RESUMO
BACKGROUND: Task-specific focal hand dystonia impairs the control of arm muscles during fine motor skills such as writing (writer's cramp (WC)). Functional imaging found abnormal task-related activation of sensorimotor areas in this disorder, but little is known on their functional connectivity (FC). METHODS: Resting-state fMRI and regions of interest (ROI)-voxel cross-correlation analyses were used for systematically analysing the FC between multiple ROIs within the cerebello-basal ganglia-thalamocortical network in 15 patients with right-sided WC and 15 healthy volunteers. RESULTS: Patients with WC showed a lower positive FC of several seed ROIs (left lateral premotor cortex, left thalamus, left/right pallidum) to the symptomatic left primary sensorimotor cortex compared with controls. The FC of the left primary motor cortex to prefrontal areas, pre- supplementary motor area and right somatosensory cortex was reduced and correlated with disease severity. Several cerebellar seed ROIs (right dentate nucleus, right crus I and bilateral crus II) revealed a stronger negative FC to primary and secondary sensorimotor areas. CONCLUSIONS: An increase of negative cerebello-cortical FC at rest is in line with the hypothesis of a pathogenetic role of the cerebellum in dystonia. The deficit of positive subcortico-cortical FC indicates more generalised changes within the basal ganglia-thalamocortical motor loops beyond primary sensorimotor areas in WC. As patients with WC are asymptomatic during rest, these functional network changes could reflect an underlying abnormality or compensatory neuroplastic changes of network architecture in this disorder.
Assuntos
Distúrbios Distônicos/fisiopatologia , Córtex Sensório-Motor/fisiopatologia , Estudos de Casos e Controles , Feminino , Lateralidade Funcional/fisiologia , Neuroimagem Funcional , Globo Pálido/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Motor/fisiopatologia , Vias Neurais/fisiopatologia , Tálamo/fisiopatologiaRESUMO
BACKGROUND: Rare autosomal-dominant mutations in ANO3 and GNAL have been recently shown to represent novel genetic factors underlying primary torsion dystonia (PTD) with predominantly craniocervical involvement. METHODS: We used high-resolution melting to screen all exons of ANO3 and GNAL for rare sequence variants in a population of 342 German individuals with mainly sporadic PTD and 376 general population controls. RESULTS: We identified 2 novel missense variants in ANO3 (p.Ile833Val and p.Gly973Arg) and 1 novel missense variant in GNAL (p.Val146Met) in three different nonfamilial cases. Variant carriers presented with adult-onset dystonia involving the neck and/or face. In controls, 3 rare ANO3 missense variants (p.Tyr235Cys, p.Asn256Ser, and p.Pro893Leu) but no rare nonsynonymous GNAL variants were present. CONCLUSIONS: GNAL variants seem to be a rare cause of PTD in our mainly sporadic German sample. Low frequency missense variants in ANO3 occur in both cases and controls, warranting further assessment of this gene in PTD pathogenesis.
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Canais de Cloreto/genética , Distonia Muscular Deformante/genética , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Mutação de Sentido Incorreto , Adulto , Idoso , Idoso de 80 Anos ou mais , Anoctaminas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Recessive DYT16 dystonia associated with mutations in PRKRA has until now been reported only in seven Brazilian patients. The aim of this study was to elucidate the genetic cause underlying disease in a Polish family with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism, and to explore further the role of PRKRA in a dystonia series of European ancestry. We employed whole-exome sequencing in two affected siblings of the Polish family and filtered for rare homozygous and compound heterozygous variants shared by both exomes. Validation of the identified variants as well as homozygosity screening and copy number variation analysis was carried out in the two affected individuals and their healthy siblings. PRKRA was analyzed in 339 German patients with various forms of dystonia and 376 population-based controls by direct sequencing or high-resolution melting. The previously described homozygous p.Pro222Leu mutation in PRKRA was found to segregate with the disease in the studied family, contained in a 1.2 Mb homozygous region identical by state with all Brazilian patients in chromosome 2q31.2. The clinical presentation with young-onset, progressive generalized dystonia and mild parkinsonism resembled the phenotype of the original DYT16 cases. PRKRA mutational screening in additional dystonia samples revealed three novel heterozygous changes (p.Thr34Ser, p.Asn102Ser, c.-14A>G), each in a single subject with focal/segmental dystonia. Our study provides the first independent replication of the DYT16 locus at 2q31.2 and strongly confirms the causal contribution of the PRKRA gene to DYT16. Our data suggest worldwide involvement of PRKRA in dystonia.
