat ATTR.


Asunto(s)
Neuropatías Amiloides Familiares , Prealbúmina , Humanos , Prealbúmina/química , Amiloide/metabolismo , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/metabolismo , Tolcapona/uso terapéutico , Cinética
8.
Neurogenetics ; 23(4): 279-283, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36114914

RESUMEN

Dementia with Lewy bodies is a neurodegenerative disease, sharing features with Parkinson's and Alzheimer's diseases. We report a case of a patient dementia with Lewy bodies carrying combined PSEN1 and ATP7B mutations. A man developed dementia with Lewy bodies starting at the age of 60 years. CSF biomarkers were of Alzheimer's disease and DaTSCAN was abnormal. Whole-exome sequencing revealed a heterozygous p.Ile408Thr PSEN1 variant and a homozygous p.Arg616Trp ATP7B variant. This case reinstates the need of considering ATP7B mutations when evaluating a patient with parkinsonism and supports p.Ile408Thr as a pathogenic PSEN1 variant.


Asunto(s)
Enfermedad de Alzheimer , Enfermedad por Cuerpos de Lewy , Enfermedades Neurodegenerativas , Humanos , Enfermedad por Cuerpos de Lewy/complicaciones , Enfermedad por Cuerpos de Lewy/genética , Secuenciación del Exoma , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Estudios de Asociación Genética , Presenilina-1/genética
9.
Biomedicines ; 10(8)2022 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-36009452

RESUMEN

Mutations in granulin (GRN) have been associated with neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). In Portugal, GRN mutations account for around half of all FTLD cases with known genetic origin. Here, we describe the generation and characterization of three human-induced pluripotent stem cell (hiPSC) lines from a Portuguese family harboring heterozygous and homozygous GRN mutation. hiPSCs were reprogrammed from human dermal fibroblasts by episomal nucleofection of the Yamanaka factors. The new generated lines were positive for pluripotency markers, could be further differentiated to cells expressing all trilineage markers, and presented a normal karyotype. They were also capable of differentiating into 3D brain organoids and presented a significant decrease in progranulin protein levels. Hence, these cell lines constitute suitable new tools to elucidate the pathophysiological mechanisms associated with the GRN mutations in the context of FTLD.

10.
Front Neurol ; 13: 886379, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35873773

RESUMEN

Introduction: Frontotemporal dementia (FTD) is considered to be part of a continuum with amyotrophic lateral sclerosis (ALS). Many genes are associated with both ALS and FTD. Yet, many genes associated with ALS have not been shown to cause FTD. We aimed to study a Portuguese cohort of FTD patients, searching for variants in genes associated with both FTD and/or ALS. Methods: We included 57 thoroughly characterized index FTD patients from our memory clinic, who were not carriers of pathogenic variants in GRN, MAPT or C9orf72. We performed exome sequencing and 1) prioritized potential FTD and ALS causing variants by using Exomiser to annotate and filter results; and 2) looked specifically at rare variability in genes associated with FTD (excluding GRN, MAPT and C9ORF72) and/or ALS. Results: We identified 13 rare missense variants in 10 patients (three patients had two variants) in the following genes: FUS, OPTN, CCNF, DCTN1, TREM2, ERBB4, ANG, CHRNA4, CHRNB4 and SETX. We found an additional frameshift variant on GLT8D1 in one patient. One variant (ERBB4 p.Arg1112His) gathered enough evidence to be classified as likely pathogenic by the ACMG criteria. Discussion: We report, for the first time, an expanded study of genes known to cause FTD-ALS, in the Portuguese population. Potentially pathogenic variants in ERBB4, FUS, SETX, ANG, CHRNA4 and CHRNB4 were identified in FTD patients. These findings provide additional evidence for the potential role of rare variability in ALS-associated genes in FTD, expanding the genetic spectrum between the two diseases.

