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1.
BMC Neurol ; 22(1): 93, 2022 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-35291973

RESUMEN

BACKGROUND: Mucopolysaccharidosis type III (Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in the heparan-N-sulfatase enzyme involved in the catabolism of the glycosaminoglycan heparan sulfate. It is characterized by early nonspecific neuropsychiatric symptoms, followed by progressive neurocognitive impairment in combination with only mild somatic features. In this patient group with a broad clinical spectrum a significant genotype-phenotype correlation with some mutations leading to a slower progressive, attenuated course has been demonstrated. CASE PRESENTATION: Our patient had complications in the neonatal period and was diagnosed with Mucopolysaccharidosis IIIa only at the age of 28 years. He was compound heterozygous for the variants p.R245H and p.S298P, the latter having been shown to lead to a significantly milder phenotype. CONCLUSIONS: The diagnostic delay is even more prolonged in this patient population with comorbidities and a slowly progressive course of the disease.


Asunto(s)
Mucopolisacaridosis III , Diagnóstico Tardío , Estudios de Asociación Genética , Humanos , Masculino , Mucopolisacaridosis III/complicaciones , Mucopolisacaridosis III/diagnóstico , Mucopolisacaridosis III/genética , Mutación , Fenotipo
2.
Ann Neurol ; 81(6): 825-836, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28470693

RESUMEN

OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective symptomatic therapy for motor deficits in Parkinson's disease (PD). An additional, disease-modifying effect has been suspected from studies in toxin-based PD animal models, but these models do not reflect the molecular pathology and progressive nature of PD that would be required to evaluate a disease-modifying action. Defining a disease-modifying effect could radically change the way in which DBS is used in PD. METHODS: We applied STN-DBS in an adeno-associated virus (AAV) 1/2-driven human mutated A53T α-synuclein (aSyn)-overexpressing PD rat model (AAV1/2-A53T-aSyn). Rats were injected unilaterally, in the substantia nigra (SN), with AAV1/2-A53T-aSyn or control vector. Three weeks later, after behavioral and nigrostriatal dopaminergic deficits had developed, rats underwent STN-DBS electrode implantation ipsilateral to the vector-injected SN. Stimulation lasted for 3 weeks. Control groups remained OFF stimulation. Animals were sacrificed at 6 weeks. RESULTS: Motor performance in the single pellet reaching task was impaired in the AAV1/2-A53T-aSyn-injected stim-OFF group, 6 weeks after AAV1/2-A53T-aSyn injection, compared to preoperative levels (-82%; p < 0.01). Deficits were reversed in AAV1/2-A53T-aSyn, stim-ON rats after 3 weeks of active stimulation, compared to the AAV1/2-A53T-aSyn stim-OFF rats (an increase of ∼400%; p < 0.05), demonstrating a beneficial effect of DBS. This motor improvement was maintained when the stimulation was turned off and was accompanied by a higher number of tyrosine hydroxylase+ SN neurons (increase of ∼29%), compared to AAV1/2-A53T-aSyn stim-OFF rats (p < 0.05). INTERPRETATION: Our data support the putative neuroprotective and disease-modifying effect of STN-DBS in a mechanistically relevant model of PD. Ann Neurol 2017;81:825-836.


Asunto(s)
Estimulación Encefálica Profunda/métodos , Enfermedad de Parkinson/terapia , Núcleo Subtalámico , alfa-Sinucleína/administración & dosificación , Animales , Conducta Animal , Dependovirus , Modelos Animales de Enfermedad , Vectores Genéticos , Humanos , Masculino , Mutación , Ratas , Ratas Sprague-Dawley , Núcleo Subtalámico/citología , Núcleo Subtalámico/metabolismo , Núcleo Subtalámico/fisiopatología
4.
Acta Neuropathol ; 133(4): 535-545, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28180961

