RESUMEN
BACKGROUND AND PURPOSE: While levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), its use is associated with an increased risk of motor complications (MCs) in the first 5 years of treatment compared to dopamine agonist (DA) first therapy. It is not known whether this translates into true benefit later in the disease. We aimed to determine whether there is a difference in the time between initial levodopa versus DA treatment and the development of disabling MCs prompting deep brain stimulation (DBS) consideration. METHODS: This was a retrospective cohort study of patients with PD attending the DBS Clinic at Toronto Western Hospital, Canada between March 2004 and February 2022, who underwent globus pallidus interna (GPI) or subthalamic nucleus (STN) DBS in 2005 or later for disabling MCs. RESULTS: Of the 438 patients included in the study, 352 underwent STN DBS and 86 underwent GPi DBS. The median (range) disease duration was 9 (2-30) years. The majority of patients (n = 312) received levodopa first and 126 received a DA. There was no significant difference in disease duration or amantadine use between the two groups. The duration from the first treatment to assesment for DBS (levodopa: median 8 years, interquartile range [IQ] 4 years; DA: median 9, IQR 4 years) or DBS surgery (levodopa: median 10 years, IIQR 5 years; DA: median 10 years, IQR 5 years) did not differ. CONCLUSION: To our knowledge, this is the only study to date to evaluate the duration between levodopa/DA-first treatment and the development of MCs of sufficient severity to warrant consideration of DBS. No association was found. The results suggest that the development of disabling MCs warranting DBS is independent of the type of first dopaminergic treatment.
Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Humanos , Levodopa , Estimulación Encefálica Profunda/métodos , Agonistas de Dopamina , Enfermedad de Parkinson/terapia , Estudios Retrospectivos , Globo Pálido , Resultado del TratamientoRESUMEN
Parkinson's disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.
Asunto(s)
Catepsina B/metabolismo , Enfermedad de Parkinson , Catepsina B/genética , Genotipo , Heterocigoto , Humanos , Enfermedad de Parkinson/genética , PenetranciaRESUMEN
Frontotemporal dementia (FTD) is the second most common cause of dementia following Alzheimer's disease (AD). Between 20 and 50% of cases are familial. Mutations in MAPT, GRN and C9orf72 are found in 60% of familial FTD cases. C9orf72 mutations are the most common and account for 25%. Rarer mutations (<5%) occur in other genes such as VPC, CHMP2B, TARDP, FUS, ITM2B, TBK1 and TBP. The diagnosis is often challenging due to symptom overlap with AD and other conditions. We review the genetics, clinical presentations, neuroimaging, neuropathology, animal studies and therapeutic trials in FTD. We describe clinical scenarios including the original family with the tau stem loop mutation (+14) and also the recently discovered 'missing tau' mutation +15 that 'closed the loop' in 2015.
Asunto(s)
Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Mutación , Proteínas/genética , Proteínas tau/genética , Encéfalo/patología , Proteína C9orf72 , Demencia Frontotemporal/patología , Humanos , ProgranulinasRESUMEN
Frontotemporal lobar degeneration comprises a group of disorders characterized by behavioural, executive, language impairment and sometimes features of parkinsonism and motor neuron disease. In 1994 we described an Irish-American family with frontotemporal dementia linked to chromosome 17 associated with extensive tau pathology. We named this disinhibition-dementia-parkinsonism-amyotrophy complex. We subsequently identified mutations in the MAPT gene. Eleven MAPT gene splice site stem loop mutations were identified over time except for 5' splice site of exon 10. We recently identified another Irish family with autosomal dominant early amnesia and behavioural change or parkinsonism associated with the 'missing' +15 mutation at the intronic boundary of exon 10. We performed a clinical, neuropsychological and neuroimaging study on the proband and four siblings, including two affected siblings. We sequenced MAPT and performed segregation analysis. We looked for a biological effect of the tau variant by performing real-time polymerase chain reaction analysis of RNA extracted from human embryonic kidney cells transfected with exon trapping constructs. We found a c.915+15A>C exon 10/intron 10 stem loop mutation in all affected subjects but not in the unaffected. The c.915+15A>C variant caused a shift in tau splicing pattern to a predominantly exon 10+ pattern presumably resulting in predominant 4 repeat tau and little 3 repeat tau. This strongly suggests that the c.915+15A>C variant is a mutation and that it causes frontotemporal dementia linked to chromosome 17 in this pedigree by shifting tau transcription and translation to +4 repeat tau. Tau (MAPT) screening should be considered in families where amnesia or atypical parkinsonism coexists with behavioural disturbance early in the disease process. We describe the final missing stem loop tau mutation predicted 15 years ago. Mutations have now been identified at all predicted sites within the 'stem' when the stem-loop model was first proposed and no mutations have been found within the 'loop' region as expected. Therefore we 'close the tau loop' having 'opened the loop' 21 years ago.