Assuntos
Variações do Número de Cópias de DNA/genética , Distúrbios Distônicos/genética , Exoma/genética , Saúde da Família , Proteínas de Ligação a RNA/genética , Adolescente , Adulto , Criança , Cromossomos Humanos Par 2/genética , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Índice de Gravidade de Doença , Adulto JovemRESUMO
The pathophysiology of idiopathic focal hand dystonia (writer's cramp) is characterized by deficient inhibitory basal ganglia function and altered cortical sensorimotor processing. To explore if this is already a primary finding in dystonia for internal movement simulation independent of dystonic motor output or abnormal sensory input, we investigated the neural correlates of movement imagination and observation in patients with writer's cramp. Event-related fMRI was applied during kinesthetic motor imagery of drawing simple geometric figures (imagination task) and passively observing videos of hands drawing identical figures (observation task). Compared with healthy controls, patients with writer's cramp showed deficient activation of the left primary sensorimotor cortex, mesial and left dorsal premotor cortex, bilateral putamen, and bilateral thalamus during motor imagery. No significant signal differences between both groups were found during the observation task. We conclude that internal movement simulation and planning as tested during imagination of hand movements appear to be dysfunctional in patients with writer's cramp, whereas visual signal processing and observation-induced activation are unaffected. Deficient basal ganglia-premotor activation could be a correlate of impaired basal ganglia inhibition and focusing during the selection of motor programs in dystonia. This finding seems to be an intrinsic deficit, as it is found during motor imagery in the absence of dystonic symptoms.
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Gânglios da Base/fisiopatologia , Distúrbios Distônicos/patologia , Distúrbios Distônicos/fisiopatologia , Imaginação/fisiologia , Córtex Motor/fisiopatologia , Movimento/fisiologia , Adulto , Gânglios da Base/irrigação sanguínea , Feminino , Lateralidade Funcional/fisiologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Motor/irrigação sanguínea , Vias Neurais/irrigação sanguínea , Vias Neurais/fisiopatologia , Oxigênio/sangue , Estimulação Luminosa , Índice de Gravidade de DoençaRESUMO
UNLABELLED: The etiology of idiopathic orofacial dystonia is incompletely understood. Neurophysiological studies indicated that a sensory dysfunction could play a key role in the pathophysiology of focal dystonia. To explore if central sensory processing is abnormal in patients with blepharospasm and Meige's syndrome and to study the effects of botulinum toxin (BTX) treatment, we systematically mapped the somatotopic representations of punctate tactile stimuli in these patients before and after therapy. METHODS: Standardized tactile stimuli were pseudorandomly applied to the forehead, upper lip, and hand by a MR-compatible stimulation device during event-related fMRI. RESULTS: Patients showed a deficient activation in primary and secondary somatosensory representations of affected and unaffected (right hand) body regions compared to healthy controls. Although clinically effective BTX treatment did not modulate this impaired cortical activation, it reduced the activation of the thalamus and contralateral putamen during forehead stimulation. CONCLUSIONS: This study reveals a more generalized dysfunction of the somatosensory cortex including asymptomatic body representations in orofacial dystonia. Deficient cortical sensory activation may be due to a dedifferentiation of somatosensory representations and could represent a critical functional change within the basal ganglia-thalamocortical loops facilitating dystonic movements. Modulation of basal ganglia activation might reflect an indirect remote effect of BTX treatment on these sensorimotor circuits.