11.
Biomedicines ; 10(2)2022 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-35203434

RESUMEN

The choroid plexus (CP), located in each of the four ventricles of the brain, is formed by a monolayer of epithelial cells that surrounds a highly vascularized connective tissue with permeable capillaries. These cells are joined by tight junctions forming the blood-cerebrospinal fluid barrier (BCSFB), which strictly regulates the exchange of substances between the blood and cerebrospinal fluid (CSF). The primary purpose of the CP is to secrete CSF, but it also plays a role in the immune surveillance of the central nervous system (CNS) and in the removal of neurotoxic compounds from the CSF. According to recent findings, the CP is also involved in the modulation of the circadian cycle and neurogenesis. In diseases such as Alzheimer's disease (AD), the function of the CP is impaired, resulting in an altered secretory, barrier, transport, and immune function. This review describes the current state of knowledge concerning the roles of the CP and BCSFB in the pathophysiology of AD and summarizes recently proposed therapies that aim to restore CP and BCSFB functions.

12.
Eur J Neurol ; 29(5): 1524-1528, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35020242

RESUMEN

BACKGROUND AND PURPOSE: TP73 was recently reported to cause amyotrophic lateral sclerosis (ALS). ALS and frontotemporal dementia (FTD) are considered to form part of a continuum. We aimed to investigate whether TP73 variants may be associated with FTD. METHODS: We studied a thoroughly investigated cohort of 65 Portuguese patients with frontotemporal dementia using whole-exome sequencing. The patients had no other known genetic cause for their disease (C9orf72 expansion was also excluded). RESULTS: Of the 65 patients studied, two had rare variants in TP73 (p.Gly605Ser and p.Arg347Trp). Both variants had minor allele frequency <0.001 and were predicted to be pathogenic in silico. The two patients displayed a phenotype that included predominant language impairment, suggestive of non-fluent progressive aphasia. CONCLUSION: We show that two thoroughly studied patients without other known genetic changes harbored TP73 rare variants, which are pathogenic in silico. This adds evidence to support the role of TP73 in the ALS-FTD spectrum, especially in primary progressive aphasia cases.


Asunto(s)
Esclerosis Amiotrófica Lateral , Afasia Progresiva Primaria , Demencia Frontotemporal , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Afasia Progresiva Primaria/genética , Proteína C9orf72/genética , Estudios de Cohortes , Demencia Frontotemporal/genética , Humanos , Fenotipo , Proteína p53 Supresora de Tumor
13.
Eur J Neurol ; 29(1): 36-46, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34375485

RESUMEN

BACKGROUND AND PURPOSE: Neurofilament light chain (NfL) has recently been proposed as a promising biomarker in frontotemporal dementia (FTD). We investigated the correlation of both cerebrospinal fluid (CSF) and serum NfL with detailed neuropsychological data and cognitive decline in a cohort of sporadic and familial FTD. METHODS: CSF and serum NfL, as well as conventional CSF Alzheimer's disease (AD) biomarkers (Aß42, t-Tau, p-Tau181), were determined in 63 FTD patients (30 sporadic-FTD, 20 with progranulin (GRN) mutations [FTD-GRN], 13 with chromosome 9 open reading frame 72 [C9orf72] expansions [C9orf72-FTD]), 37 AD patients, and 31 neurologic controls. Serum NfL was also quantified in 37 healthy individuals. Correlations between baseline CSF and serum NfL levels, standardized neuropsychological tests, and the rate of cognitive decline in FTD patients were assessed. RESULTS: CSF and serum NfL presented with significantly higher levels in FTD than in AD patients and both control groups. Within FTD subtypes, genetic cases, and particularly FTD-GRN, had higher CSF and serum NfL levels. Significant correlations between NfL levels and overall cognitive function, abstract reasoning (CSF and serum), executive functions, memory, and language (serum) were found. A relationship between increased baseline CSF and serum NfL and a decay in cognitive performance over time was also observed. CONCLUSIONS: Our findings highlight the potential of serum NfL as a useful surrogate end point of disease severity in upcoming targeted treatments.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Demencia Frontotemporal , Enfermedad de Alzheimer/líquido cefalorraquídeo , Disfunción Cognitiva/genética , Demencia Frontotemporal/líquido cefalorraquídeo , Demencia Frontotemporal/genética , Humanos , Filamentos Intermedios , Proteínas tau/líquido cefalorraquídeo
14.
Neurogenetics ; 23(1): 1-9, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34851492