RESUMEN

Phosphorylated alpha-synuclein (p-alpha-syn) deposits, one of the neuropathological hallmarks of Parkinson's disease (PD), have recently been detected in dermal nerve fibres in PD patients with good specificity and sensitivity. Here, we studied whether p-alpha-syn may serve as a biomarker in patients with a high risk of developing PD, such as those with REM sleep behaviour disorder (RBD). We compared the presence and distribution of p-alpha-syn deposits in dermal nerve fibres in 18 patients with RBD, 25 patients with early PD and 20 normal controls. Skin biopsy was taken at C7, Th10, and the upper and lower leg. Presynaptic dopamine transporter imaging using FP-CIT-SPECT was performed in all patients with RBD and in 11 patients with PD. All RBD patients underwent olfactory function testing. The likelihood ratio (LR) for prodromal PD was calculated for each patient based on published research criteria. Skin serial sections were assessed by double-immunofluorescence labelling with antibodies to pSer129-alpha-syn under blinded conditions. P-alpha-syn was visualized in 10/18 patients with RBD (sensitivity of 55.6%) and in 20/25 early PD patients (sensitivity of 80%) but in none of the controls (specificity of 100%). The percentage of dermal structures innervated by p-alpha-syn-positive fibres was negatively correlated with dopamine transporter binding in the FP-CIT-SPECT (ρ = -0.377, p = 0.048), with olfactory function (ρ = -0.668, p = 0.002), and positively correlated with the total LR for RBD to present prodromal PD (ρ = 0.531, p = 0.023). Dermal p-alpha-syn can be considered a peripheral histopathological marker of synucleinopathy and can be detected in a subgroup of RBD patients presumably representing prodromal PD. Dermal p-alpha-syn is detectable in RBD patients without PD motor symptoms, thereby stratifying a patient group that is of great interest for clinical trials testing disease-modifying drugs.


Asunto(s)
Enfermedad de Parkinson/diagnóstico , Trastorno de la Conducta del Sueño REM/diagnóstico , Piel/metabolismo , Piel/patología , alfa-Sinucleína/metabolismo , Anciano , Biomarcadores/metabolismo , Biopsia , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Estudios de Casos y Controles , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Pierna/inervación , Pierna/patología , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Fosforilación , Síntomas Prodrómicos , Estudios Prospectivos , Trastorno de la Conducta del Sueño REM/metabolismo , Trastorno de la Conducta del Sueño REM/patología , Radiofármacos , Piel/inervación , Olfato , Tomografía Computarizada de Emisión de Fotón Único , Tropanos
5.
Brain ; 139(11): 2948-2956, 2016 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-27658421

RESUMEN

Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple 18 F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar syndrome caused by a maladaptive response to neurostimulation of the (sub)thalamic area. The metabolic signature of progressive gait ataxia is an activation of the cerebellar nodule, which may be caused by inadvertent current spread and antidromic stimulation of a cerebellar outflow pathway originating in the vermis. An anatomical candidate could be the ascending limb of the uncinate tract in the subthalamic area. Adjustments in programming and precise placement of the electrode may prevent this adverse effect and help fine-tuning deep brain stimulation to ameliorate tremor without negative cerebellar signs.


Asunto(s)
Estimulación Encefálica Profunda/efectos adversos , Ataxia de la Marcha/etiología , Tálamo/fisiología , Anciano , Anciano de 80 o más Años , Biofisica , Temblor Esencial/diagnóstico por imagen , Temblor Esencial/terapia , Femenino , Fluorodesoxiglucosa F18/metabolismo , Ataxia de la Marcha/diagnóstico por imagen , Humanos , Imagenología Tridimensional , Imagen por Resonancia Magnética , Masculino , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X
6.
Orphanet J Rare Dis ; 19(1): 62, 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38347616