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Antidiscinéticos/farmacologia , Gânglios da Base/efeitos dos fármacos , Toxinas Botulínicas/farmacologia , Distúrbios Distônicos/patologia , Córtex Somatossensorial/efeitos dos fármacos , Idoso , Antidiscinéticos/uso terapêutico , Gânglios da Base/irrigação sanguínea , Toxinas Botulínicas/uso terapêutico , Mapeamento Encefálico , Distúrbios Distônicos/tratamento farmacológico , Feminino , Lateralidade Funcional , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Estimulação Física , Psicofísica , Tempo de Reação , Limiar Sensorial/efeitos dos fármacos , Limiar Sensorial/fisiologia , Córtex Somatossensorial/irrigação sanguínea , Tato/fisiologiaRESUMO
Afferent feedback from muscles and skin has been suggested to influence our emotions during the control of facial expressions. Recent imaging studies have shown that imitation of facial expressions is associated with activation in limbic regions such as the amygdala. Yet, the physiological interaction between this limbic activation and facial feedback remains unclear. To study if facial feedback effects on limbic brain responses during intentional imitation of facial expressions, we applied botulinum toxin (BTX)-induced denervation of frown muscles in combination with functional magnetic resonance imaging as a reversible lesion model to minimize the occurrence of afferent muscular and cutaneous input. We show that, during imitation of angry facial expressions, reduced feedback due to BTX treatment attenuates activation of the left amygdala and its functional coupling with brain stem regions implicated in autonomic manifestations of emotional states. These findings demonstrate that facial feedback modulates neural activity within central circuitries of emotion during intentional imitation of facial expressions. Given that people tend to mimic the emotional expressions of others, this could provide a potential physiological basis for the social transfer of emotion.
Assuntos
Toxinas Botulínicas/toxicidade , Emoções/fisiologia , Expressão Facial , Músculos Faciais/fisiologia , Retroalimentação Psicológica/fisiologia , Rede Nervosa/fisiologia , Emoções/efeitos dos fármacos , Músculos Faciais/inervação , Feminino , Humanos , Comportamento Imitativo/fisiologia , Denervação Muscular/métodos , Rede Nervosa/efeitos dos fármacos , Estimulação Luminosa/métodosRESUMO
INTRODUCTION: Thirty years after their approval, botulinum toxin injections still are the first-line therapy for blepharospasm. The aim of our study was to analyze long-term data concerning safety and efficacy in a large cohort over decades. METHODS: Treatment data of all patients with blepharospasm and Meige´s syndrome in our outpatient clinic having undergone at least three subsequent treatment sessions with current onabotulinumtoxinA or abobotulinumtoxin A were analyzed with respect to the course of dose, effect duration, side effects, patients´ satisfaction and occurrence/reasons for treatment discontinuation. RESULTS: The observation period was up to 18 years for onabotulinumtoxinA and 29 years for abobotulinumtoxinA with a total of 1778 and 9319 treatment sessions in 69 patients with onabotulinumtoxinA, 281 with abobotulinumtoxin A and 2 of these having used both products. The dose increased in the first years followed by a stable dose in the following years. The mean dose was 39.1/198.7 mouse units (onabotulinumtoxinA/abobotulinumtoxinA). In over 25% of all sessions, inhibition of the eyelid opening was effectively treated with pretarsal injections. The most common adverse events included ptosis (4%/5%), epiphora/sicca (4%/5%), double vision (1%/1%) and facial asymmetry (1%/1%). Reasons for therapy discontinuation were change to a nearby doctor, age, other diseases, spontaneous improvement, side effects or possible treatment failure. Only one patient was tested positive for neutralizing antibodies against botulinum toxin A. CONCLUSION: The treatment of blepharospasm and Meige's syndrome with onabotulinumtoxinA and abobotulinumtoxinA is safe and effective, also over a long observation period of up to 29 years.