RESUMEN

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common inherited cerebral small vessel disease. It is caused by mutations in the NOTCH3 gene, which encodes a membranebound receptor protein with three main distinct functional domains. Thus far, several different NOTCH3 mutations, most of them cysteine altering variants, have been described and although they tend to cluster in certain exons, their distribution varies in different geographically populations. Therefore, in this study, we describe the mutation analysis of NOTCH3 gene in 24 Portuguese families with small vessel disease suspected to have CADASIL from the central region of Portugal. The genetic analysis revealed 15 different heterozygous variants, eight pathogenic cysteine altering variants, six cysteine sparing variants and one nonsense variant, located mainly in the exons 4, 8 and 11. Thus, in our population, the genetic testing should initially be focused on these exons. In addition, the genetic findings broaden the mutational and clinical spectrum of CADASIL related phenotype and provide additional evidences for genetic counseling and clinical management.


Asunto(s)
CADASIL , Receptor Notch3 , CADASIL/genética , CADASIL/patología , Humanos , Imagen por Resonancia Magnética , Mutación , Fenotipo , Portugal , Receptor Notch3/genética
15.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-34502397

RESUMEN

Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo.


Asunto(s)
Prealbúmina/metabolismo , alfa 1-Antitripsina/metabolismo , Factores de Edad , Amiloide/metabolismo , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/fisiopatología , Amiloidosis/genética , Amiloidosis/fisiopatología , Animales , Modelos Animales de Enfermedad , Femenino , Fibrinolisina , Hepatocitos/metabolismo , Humanos , Masculino , Ratones , Ratones Transgénicos , Prealbúmina/genética , Prealbúmina/fisiología , Proteolisis , alfa 1-Antitripsina/fisiología
16.
Neuromuscul Disord ; 31(9): 891-895, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34210540

RESUMEN

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory vasculopathy characterized by systemic vasculitis, early-onset stroke and livedo racemosa. We report a family cohort of 3 patients with ADA2 compound heterozygous mutation p.[Thr360Ala] and [Gly383Ser]. Two of them had progressive involvement of the peripheral nervous system in the fourth decade, both after stroke. In one patient, clinical and neurophysiological studies showed progression of mononeuritis multiplex to chronic axonal sensorimotor polyneuropathy, nerve biopsy had features of small vessel vasculitic neuropathy, and muscle biopsy disclosed neurogenic atrophy with reinnervation. The second patient presented with progressive sensory symptoms of the lower limbs and chronic axonal sensorimotor polyneuropathy in nerve conduction studies. These two patients had absent plasma ADA2 activity. The third patient had no neurological affection despite low, but not absent, plasma ADA2 activity. Patients were started on a tumor necrosis factor (TNF) inhibitor, which has presumed benefits for the vasculitic phenotype of DADA2.


Asunto(s)
Adenosina Desaminasa/deficiencia , Enfermedades del Sistema Nervioso Periférico/etiología , Vasculitis/etiología , Adulto , Estudios de Cohortes , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular , Masculino , Mutación , Fenotipo , Adulto Joven
17.
J Clin Neurosci ; 88: 34-38, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33992200