Asunto(s)
Encéfalo/patología , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Mutación Missense/genética , Proteínas tau/genética , Salud de la Familia , Fluorodesoxiglucosa F18 , Demencia Frontotemporal/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de PositronesRESUMEN
Precision medicine is a patient-centered approach that aims to translate new knowledge to optimize the type and timing of interventions for the greatest benefit to individual patients. There is considerable interest in applying this approach to treatments designed to slow or halt the progression of neurodegenerative diseases. Indeed, effective disease-modifying treatment (DMT) remains the greatest unmet therapeutic need in this field. In contrast to the enormous progress in oncology, precision medicine in the field of neurodegeneration faces multiple challenges. These are related to major limitations in our understanding of many aspects of the diseases. A critical barrier to advances in this field is the question of whether the common sporadic neurodegenerative diseases (of the elderly) are single uniform disorders (particularly related to their pathogenesis) or whether they represent a collection of related but still very distinct disease states. In this chapter, we briefly touch on lessons from other fields of medicine that might be applied to the development of precision medicine for DMT in neurodegenerative diseases. We discuss why DMT trials may have failed to date, and particularly the importance of appreciating the multifaceted nature of disease heterogeneity and how this has and will impact on these efforts. We conclude with comments on how we can move from this complex disease heterogeneity to the successful application of precision medicine principles in DMT for neurodegenerative diseases.
Asunto(s)
Enfermedades Neurodegenerativas , Medicina de Precisión , Humanos , Anciano , Enfermedades Neurodegenerativas/terapiaRESUMEN
Background: Periodic limb movements while awake (PLMA) are similar to Periodic limb movements in sleep (PLMS) but occurring during wakefulness and seen in association with restless leg syndrome (RLS). Objectives: To describe PLMA as a wearing-off phenomenon in Parkinson's Disease (PD). Methods: We describe four individuals with PD and PLMS, who had associated similar periodic and stereotypic lower extremity movements during wakefulness, thought to be secondary to PLMA, and were highly responsive to dopaminergic treatment. Results: Despite the prevalence of RLS and PLMS in individuals with PD, the presence of similar movements during wakefulness has not been well characterized. The lack of a specific diagnostic criteria poses a significant diagnostic challenge. Conclusions: We describe, for the first time to our knowledge, PLMA as a wearing-off phenomenon in PD. This entity could be classified in the spectrum of "low-dose dyskinesia," as we found that it was highly responsive to dopaminergic treatment.
RESUMEN
BACKGROUND: Variants in PARKIN, PINK1, and DJ1 are associated with early-onset Parkinson' disease (EOPD, age-at-onset < 45). We previously reported a single PINK1 and a single DJ1 heterozygous variant carrier. PURPOSE: We aimed to expand upon our previous EOPD studies and investigate for any genotype-phenotype correlations in Irish PD. METHODS: Three hundred fourteen PD patients were recruited from Dublin Neurological Institute, Ireland. Genetic analysis was performed at the Mayo Clinic, Jacksonville, USA. We screened 81 patients with young-onset PD (age-at-onset < 50), of which 58 had EOPD. RESULTS: We identified 4 patients with homozygous/compound heterozygous variants and 3 heterozygote carriers (pathogenic PINK1/DJ1 variants were not found). Expansion of one of the pedigrees showed a novel variant in exon 9, in a symptomatic patient. We identified 6.89% PARKIN variant carriers associated with EOPD. CONCLUSION: These findings suggest that PINK1 and DJ1 are rarely associated with Irish YOPD, while PARKIN variant frequency is similar to that reported worldwide.