Assuntos
Blefarospasmo/tratamento farmacológico , Toxinas Botulínicas Tipo A/farmacologia , Síndrome de Meige/tratamento farmacológico , Fármacos Neuromusculares/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Idoso , Toxinas Botulínicas Tipo A/administração & dosagem , Toxinas Botulínicas Tipo A/efeitos adversos , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fármacos Neuromusculares/administração & dosagem , Fármacos Neuromusculares/efeitos adversosRESUMO
BACKGROUND: Chorea-acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition with onset in early adulthood that is caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein. Several diagnostic genomic DNA (gDNA) sequencing approaches are widely used. However, their limitations appear not to be acknowledged thoroughly enough. METHODS: Clinically, we deployed magnetic resonance imaging, blood smear analysis, and clinical chemistry for the index patient's characterization. The molecular analysis of the index patient next to his parents covered genomic DNA (gDNA) sequencing approaches, RNA/cDNA sequencing, and chorein specific Western blot. RESULTS: We report a 33-year-old male patient without functional protein due to compound heterozygosity for two VPS13A large deletions of 1168 and 1823 base pairs (bp) affecting, respectively, exons 8 and 9, and exon 13. To our knowledge, this represents the first ChAc case with two compound heterozygous large deletions identified so far. Of note, standard genomic DNA (gDNA) Sanger sequencing approaches alone yielded false negative findings. CONCLUSION: Our case demonstrates the need to carry out detection of chorein in patients suspected of having ChAc as a helpful and potentially decisive tool to establish diagnosis. Furthermore, the course of the molecular analysis in this case discloses diagnostic pitfalls in detecting some variations, such as deletions, using only standard genomic DNA (gDNA) Sanger sequencing approaches and exemplifies alternative methods, such as RNA/cDNA sequencing or qRT-PCR analysis, necessary to avoid false negative results.
Assuntos
Deleção de Genes , Testes Genéticos/métodos , Neuroacantocitose/genética , Proteínas de Transporte Vesicular/genética , Adulto , Western Blotting/métodos , Heterozigoto , Humanos , Masculino , Neuroacantocitose/diagnóstico , Reação em Cadeia da Polimerase em Tempo Real/métodos , Proteínas de Transporte Vesicular/metabolismoRESUMO
INTRODUCTION: Treatment with botulinum toxin A is the evidence-based first-line therapy of cervical dystonia. The aim of this study was to analyze long-term data of the most commonly used products concerning safety and efficacy in a big cohort over decades. METHODS: We retrospectively analyzed the treatment data of all cervical dystonia patients in our outpatient clinic having at least three treatment sessions with current onabotulinumtoxinA or abobotulinumtoxinA. The observation period was up to 17 years for onabotulinumtoxinA and 27 years for abobotulinumtoxinA. We report on safety and efficacy, comparing parameters such as dose, treatment intervals, side effects, occurrence and reasons of primary or secondary non-response. RESULTS: We analyzed a total of 2592 and 6660 treatment sessions in 135 patients with onabotulinumtoxinA, 209 with abobotulinumtoxinA and 10 having received both preparations. We found a moderate increase of dosage in the first years which was succeeded by a stable mean dose (138 and 663 mouse units, respectively) and stable injection intervals from the beginning. The most frequent side effects were mild dysphagia (2/6%), muscle weakness (2/6%) and pain (2/2%). Reasons for therapy discontinuation were change to a nearby doctor, age, other diseases, spontaneous improvement, side effects or possible treatment failure. Of all patients, only two tested positive for neutralizing antibodies against botulinum toxin A. CONCLUSION: We show that treatment of cervical dystonia with the two most frequently used botulinum toxin A preparations is a safe and effective therapy even over a long treatment duration of up to 27 years.