RESUMEN

BACKGROUND: APOE ε4 is independently associated with lobar intracranial hemorrhages (ICH). Although the ε4 allele enhances amyloid deposition in blood vessels, the ε2 allele predisposes to vasculopathic changes leading to rupture of amyloid laden vessels. Thus, ε4 and ε2 carriers might have increased susceptibility to ICH. We aimed to study the impact of the apolipoprotein E alleles in the development of symptomatic ICH (sICH). METHODS: We included 384 consecutive ischemic anterior circulation stroke patients submitted to thrombolysis between January 2014 and March 2016. Admission CT-scans were reviewed to calculate the ASPECTS. Patients were followed for up to at least 6 months post-stroke or until death. Outcome was development of sICH, defined according to the ECASS III. RESULTS: Considering APOE genotyping, three patients had ε2/ε2, four had ε2/ε4, 38 had ε2/ε3, 284 had ε3/ε3, 51 had ε3/ε4 and four had ε4/ε4. sICH was associated with sex and diabetes. In multivariate analysis, sICH was not associated with carrying one or more ε4 alleles (OR: 0.483, 95%CI = [0.059, 3.939], p = 0.497) nor with carrying one or more ε2 alleles (OR: 1.369, 95%CI = [0.278, 6.734], p = 0.699). CONCLUSION: No association was found between APOE genotype and the development of symptomatic intracranial hemorrhage.


Asunto(s)
Apolipoproteínas E/genética , Hemorragia Cerebral/etiología , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Activador de Tejido Plasminógeno/uso terapéutico , Anciano , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Terapia Trombolítica/métodos
18.
Case Rep Nephrol Dial ; 11(3): 340-347, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35083289

RESUMEN

Deficiency of adenosine deaminase 2 (DADA2) is a unique monogenic autoinflammatory disease caused by autosomal recessive loss-of-function mutations in the CECR1 gene which presents as childhood-onset small- and medium-vessel vasculitis. Previously, many of these patients were misdiagnosed and thought to have clinical features of systemic polyarteritis nodosum, which negatively influenced its outcome, since TNF inhibitors seem to have efficacy on the vasculitic phenotype of DADA2. We present a case of a 28-year-old woman with a lifelong unknown syndrome and unique clinical manifestations recently recognized as DADA2. The first manifestation, at 3 months of age, was an episode of facial paralysis during which renovascular hypertension was diagnosed. Later, she developed episodes of prolonged fever, polyarthritis, Raynaud's phenomenon, gastrointestinal bleeding, and intracerebral hemorrhage. This inflammatory state ultimately led to the development of amyloid A amyloidosis and renal insufficiency.

19.
Neurobiol Aging ; 99: 99.e15-99.e22, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32972771

RESUMEN

Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.


Asunto(s)
Apolipoproteínas E/genética , Demencia Frontotemporal/genética , Estudios de Asociación Genética , Variación Genética/genética , Progranulinas/genética , Proteína p53 Supresora de Tumor/genética , Proteína C9orf72 , Femenino , Heterocigoto , Humanos , Masculino , Fenotipo
20.
J Neurol ; 268(4): 1453-1460, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33216222

RESUMEN

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common inherited cerebral small vessel disease and is caused by mutations in the NOTCH3 gene. Interestingly, CADASIL patients present a large phenotypic variability even harboring the same pathogenic variant. We describe two CADASIL siblings with a particularly aggressive clinical phenotype characterized by early-onset stroke, gait disturbances and/or dementia, severe emotional dysregulation, and dysexecutive syndrome together with a severe white matter burden on MRI. The genetic analysis revealed the co-occurrence of NOTCH3 (p.Gly420Cys) and SQSTM1 (p.Ser275Phefs*17) pathogenic variants which might worsen the aggressiveness of disease progression in both siblings. Interestingly, to the best of our knowledge, mutations in SQSTM1 gene have never been described in CADASIL patients before. Curiously, both Notch3 and p62 encoded proteins have a key role in the autophagy-lysosomal pathway which is impaired in CADASIL patients. Thus, the contribution of SQSTM1 gene to the clinical heterogeneity of CADASIL patients, in particular for those who develop cognitive impairment or dementia at an early age, is certainly overlooked. Therefore, we advocate expanding the genetic analysis to other genes associated with the phenotype spectrum of CADASIL patients using NGS-customized gene panel.


Asunto(s)
CADASIL , Proteína Sequestosoma-1/genética , CADASIL/genética , Humanos , Imagen por Resonancia Magnética , Mutación , Fenotipo , Receptor Notch3/genética
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