RESUMEN

BACKGROUND: In 2017, the German Academy for Rare Neurological Diseases (Deutsche Akademie für Seltene Neurologische Erkrankungen; DASNE) was founded to pave the way for an optimized personalized management of patients with rare neurological diseases (RND) in all age groups. Since then a dynamic national network for rare neurological disorders has been established comprising renowned experts in neurology, pediatric neurology, (neuro-) genetics and neuroradiology. DASNE has successfully implemented case presentations and multidisciplinary discussions both at yearly symposia and monthly virtual case conferences, as well as further educational activities covering a broad spectrum of interdisciplinary expertise associated with RND. Here, we present recommendation statements for optimized personalized management of patients with RND, which have been developed and reviewed in a structured Delphi process by a group of experts. METHODS: An interdisciplinary group of 37 RND experts comprising DASNE experts, patient representatives, as well as healthcare professionals and managers was involved in the Delphi process. First, an online collection was performed of topics considered relevant for optimal patient care by the expert group. Second, a two-step Delphi process was carried out to rank the importance of the selected topics. Small interdisciplinary working groups then drafted recommendations. In two consensus meetings and one online review round these recommendations were finally consented. RESULTS: 38 statements were consented and grouped into 11 topics: health care structure, core neurological expertise and core mission, interdisciplinary team composition, diagnostics, continuous care and therapy development, case conferences, exchange / cooperation between Centers for Rare Diseases and other healthcare partners, patient advocacy group, databases, translation and health policy. CONCLUSIONS: This German interdisciplinary Delphi expert panel developed consented recommendations for optimal care of patients with RND in a structured Delphi process. These represent a basis for further developments and adjustments in the health care system to improve care for patients with RND and their families.


Asunto(s)
Enfermedades del Sistema Nervioso , Neurología , Niño , Humanos , Enfermedades Raras/terapia , Atención a la Salud , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/terapia , Consenso
8.
Brain Stimul ; 16(5): 1243-1251, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37619891

RESUMEN

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson's disease (PD). Clinical outcomes after DBS can be limited by poor programming, which remains a clinically driven, lengthy and iterative process. Electrophysiological recordings in PD patients undergoing STN-DBS have shown an association between STN spectral power in the beta frequency band (beta power) and the severity of clinical symptoms. New commercially-available DBS devices now enable the recording of STN beta oscillations in chronically-implanted PD patients, thereby allowing investigation into the use of beta power as a biomarker for DBS programming. OBJECTIVE: To determine the potential advantages of beta-guided DBS programming over clinically and image-guided programming in terms of clinical efficacy and programming time. METHODS: We conducted a randomized, blinded, three-arm, crossover clinical trial in eight Parkinson's patients with STN-DBS who were evaluated three months after DBS surgery. We compared clinical efficacy and time required for each DBS programming paradigm, as well as DBS parameters and total energy delivered between the three strategies (beta-, clinically- and image-guided). RESULTS: All three programming methods showed similar clinical efficacy, but the time needed for programming was significantly shorter for beta- and image-guided programming compared to clinically-guided programming (p < 0.001). CONCLUSION: Beta-guided programming may be a useful and more efficient approach to DBS programming in Parkinson's patients with STN-DBS. It takes significantly less time to program than traditional clinically-based programming, while providing similar symptom control. In addition, it is readily available within the clinical DBS programmer, making it a valuable tool for improving current clinical practice.


Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Enfermedad de Parkinson/terapia , Estimulación Encefálica Profunda/métodos , Estudios de Factibilidad , Proyectos Piloto , Núcleo Subtalámico/fisiología
9.
Brain Stimul ; 16(4): 1105-1111, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37422109