Assuntos
Inibidores da Liberação da Acetilcolina/administração & dosagem , Toxinas Botulínicas Tipo A/administração & dosagem , Duração da Terapia , Torcicolo/diagnóstico , Torcicolo/tratamento farmacológico , Inibidores da Liberação da Acetilcolina/efeitos adversos , Adulto , Toxinas Botulínicas Tipo A/efeitos adversos , Estudos de Coortes , Transtornos de Deglutição/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/induzido quimicamente , Distribuição Aleatória , Estudos Retrospectivos , Resultado do TratamentoAssuntos
Estimulação Encefálica Profunda/métodos , Tremor/terapia , Adulto , Malformações Vasculares do Sistema Nervoso Central/complicações , Malformações Vasculares do Sistema Nervoso Central/patologia , Malformações Vasculares do Sistema Nervoso Central/cirurgia , Humanos , Hemorragias Intracranianas/complicações , Hemorragias Intracranianas/patologia , Imageamento por Ressonância Magnética , Masculino , Mesencéfalo/patologia , Transtornos dos Movimentos/etiologia , Núcleos Talâmicos/fisiologia , Tálamo/fisiologiaRESUMO
Introduction: Blepharospasm is characterized by involuntary eyelid spasms. It can be associated with perioral dystonia (Meige's syndrome or orofacial dystonia). We aimed at studying resting-state functional brain connectivity in these patients and its potential modulation by therapeutic botulinum toxin injections. Methods: We performed resting-state functional MRI and a region of interest-based analysis of functional connectivity in 13 patients with blepharospasm/Meige's syndrome in comparison to 13 healthy controls. Patients were studied before and 4 weeks after botulinum toxin treatment. Simultaneous facial electromyography was applied to control for involuntary facial movements. Results: Before botulinum toxin treatment, patients showed reduced functional connectivity between caudate and primary sensorimotor, somatosensory association and visual cortices as well as between putamen and parietal association cortex. Cerebellar areas displayed decreased functional connectivity to somatosensory and visual association cortices. On the cortical level, connectivity was reduced between the cingulate cortex and the primary sensorimotor/premotor and parietal association cortex, between premotor areas and the primary somatosensory cortices, and between the postcentral gyrus and temporoparietal, secondary somatosensory, cingular, and cerebellar regions. Botulinum toxin treatment modulated functional connectivity, especially between cerebellum and visual cortices. Conclusions: Patients with blepharospasm/Meige's syndrome show altered functional connectivity at rest in widespread brain regions including basal ganglia, cerebellar, primary/secondary sensorimotor, and visual areas. Functionally, this may reflect a predisposition for defective movement inhibition and sensorimotor integration. Botulinum toxin treatment could modulate brain connectivity in blepharospasm by altering visual and sensory input.
Assuntos
Blefarospasmo/fisiopatologia , Encéfalo/fisiopatologia , Distonia/fisiopatologia , Distúrbios Distônicos/fisiopatologia , Idoso , Blefarospasmo/diagnóstico por imagem , Blefarospasmo/tratamento farmacológico , Toxinas Botulínicas/uso terapêutico , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Distonia/diagnóstico por imagem , Distonia/tratamento farmacológico , Distúrbios Distônicos/diagnóstico por imagem , Distúrbios Distônicos/tratamento farmacológico , Eletromiografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neurotoxinas/uso terapêutico , Resultado do TratamentoRESUMO
Previous studies showed cortical dysfunction and impaired sensorimotor integration in primary generalized and focal hand dystonia. We used a whistling task and silent event-related fMRI to investigate functional changes in patients with blepharospasm and patients with a combination of blepharospasm and oromandibular dystonia (Meige's syndrome). Whistling served as a model for a skilful orofacial movement with a high demand on sensorimotor integration. It allowed us to study the oromandibular motor system that is clinically affected in Meige's syndrome but not in isolated blepharospasm. In Meige's syndrome, functional MRI revealed deficient activation of the primary motor and ventral premotor cortex within the mouth representation area during whistling. Compared with healthy controls, both forms of orofacial dystonia had increased activation of bilateral somatosensory areas and the caudal supplementary motor area (SMA) in common. While overactivity of somatosensory areas and caudal SMA in Meige patients was partly reversed by botulinum toxin treatment, impaired motor activation was not. We conclude that impaired motor activation appears to be specific for the clinically affected oromandibular motor system in Meige's syndrome while enhanced somatosensory activation is a common abnormality in both forms of orofacial dystonia independent of the affected motor system. Somatosensory overactivity indicates an altered somatosensory representation in orofacial dystonia while impaired motor activation may be a functional correlate of reduced cortical inhibition during oromandibular motor execution in Meige's syndrome.