Asunto(s)
Enfermedad de Parkinson , Proteína Desglicasa DJ-1/genética , Proteínas Quinasas/genética , Edad de Inicio , Humanos , Irlanda/epidemiología , Mutación , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
We selected several "imaging pearls" presented during the Movement Disorder Society (MDS) Video Challenge for this review. While the event, as implicated by its name, was video-centered, we would like to emphasize the important role of imaging in making the correct diagnosis. We divided this anthology into two parts: genetic and acquired disorders. Genetic cases described herein were organized by the inheritance pattern and the focus was put on the imaging findings and differential diagnoses. Despite the overlapping phenotypes, certain described disorders have pathognomonic MRI brain findings that would provide either the "spot" diagnosis or result in further investigations leading to the diagnosis. Despite this, the diagnosis is often challenging with a broad differential diagnosis, and hallmark findings may be present for only a limited time.
RESUMEN
BACKGROUND: "Ondine's curse" or central hypoventilation, induces an apparently spontaneous failure of automatic respiratory drive, henceforth necessitating a conscious effort to breathe and sleep induced hypoventilation. It is typically seen in congenital central hypoventilation syndrome, but may be acquired. OBJECTIVES: To highlight Ondine's curse as part of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) secondary to microtubule associated protein tau (MAPT) variants. METHODS: We describe the clinical and neuropathological findings in two patients with fatal Ondine's curse associated with FTDP-17 and secondary to MAPT variants (FTDP-17t). We discuss neuroanatomical correlates. We review two prior reports of central hypoventilation associated with MAPT variants suggesting that Ondine's curse occurs uncommonly in FTDP-17t. RESULTS: Despite variants affecting different regions of MAPT and a degree of heterogeneity in pathological findings, the patients reviewed all experienced central hypoventilation during their disease course. CONCLUSION: Tauopathy should be considered in patients with adult-onset Ondine's curse.
RESUMEN
We report the first clinical-radiological-genetic-molecular-pathological study of a kindred with c.823-10G>T MAPT intronic variant (rs63749974) associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We describe the clinical spectrum within this family and emphasize the association between MAPT gene variants and motor neuron disease. This report of a second family with FTDP-17 associated with c.823-10G>T MAPT variant strongly supports pathogenicity of the variant and confirms it is a 4-repeat (4R) tauopathy. This intronic point mutation, probably strengthens the polypyrimidine tract and alters the splicing of exon 10 (10 nucleotides into intron 9) close to the 3' splice site.
Asunto(s)
Exones/genética , Demencia Frontotemporal/genética , Estudios de Asociación Genética/métodos , Heterocigoto , Intrones/genética , Trastornos Parkinsonianos/genética , Mutación Puntual/genética , Proteínas tau/genética , Anciano , Encéfalo/diagnóstico por imagen , Cromosomas Humanos Par 17/genética , Femenino , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedad de la Neurona Motora/genética , Neuroimagen , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/patología , Tauopatías/genéticaRESUMEN
BACKGROUND: Mutations in the STIP1 homology and U-box containing protein 1 gene were first described in 2013 and lead to disorders with symptoms including ataxia and dysarthria, such as spinocerebellar autosomal-recessive ataxia type 16 (SCAR16), Gordon-Holmes syndrome, and spinocerebellar ataxia type 48. There have been 15 families described to date with SCAR16. CASES: We describe a 45-year-old right-handed woman with dysarthria, ataxia, and cervical dystonia with SCAR16 with 2 compound heterozygous variants in the STIP1 homology and U-box containing protein 1 gene, and a family history significant for her 47-year-old sister with dysarthria and cognitive problems. CONCLUSION: We present a comprehensive overview of the phenotypic data of all 15 families with SCAR16 and expand the phenotype by describing a third patient with SCAR16 and dystonia reported to date in the literature.
RESUMEN
Multiple studies implicate heterozygous GBA mutations as a major genetic risk factor for Parkinson's disease (PD); however, the frequency of mutations has never been examined in PD patients from the Irish population. We prospectively recruited 314 unrelated Irish PD patients (UK Brain Bank Criteria) and 96 Irish healthy controls (without any signs or family history of parkinsonism) attending. The Dublin Neurological Institute (DNI). Complete exon GBA Sanger sequencing analysis with flanking intronic regions was performed. The GBA carrier frequency was 8.3% in PD and 3.1% in controls. We identified a number of potentially pathogenic mutations including a p.G195E substitution and a p.G377C variant, previously described in a case study of Gaucher's disease in Ireland. On genotype-phenotype assessment hallucinations, dyskinesia, and dystonia were more prevalent in GBA-PD. The genetic etiology of PD in Ireland differs from the continental Europe as seen with the lower LRRK2 and higher than in most European countries GBA mutation frequency. Determining genetic risk factors in different ethnicities will be critical for future personalized therapeutic approach.