RESUMEN

BACKGROUND: Deep brain stimulation of the internal globus pallidus effectively alleviates dystonia motor symptoms. However, delayed symptom control and a lack of therapeutic biomarkers and a single pallidal sweetspot region complicates optimal programming. Postoperative management is complex, typically requiring multiple, lengthy follow-ups with an experienced physician - an important barrier to widespread adoption in medication-refractory dystonia patients. OBJECTIVE: Here we prospectively tested the best machine-predicted programming settings in a dystonia cohort treated with GPi-DBS against the settings derived from clinical long-term care in a specialised DBS centre. METHODS: Previously, we reconstructed an anatomical map of motor improvement probability across the pallidal region using individual stimulation volumes and clinical outcomes in dystonia patients. We used this to develop an algorithm that tests in silico thousands of putative stimulation settings in de novo patients after reconstructing an individual, image-based anatomical model of electrode positions, and suggests stimulation parameters with the highest likelihood of optimal symptom control. To test real-life application, our prospective study compared results in 10 patients against programming settings derived from long-term care. RESULTS: In this cohort, dystonia symptom reduction was observed at 74.9 ± 15.3% with C-SURF programming as compared to 66.3 ± 16.3% with clinical programming (p < 0.012). The average total electrical energy delivered (TEED) was similar for both the clinical and C-SURF programming (262.0 µJ/s vs. 306.1 µJ/s respectively). CONCLUSION: Our findings highlight the clinical potential of machine-based programming in dystonia, which could markedly reduce the programming burden in postoperative management.


Asunto(s)
Estimulación Encefálica Profunda , Distonía , Trastornos Distónicos , Humanos , Distonía/terapia , Estimulación Encefálica Profunda/métodos , Estudios Prospectivos , Estudios de Factibilidad , Resultado del Tratamiento , Trastornos Distónicos/terapia , Globo Pálido/fisiología
10.
Behav Brain Res ; 432: 113968, 2022 08 26.
Artículo en Inglés | MEDLINE | ID: mdl-35738338

RESUMEN

Degeneration of the nigrostriatal tract is a neuropathological hallmark of Parkinson's disease (PD). A differential intraneuronal vulnerability of dopaminergic neurons within the substantia nigra (SN) has been suggested, starting as an axonopathy followed by neuronal cell loss that is accompanied with motor deficits. To date, there is no therapy available to delay or halt this neurodegeneration. Nuclear factor (erythroid-derived 2)-like-2 factor (Nrf2) and histone deacetylase 1 (HDAC1) are crucial molecular regulators that undergo nucleo-cytoplasmic shuttling and are involved in regulation of axonal and perikarya degeneration of neurons under various pathologic conditions. We here aimed to analyze the time course of dopaminergic neurodegeneration in an AAV PD rat model overexpressing human mutated A53T α-synuclein (haSyn), differentially correlate striatal terminal and SN perikarya loss with behavioral deficits and investigate if nucleo-cytoplasmic Nrf2 and HDAC1 expression are altered in dopaminergic perikarya of the haSyn PD rat model. We observed impaired motor performance in haSyn PD rats assessed by the single pellet reaching task at four- and six-weeks post AAV injection (P < 0.05 each). However, only striatal terminal loss correlated significantly with motor deficits in haSyn PD rats, indicating that parkinsonian motor features reflect the striatal dopaminergic denervation, but cannot be taken as an indirect measure of neurodegeneration per se. Immunofluorescence staining demonstrated an upregulation of HDAC1 in the dopaminergic cell nucleus (P < 0.05) while no changes were observed for Nrf2. These data suggest a critical functional role of the axonopathy on motor behavior in haSyn PD rats and mechanistically point towards an impaired nucleo-cytoplasmic translocation of HDAC1 and thus a potential role of disturbed histone acetylation in neurodegeneration.


Asunto(s)
Enfermedad de Parkinson , alfa-Sinucleína , Animales , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Enfermedad de Parkinson/metabolismo , Ratas , Sustancia Negra/metabolismo , alfa-Sinucleína/metabolismo
11.
Exp Neurol ; 348: 113926, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34793784

RESUMEN

Deep brain stimulation (DBS) is the preferred treatment for therapy-resistant movement disorders such as dystonia and Parkinson's disease (PD), mostly in advanced disease stages. Although DBS is already in clinical use for ~30 years and has improved patients' quality of life dramatically, there is still limited understanding of the underlying mechanisms of action. Rodent models of PD and dystonia are essential tools to elucidate the mode of action of DBS on behavioral and multiscale neurobiological levels. Advances have been made in identifying DBS effects on the central motor network, neuroprotection and neuroinflammation in DBS studies of PD rodent models. The phenotypic dtsz mutant hamster and the transgenic DYT-TOR1A (ΔETorA) rat proved as valuable models of dystonia for preclinical DBS research. In addition, continuous refinements of rodent DBS technologies are ongoing and have contributed to improvement of experimental quality. We here review the currently existing literature on experimental DBS in PD and dystonia models regarding the choice of models, experimental design, neurobiological readouts, as well as methodological implications. Moreover, we provide an overview of the technical stage of existing DBS devices for use in rodent studies.


Asunto(s)
Estimulación Encefálica Profunda/métodos , Modelos Animales de Enfermedad , Trastornos del Movimiento/genética , Trastornos del Movimiento/terapia , Animales , Animales Modificados Genéticamente , Encéfalo/metabolismo , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cricetinae , Humanos , Trastornos del Movimiento/metabolismo , Trastornos del Movimiento/patología , Ratas , Roedores
12.
Brain Commun ; 4(4): fcac175, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35855480

RESUMEN

Multiple system atrophy is considered a sporadic disease, but neuropathologically confirmed cases with a family history of parkinsonism have been occasionally described. Here we report a North-Bavarian (colloquially, Lion's tail region) six-generation pedigree, including neuropathologically confirmed multiple system atrophy and Parkinson's disease with dementia. Between 2012 and 2020, we examined all living and consenting family members of age and calculated the risk of prodromal Parkinson's disease in those without overt parkinsonism. The index case and one paternal cousin with Parkinson's disease with dementia died at follow-up and underwent neuropathological examination. Genetic analysis was performed in both and another family member with Parkinson's disease. The index case was a female patient with cerebellar variant multiple system atrophy and a positive maternal and paternal family history for Parkinson's disease and dementia in multiple generations. The families of the index case and her spouse were genealogically related, and one of the spouse's siblings met the criteria for possible prodromal Parkinson's disease. Neuropathological examination confirmed multiple system atrophy in the index case and advanced Lewy body disease, as well as tau pathology in her cousin. A comprehensive analysis of genes known to cause hereditary forms of parkinsonism or multiple system atrophy lookalikes was unremarkable in the index case and the other two affected family members. Here, we report an extensive European pedigree with multiple system atrophy and Parkinson`s disease suggesting a complex underlying α-synucleinopathy as confirmed on neuropathological examination. The exclusion of known genetic causes of parkinsonism or multiple system atrophy lookalikes suggests that variants in additional, still unknown genes, linked to α-synucleinopathy lesions underlie such neurodegenerative clustering.

13.
Parkinsonism Relat Disord ; 56: 41-46, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29937099

RESUMEN

BACKGROUND: The topic of retinal neurodegeneration in PD is controversial, therefore the objective was to compare macular ganglion cell complex (mGCC) and peripapillary retinal nerve fiber layer (pRNFL) thickness in PD using 2 Spectral-Domain (SD) Optical Coherence Tomography (OCT) devices. METHODS: In total, 146 eyes of 130 age-similar patients were included, of these 46 eyes of 30 PD patients, 60 eyes of 60 glaucoma patients and 40 eyes of 40 healthy controls. Peripapillary RNFL and mGCC were measured. Correlation analyses were performed for evaluation of association between pRNFL or mGCC and PD severity using the Movement Disorder Society (MDS)-Unified Parkinson Disease Rating Scale (UPDRS). Scatterplots were used to evaluate relationships between disease duration, dopamine dose, olfactory assessment and retinal thickness. RESULTS: No significant difference was found for both eyes of PD patients compared to healthy subjects neither for overall mGCC nor each sector. However, the ipsilateral eye to the most-affected body side with bradykinesia in PD patients had a statistically significant thinner superior pRNFL compared to healthy controls (P = 0.03). There was no significant correlation between pRNFL or mGCC and disease severity; also, the scatterplots did not indicate a correlation between disease duration, dopamine dose, olfactory testing and OCT results. CONCLUSIONS: Imaging of the retina revealed thinning of some retinal layers of the ipsilateral eye to the most-affected body side in PD patients compared to healthy controls. Peripapillary RNFL and mGCC did not correlate to disease severity; however, this was a fairly small and heterogeneous group of PD patients.