Assuntos
Blefarospasmo/fisiopatologia , Imageamento por Ressonância Magnética , Síndrome de Meigs/fisiopatologia , Córtex Motor/fisiopatologia , Córtex Somatossensorial/fisiopatologia , Idoso , Blefarospasmo/complicações , Blefarospasmo/psicologia , Estudos de Casos e Controles , Músculos Faciais/fisiopatologia , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Síndrome de Meigs/complicações , Síndrome de Meigs/psicologia , Pessoa de Meia-Idade , Movimento/fisiologia , Estudos Prospectivos , Tempo de Reação , Análise e Desempenho de TarefasRESUMO
The inability to imitate gestures is an essential feature of apraxia. However, discrepancies exist between clinical studies in apraxic patients and neuroimaging findings on imitation. We therefore aimed to investigate: (1) which areas are recruited during imitation under conditions similar to clinical tests for apraxic deficits; (2) whether there are common lateralized areas subserving imitation irrespective of the acting limb side; and also (3) whether there are differences between hand and finger gestures. We used fMRI in 12 healthy, right handed subjects to investigate the imitation of four types of variable gestures that were presented by video clips (16 different finger and 16 different hand gestures with either the right or the left arm). The respective control conditions consisted of stereotyped gestures (only two gestures presented in pseudorandom order). Subtraction analysis of each type of gesture imitation (variable>stereotyped) revealed a bilateral activation pattern including the inferior parietal cortex Brodmann Area (BA 40), the superior parietal cortex, the inferior frontal cortex (opercular region), the prefrontal motor cortex, the lateral occipito-temporal junction, and the cerebellum. These results were supported by statistical conjunction of all four subtraction analyses and by the common analysis of all four types of gesture imitation. The direct comparison of the right and left hemispheric activation revealed a lateralization to the left only of the inferior parietal cortex. Comparisons between different types of gesture imitation yielded no significant results. In conclusion, gesture imitation recruits bilateral fronto-parietal regions, with significant lateralization of only one area, namely the left inferior parietal cortex. These in vivo data indicate left inferior parietal dominance for gesture imitation in right handers, confirming lesion-based theories of apraxia.
Assuntos
Mapeamento Encefálico , Dominância Cerebral/fisiologia , Gestos , Comportamento Imitativo/fisiologia , Movimento/fisiologia , Lobo Parietal/fisiologia , Adulto , Idoso , Cerebelo/fisiologia , Feminino , Dedos/fisiologia , Lobo Frontal/fisiologia , Mãos/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Lobo Occipital/fisiologia , Valores de Referência , Lobo Temporal/fisiologiaRESUMO
Multiple sclerosis (MS) is a common neurological disease with increasing incidence and prevalence. Onset of disease is most frequently in young adulthood when productivity is usually highest; it is of chronic nature and, in the majority of patients, it will result in accumulation of disability. Due to loss of productivity in patients and caregivers as well as high expenses for medical treatment, MS is considered a disease with high economic burden for patients and society. Several drugs have been approved for treatment of MS. While treatment ameliorates the course of the disease, it is very costly; therefore, pharmacoeconomics, evaluating costs and effects of disease-modifying treatment in MS, has become an important issue. Here, we review the economic impact and treatment strategies of MS and discuss recent studies on pharmacoeconomics of early treatment with interferon beta.
RESUMO
Niemann-Pick type C (NPC) disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95%) or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n = 563), FTLD (n = 133) and PSP (n = 94), and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1%) and seven control subjects (0.8%), but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted.