RESUMO
Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD and parkinsonism to perinatal lethality with neurological manifestations across 15 unrelated pedigrees with 22 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants impair mitochondrial membrane potential, dynamics and mitophagy in patient-derived fibroblasts. Additionally, we develop models of psmf1 knockdown Drosophila and Psmf1 conditional knockout mouse exhibiting age-dependent motor impairment, with diffuse gliosis in mice. These findings unequivocally link defective PSMF1 to early-onset PD and neurodegeneration and suggest mitochondrial dysfunction as a mechanistic contributor.
RESUMO
INTRODUCTION: Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype. METHODS: Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments. RESULTS: Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations. DISCUSSION: This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients. HIGHLIGHTS: This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.
Assuntos
Demência Frontotemporal , Lobo Temporal , Humanos , Masculino , Demência Frontotemporal/diagnóstico , Estudos Retrospectivos , Feminino , Lobo Temporal/patologia , Lobo Temporal/diagnóstico por imagem , Idoso , Pessoa de Meia-Idade , Testes Neuropsicológicos/estatística & dados numéricos , Atrofia/patologiaRESUMO
OBJECTIVE: Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by motor and early non-motor symptoms. The habenula is implicated in the pathophysiology of depression. This study investigates habenular volume in PD patients without clinical depression to show the changes in PD unrelated to depression. METHODS: The study used high-resolution 7 Tesla MRI data from the TRACK-PD study involving 104 PD patients and 44 healthy controls (HCs). The habenula was manually segmented, and volumes were measured, considering demographic data and depression scores via the Beck Depression Inventory (BDI). RESULTS: No significant correlation was found between habenular volume and BDI scores in PD patients or HCs. However, the PD group exhibited a significantly larger mean and right habenular volume than HCs. Although PD patients showed higher BDI scores, indicating more subthreshold depression, these did not correlate with the habenular volume. CONCLUSION: The results suggest that while the habenula may be involved in the symptoms of PD, its role in depression within this cohort is unclear. The changes might be related to the role of the habenula in motor symptoms. This study provides a new perspective on the role of the habenula in PD, but future research could lead to a greater understanding of the neuroanatomical features of the habenula in PD.
Assuntos
Depressão , Habenula , Imageamento por Ressonância Magnética , Doença de Parkinson , Humanos , Habenula/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Masculino , Feminino , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética/métodos , Idoso , Depressão/diagnóstico por imagemRESUMO
BACKGROUND AND PURPOSE: Studies have found that up to 73% of COVID-19 patients experience hyposmia. It is unclear if the loss of smell in COVID-19 is due to damage to the peripheral or central mechanisms. This study aimed to explore the impacts of COVID-19-induced hyposmia on brain structure and cognitive functions. METHODS: The study included 36 hyposmic (h-COV) and 21 normosmic (n-COV) participants who had recovered from mild COVID-19 infection, as well as 25 healthy controls (HCs). All participants underwent neurological examination, neuropsychiatric assessment and Sniffin' Sticks tests. High-resolution anatomical images were collected; olfactory bulb (OB) volume and cortical thickness were measured. RESULTS: Addenbrooke's Cognitive Examination-Revised total and language sub-scores were slightly but significantly lower in the h-COV group compared to the HC group (p = 0.04 and p = 0.037). The h-COV group exhibited poorer performance in the Sniffin' Sticks test terms of discrimination score, identification score and the composite score compared to the n-COV and HC groups (p < 0.001, p = 0.001 and p = 0.002 respectively). A decrease in left and right OB volumes was observed in the h-COV group compared to the n-COV and HC groups (p = 0.003 and p = 0.006 respectively). The cortical thickness analysis revealed atrophy in the left lateral orbitofrontal cortex in the h-COV group compared to HCs. A significant low positive correlation of varying degrees was detected between discrimination and identification scores and both OB and left orbital sulci. CONCLUSION: Temporary or permanent hyposmia after COVID-19 infection leads to atrophy in the OB and olfactory-related cortical structures and subtle cognitive problems in the long term.
RESUMO
BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease. METHODS: We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities. FINDINGS: Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I2=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31-81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71. INTERPRETATION: RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling. FUNDING: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council.
Assuntos
Doença de Parkinson , Proteínas rab de Ligação ao GTP , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Canadá/epidemiologia , Estudos de Casos e Controles , Sequenciamento do Exoma , Ligação Genética/genética , Predisposição Genética para Doença/genética , Genótipo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doença de Parkinson/genética , Proteínas rab de Ligação ao GTP/genética , TunísiaRESUMO
Introduction: Limbic encephalitis is a rapidly progressing disease that presents with seizures, psychiatric symptoms, and recent memory loss. Detection of more than one autoantibody is a rare condition in this disease where an underlying autoantibody is frequently detected. Although different autoantibodies have been reported in the literature, no case has been reported regarding the association of anti-γ-aminobutyric acid-beta-receptor (anti-GABABR) and anti-α-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (anti-AMPAR). Case: In this presentation, a 46-year-old female patient with subacute development of short-term memory loss and behavioral symptoms will be described. Anti-GABABR and anti-AMPAR were positive in the anti-neuronal antibody panel sent from the cerebrospinal fluid and serum. Small cell lung cancer was detected as a result of malignancy screening tests. The patient's complaints and autoantibody positivity regressed after immunotherapy. Conclusion: In this case report, a case with coexistence of anti-GABABR and anti-AMPAR antibodies, which has not been previously reported in the literature, is described. As more cases with the coexistence of these two antibodies are detected, knowledge on clinical aspect, laboratory and treatment will increase.
RESUMO
Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD. Methods: Affected probands from 130 multi-incident PD families underwent whole-exome sequencing and genotyping, Potential pathogenic variants in 61 RAB GTPases were genotyped in relatives to assess disease segregation. These variants were also genotyped in a larger case-control series, totaling 3,078 individuals (2,734 with PD). The single most significant finding was subsequently validated within genetic data (6,043 with PD). Clinical and pathologic findings were summarized for gene-identified patients, and haplotypes were constructed. In parallel, wild-type and mutant RAB GTPase structural variation, protein interactions, and resultant enzyme activities were assessed. Findings: We found RAB32 c.213C>G (Ser71Arg) to co-segregate with autosomal dominant parkinsonism in three multi-incident families. RAB32 Ser71Arg was also significantly associated with PD in case-control samples: genotyping and database searches identified thirteen more patients with the same variant that was absent in unaffected controls. Notably, RAB32 Ser71Arg heterozygotes share a common haplotype. At autopsy, one patient had sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In transfected cells the RAB32 Arg71 was twice as potent as Ser71 wild type to activate LRRK2 kinase. Interpretation: Our study provides unequivocal evidence to implicate RAB32 Ser71Arg in PD. Functional analysis demonstrates LRRK2 kinase activation. We provide a mechanistic explanation to expand and unify the etiopathogenesis of monogenic PD. Funding: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J. Fox Foundation for Parkinson's Research, and the UK Medical Research Council.
RESUMO
Parkinson's disease (PD), a widespread neurodegenerative disorder, often coexists with mood disorders. Degeneration of serotonergic neurons in brainstem raphe nuclei have been linked to depression and anxiety. Additionally, the locus coeruleus and its noradrenergic neurons are among the first areas to degenerate in PD and contribute to stress, emotional memory, motor, sensory, and autonomic symptoms. Another brain region of interest is habenula, which is especially related to anti-reward processing, and its function has recently been linked to PD and to mood-related symptoms. There are several neuroimaging studies that investigated role of the habenula in mood disorders. Differences in habenular size and hemispheric symmetry were found in healthy controls compared to individuals with mood disorders. The lateral habenula, as a link between the dopaminergic and serotonergic systems, is thought to contribute to depressive symptoms in PD. However, there is only one imaging study about role of habenula in mood disorders in PD, although the relationship between PD and mood disorders is known. There is little known about habenula pathology in PD but given these observations, the question arises whether habenular dysfunction could play a role in PD and the development of PD-related mood disorders. In this review, we evaluate neuroimaging techniques and studies that investigated the habenula in the context of PD and mood disorders. Future studies are important to understand habenula's role in PD patients with mood disorders. Thus, new potential diagnostic and treatment opportunities would be found for mood disorders in PD.
Assuntos
Habenula , Doença de Parkinson , Humanos , Transtornos do Humor , Emoções , Núcleos da RafeRESUMO
Objectives: Dysphagia is common in idiopathic Parkinson's disease (IPD) and is associated with impairments in both swallowing safety and swallowing efficiency. The goals of this study were to define post-swallow residue patterns in people with IPD and describe pathophysiological endoscopic findings affecting residue accumulation. Methods: This was a prospective single-blinded cross-sectional cohort study of patients with the diagnosis of IPD recruited from a Movement Disorder Clinic. Clinical variables included patient age, cognitive function, and measures of disease severity, and laryngoscopic examinations with a flexible endoscopic evaluation of swallowing (FEES) were completed for each patient. Visual Analysis of Swallowing Efficiency and Safety (VASES) was used to analyze FEES. Post-swallow residue outcomes and non-residue endoscopic outcomes including the Bowing index, Penetration Aspiration Scale (PAS) score, premature leakage, and build-up phenomenon were evaluated. Multiple regression models were used to evaluate factors affecting the residue at different anatomic levels. Results: Overall 53 patients completed the study. The multiple regression analyses showed a relation between (1) the presence of residue at the level of oropharynx and epiglottis with premature leakage, (2) the presence of residue at the level of the laryngeal vestibule and vocal folds with build-up phenomenon, and (3) the presence of residue at the level of the hypopharynx, laryngeal vestibule, and subglottis with airway invasion. Conclusion: Residue pattern during FEES is associated with specific swallow dysfunctions in IPD. Using residue localization and quantification may be a helpful tool in assessing the impact of targeted swallowing interventions in patients with IPD and dysphagia.
RESUMO
With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid, finely granulated, digital health measures are highly warranted to augment clinical and patient-reported outcome measures. Gait and balance disturbances most often present as the first signs of degenerative cerebellar ataxia and are the most reported disabling features in disease progression. Thus, digital gait and balance measures constitute promising and relevant performance outcomes for clinical trials.This narrative review with embedded consensus will describe evidence for the sensitivity of digital gait and balance measures for evaluating ataxia severity and progression, propose a consensus protocol for establishing gait and balance metrics in natural history studies and clinical trials, and discuss relevant issues for their use as performance outcomes.
RESUMO
Introduction: This study aimed to conduct the validity and reliability of the (Pictures of Facial Affect) POFA test for the Turkish population and contribute to increasing the number of tests that are still insufficient in our country. Methods: This descriptive, randomized controlled study was conducted in two steps, namely Step 1 (Pilot Study and Validity Studies) and Step 2 (Reliability Study Step). The number of participants was planned regarding the original study by which the POFA test was developed. The EYES test was also used for comparison. In the pilot study, the most widely identified emotions from 47 of 110 photos in the POFA test were chosen as the new POFA picture set to be used in the reliability and validity study under the name "POFA Test Short Form". A total of 100 participants, including 82 healthy volunteers and 18 essential tremor (ET) patients, were enrolled in the first step of the study. Another cohort of 22 healthy volunteers was enrolled in the second step of the study for test-retest reliability analysis. Results: A significant positive correlation was found between the total POFA Test Short Form and EYES Test scores in the healthy volunteer group in terms of criterion-related validity (r=0.44, p<0.01). There were statistically significant differences between healthy volunteers and ET groups regarding EYES Total, POFA Total, POFA Sadness, POFA Anger, and POFA Neutral scores. It was observed that the 47-item POFA Test Short Form total score showed skewness and kurtosis, which demonstrated suitability for clinical use. Conclusion: The POFA Test Short Form was found to be a valid and reliable assessment tool in the Turkish population to be used in studies on emotion recognition and was shown to be beneficial for the discrimination of healthy individuals and ET patients.
RESUMO
In this review, the history and current status of the topic of disconnection syndromes, which was introduced to the discipline of Behavioral Neurology by the founding father Norman Geschwind and that has become the dominant paradigm for the explanation of neuropsychiatric disorders with new developments, like network connectivity imaging in the living human brain are discussed.
RESUMO
The intermittent subcutaneous injection of apomorphine is highly effective in the management of motor and non-motor symptoms of Parkinson's disease. Although it has been shown that apomorphine injection can be safely used in selected cases at all stages of the disease, there is no consensus regarding intermittent administration strategies. This review aimed to discuss the indications for intermittent subcutaneous apomorphine use in clinical practice, possible side effects and their management, and contraindicated cases in light of the literature and to present practical recommendations for clinical practice.
RESUMO
Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slowly progressive disorder characterized by cerebellar ataxia, sensory neuropathy and bilateral vestibulopathy. Recently, a biallelic intronic AAGGG repeat expansion, (AAGGG)exp, in the Replication Factor C1 (RFC1) gene was identified as the cause of this disorder. In this study, we describe the phenotypic features of five patients from five different families diagnosed as CANVAS. The mean age at onset was 49.00 ± 9.05 years (between 34 and 56 years) and the most frequent presenting symptom in CANVAS was gait ataxia, followed by sensory disturbances. Persistent coughing was prominent in three patients, and it preceded the onset of ataxia and sensory symptoms in two patients. Parental consanguinity was present in three patients. Two patients showed symptoms or signs suggesting autonomic involvement. Sural nerve biopsy revealed axonal neuropathy in two patients. The mean age at onset was 49.00 ± 9.05 years (between 34 and 56 years) and the most frequent presenting symptom in CANVAS was gait ataxia, followed by sensory disturbances. Persistent coughing was prominent in three patients, and it preceded the onset of ataxia and sensory symptoms in two patients. Parental consanguinity was present in three patients. Two patients showed symptoms or signs suggesting autonomic involvement. Sural nerve biopsy revealed axonal neuropathy in two patients. Our study describes clinical findings, histopathological features and diagnostic clues of CANVAS from Turkey, a country with a high consanguineous marriage rate. Repeat expansion in the RFC1 gene should be considered in all cases with late-onset ataxia, especially when sensory disturbances, vestibular involvement and persistent coughing coexist.
Assuntos
Vestibulopatia Bilateral , Ataxia Cerebelar , Doenças do Sistema Nervoso Periférico , Doenças Vestibulares , Adulto , Ataxia/complicações , Vestibulopatia Bilateral/complicações , Vestibulopatia Bilateral/diagnóstico , Vestibulopatia Bilateral/genética , Ataxia Cerebelar/complicações , Ataxia Cerebelar/genética , Marcha Atáxica , Humanos , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/complicações , Transtornos de Sensação/complicações , Síndrome , Doenças Vestibulares/etiologiaRESUMO
INTRODUCTION: The majority of Parkinson's disease (PD) ensue late-onset with a complex spectrum of environmental and genetic risk factors. Awareness of genetic causes in patients with PD is essential for genetic counseling and future genotype-oriented therapeutic developments. METHODS: Large pathogenic changes in eight PD-related genes and small pathogenic sequence variants in 22 PD-related genes were investigated simultaneously in 82 PD patients from 79 families where clinical evaluations were performed. The phenotypic characteristics of the patients with molecular changes were examined for genotype-phenotype relations. RESULTS: Pathogenic variants in SNCA, PRKN, DJ-1, FBXO7, and GBA genes were determined in 25 patients from 24 families (24/79, 30%). Associated variants were found in PRKN in 14, SNCA in three, FBXO7 in two, and DJ-1 in one patient. A novel homozygous deletion (c.491delT, p.(V164Dfs*13) (SCV001733595)) leading to protein truncation in the PRKN gene was identified in two patients from the same family. Furthermore, heterozygous GBA gene variants were detected in five patients from different families. CONCLUSION: It has been shown that the most common cause of genetically transmitted PD is the PRKN gene, while LRRK2 does not play an essential role in this selected population. It has been suggested that even if the autosomal recessive inheritance is expected, genes with autosomal dominant effects such as SNCA should not be overlooked and suggested for investigation. Our study is also the first for evaluating the pathogenic GBA variants' frequency in PD patients from Turkey.
Assuntos
Predisposição Genética para Doença/genética , Doença de Parkinson/genética , Adulto , Proteínas F-Box , Feminino , Variação Genética , Genótipo , Glucosilceramidase , Heterozigoto , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , Proteína Desglicase DJ-1 , Deleção de Sequência , Turquia , Ubiquitina-Proteína Ligases , alfa-SinucleínaRESUMO
BACKGROUND: Copy number variants (CNVs) include deletions or multiplications spanning genomic regions. These regions vary in size and may span genes known to play a role in human diseases. As examples, duplications and triplications of SNCA have been shown to cause forms of Parkinson's disease, while duplications of APP cause early onset Alzheimer's disease (AD). RESULTS: Here, we performed a systematic analysis of CNVs in a Turkish dementia cohort in order to further characterize the genetic causes of dementia in this population. One hundred twenty-four Turkish individuals, either at risk of dementia due to family history, diagnosed with mild cognitive impairment, AD, or frontotemporal dementia, were whole-genome genotyped and CNVs were detected. We integrated family analysis with a comprehensive assessment of potentially disease-associated CNVs in this Turkish dementia cohort. We also utilized both dementia and non-dementia individuals from the UK Biobank in order to further elucidate the potential role of the identified CNVs in neurodegenerative diseases. We report CNVs overlapping the previously implicated genes ZNF804A, SNORA70B, USP34, XPO1, and a locus on chromosome 9 which includes a cluster of olfactory receptors and ABCA1. Additionally, we also describe novel CNVs potentially associated with dementia, overlapping the genes AFG1L, SNX3, VWDE, and BC039545. CONCLUSIONS: Genotyping data from understudied populations can be utilized to identify copy number variation which may contribute to dementia.
Assuntos
Variações do Número de Cópias de DNA/genética , Demência/genética , Predisposição Genética para Doença , Genômica , Transportador 1 de Cassete de Ligação de ATP/genética , Adenosina Trifosfatases/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Demência/patologia , Feminino , Genoma Humano/genética , Genótipo , Humanos , Carioferinas/genética , Fatores de Transcrição Kruppel-Like/genética , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Receptores Citoplasmáticos e Nucleares/genética , Nexinas de Classificação/genética , Turquia/epidemiologia , Proteases Específicas de Ubiquitina/genética , Proteína Exportina 1RESUMO
Just as its clinical heterogeneity, genetic basis of Frontotemporal dementia (FTD) is also diverse and multiple molecular pathways are thought to be involved in disease pathogenesis. In the present study, FTD- related genes were evaluated in a Turkish cohort of 175 index FTD patients with a gene panel including GRN, MAPT, TARDBP, FUS, CHMP2B and VCP genes. Potential genetic associations were prospected in 16 patients (9.1%); five variants (p.(Gly35Glufs) and p.(Cys253Ter) in GRN; p.(Arg95Cys) in VCP; p.(Met405Val) in TARDBP and p.(Pro636Leu) in MAPT) were classified as pathogenic (P) or likely pathogenic (LP), in four familial and one sporadic patients. Three novel variants in MAPT, CHMP2B and FUS were also identified in familial cases. The most common pathogenic variants were observed in the GRN gene with a frequency of 1.14% (2/175) and this rate was 4.57% (8/175), including variants of uncertain significance (VUS). In this study with the largest cohort of Turkish FTD patients, GRN and MAPT variants were identified as the most common genetic associations; and rare causes like VCP, TARDBP, CHMP2B and FUS variants are recommended to be considered in patients with compatible clinical findings.
Assuntos
Demência Frontotemporal/epidemiologia , Demência Frontotemporal/genética , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Variação Genética/genética , Progranulinas/genética , Proteínas tau/genética , Idoso , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Proteína FUS de Ligação a RNA/genética , Turquia/epidemiologia , Proteína com Valosina/genéticaRESUMO
BACKGROUND AND PURPOSE: Nasu-Hakola disease (NHD) is a rare, autosomal recessive disorder characterized by skeletal and neurological symptoms. Behavioral symptoms with cognitive impairment may mimic the behavioral variant of frontotemporal dementia (bvFTD) and other early-onset dementias. Our patients were analyzed and the literature was reviewed to delineate neurological and neuroimaging findings suggestive of NHD. METHOD: Fourteen patients carrying a pathogenic mutation in the TREM2 gene were found in our database. Demographic, clinical, laboratory and radiological data were retrieved and analyzed. RESULTS: The presenting clinical picture was behavioral changes with cognitive decline resembling bvFTD in all patients. The mean age was 37.1 ± 4.97 years and the mean duration of the disease was 8.9 ± 3.51 years. Only two patients had typical bone cysts. Seven patients had bilateral calcification of the basal ganglia in computed tomography of the brain. Magnetic resonance imaging of the brain revealed severe atrophy of the corpus callosum, enlargement of the ventricles, atrophy of the caudate nuclei and periventricular white matter changes in all patients. Symmetrical global atrophy of the brain mainly affecting frontoparietal and lateral temporal regions were observed in all cases, and 13 patients had atrophy of the hippocampus. Cerebrospinal fluid examination of 10 patients showed elevated protein levels in six and the presence of oligoclonal bands in four patients. CONCLUSION: A combination of white matter changes, enlarged ventricles, atrophy of the caudate nuclei and thinning of the corpus callosum in magnetic resonance imaging strongly suggests NHD in patients with FTD syndrome. Molecular genetic analysis should be performed in suspected cases, and families should receive genetic counseling.