Asunto(s)
Glaucoma/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico por imagen , Retina/diagnóstico por imagen , Tomografía de Coherencia Óptica/tendencias , Anciano , Estudios de Cohortes , Femenino , Glaucoma/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Estudios Prospectivos
14.
Front Neurol ; 8: 108, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28421028

RESUMEN

Niemann-Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). However, due to the low frequency of NP-C, experience with this therapy is still limited. We describe two adult-onset cases of NP-C. In both cases, vertical supranuclear gaze palsy was not recognized at symptom onset. Correct diagnosis was delayed from onset of symptoms by more than 10 years. The video demonstrates the broad spectrum of symptoms in later stages of the disease. Compared with published data, the treatment outcome observed in our cases after delayed initiation of Miglustat therapy was disappointing, with continuing disease progression in both cases. Thus, early treatment initiation could be necessary to achieve a good symptomatic effect. Hence, early biochemical testing for NP-C should be considered in patients suffering from atypical neurological/neuropsychological and psychiatric symptoms, even in cases of uncertainty.

15.
J Neurol ; 264(1): 11-20, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27738760

RESUMEN

Silver syndrome/SPG17 is a motor manifestation of mutations in the BSCL2 gene and usually presents as a complicated form of hereditary spastic paraplegia (HSP). We present clinical data, follow-up, and genetic results of seven patients with Silver syndrome/SPG17 including a family with a variable intrafamilial phenotype ranging from subclinical signs to a severe and rapidly progressing amyotrophic lateral sclerosis (ALS)-like phenotype. For molecular diagnosis of the family, we used the TruSight Exome sequencing panel consisting of 2761 genes. We filtered for variants common to affected family members and for exclusive variants in the ALS-like index patient to find possible modifier mutations. We found that de novo mutations and/or incomplete penetrance in BSCL2 has been taken into account for Silver syndrome/SPG17 and confirm the large phenotypical heterogeneity of BSCL2 mutations. Our findings broaden the reported spectrum of the disease to an ALS-like and multifocal motor neuropathy phenotype and underline the need for further research for genetic modifiers due to the striking interindividual and intrafamilial variability.


Asunto(s)
Esclerosis Amiotrófica Lateral/diagnóstico , Subunidades gamma de la Proteína de Unión al GTP/genética , Mutación , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética , Anciano , Diagnóstico Diferencial , Familia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Paraplejía Espástica Hereditaria/fisiopatología , Paraplejía Espástica Hereditaria/terapia , Adulto Joven
16.
Artículo en Inglés | MEDLINE | ID: mdl-26989573

RESUMEN

BACKGROUND: Several publications have focused on accompanying non-motor symptoms (NMS) in essential tremor (ET) patients; however, it remains unclear if NMS are an intrinsic part of the disease or secondary phenomena. We present the results of several neuropsychiatric tests and their impact on quality of life (QoL) in community-dwelling patients with ET. METHODS: Participants were recruited via a newspaper article about ET published in the local media and on the internet. All participants completed several standard neuropsychiatric tests, including those that assess QoL. To compare differences between cases and controls, Student's t-tests with Bonferroni-Holm post hoc tests were performed. Spearman's correlation coefficients were also calculated. RESULTS: We enrolled 110 patients with definite or probable ET. Highly significant changes were observed for apathy, anxiety, and cognition and negatively impacted QoL. Most aberrations were independent of tremor severity and duration. DISCUSSION: The significant neuropsychiatric deficits and reduced QoL demonstrate a degree of illness that appears to be a non-motor phenotype rather than a secondary effect of ET. In the future, NMS should carefully be explored in ET patients as they may have an impact on QoL and treatment.

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