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Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (â¼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that â¼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.
Assuntos
Testes Genéticos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , Humanos , Doença de Parkinson/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Testes Genéticos/métodos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Glucosilceramidase/genética , alfa-Sinucleína/genética , Predisposição Genética para Doença , Ubiquitina-Proteína Ligases/genética , Estudos de Coortes , Proteínas Quinases/genética , Mutação , AdultoRESUMO
BACKGROUND: Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy. OBJECTIVES: We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia. METHODS: We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants. RESULTS: We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat. CONCLUSIONS: We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society.
Assuntos
Proteínas de Transporte , Ataxia Cerebelar , Deficiência Intelectual , Proteínas dos Microfilamentos , Paraplegia Espástica Hereditária , Proteínas de Transporte/genética , Ataxia Cerebelar/genética , Humanos , Deficiência Intelectual/genética , Proteínas dos Microfilamentos/genética , Mutação/genética , Paraplegia/genética , Linhagem , Fenótipo , Paraplegia Espástica Hereditária/genética , Espectrina/genéticaRESUMO
Background/aim: Our purpose was to determine the efficacy of levodopa carbidopa intestinal gel (LCIG) in a series of Turkish patients with Parkinson's disease (PD). Materials and methods: We had telephone calls with 54 patients from 11 neurology centers who were on LCIG treatment, and 44 patients or their caregivers were included in an eight-item survey between September 2015 and June 2016. The reliability and validity of the survey were evaluated with intraclass correlation coefficients for every question separately. Results: Average age of the patients were 63.48 and the duration of PD was 12.79 years. Average LCIG treatment period was 15.63 months. Percentages of the patients who reported they were 'better' after LCIG treatment were as follows: 80% for time spent off, 55% for dyskinesia, 65% for tremor, 85% for gait disorder, 50% for pain, 50% for sleep disorders, 42.5% for depression, 32.5% for incontinence, and 70% for activities of daily living. Cronbach's alpha was 0.795 and the intraclass correlation coefficient was reliable for the items. Conclusion: As detected by a survey performed by telephone calls with good interrater reliability, patients with PD improve with LCIG treatment in many aspects of the disease.
Assuntos
Carbidopa/uso terapêutico , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Atividades Cotidianas , Idoso , Carbidopa/administração & dosagem , Combinação de Medicamentos , Feminino , Géis , Humanos , Levodopa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Reprodutibilidade dos TestesRESUMO
OBJECTIVES: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive inborn lipid storage disorder due to various pathogenic mutations in the CYP27A1 gene. Although the symptoms begin commonly in infancy, CTX diagnosis is often delayed. In this study, we report 7 Turkish CTX patients who had a delayed diagnosis despite early clinical signs and belonged to 6 unrelated families. METHODS: We have retrospectively evaluated clinical, laboratory, imaging, and genetic findings of CTX patients, which were collected from 2 centers specialized in movement disorders: the Department of Neurology, Faculty of Medicine, Istanbul University, and the Department of Neurology, Faculty of Medicine, Mersin University. RESULTS: All patients were diagnosed with CTX after neurological symptom development, and their mean age at diagnosis was 38.7 ± 9.6 years, despite a mean onset age of 12.4 ± 10.6 years. The mean follow-up period was 28 months (range: 3-60 months). The most common initial clinical abnormalities in our cohort were unexplained chronic diarrhea (42%), febrile convulsion (42%), juvenile cataract (85%), childhood depression and autism (14%), parkinsonism (14%), and intellectual disability (100%). The most prominent neurological findings were the pyramidal-cerebellar syndrome (85%) and extrapyramidal signs (42%). All patients were genetically confirmed. Serum cholestanol levels were elevated in all patients and decreased after chenodeoxycholic acid (CDCA) treatment in 6 patients. CONCLUSION: This cohort is the largest CTX case series in Turkey. All cases showed improvement in gastrointestinal symptoms as a response to CDCA treatment and stabilization on neurological symptoms, i.e., no further progression of neurological abnormalities were noted during this treatment. Therefore, early diagnosis and treatment is crucial in preventing clinical deterioration.
Assuntos
Xantomatose Cerebrotendinosa/diagnóstico , Adulto , Encéfalo/diagnóstico por imagem , Ácido Quenodesoxicólico/uso terapêutico , Colestanotriol 26-Mono-Oxigenase/genética , Diagnóstico Tardio , Progressão da Doença , Feminino , Seguimentos , Fármacos Gastrointestinais/uso terapêutico , Humanos , Masculino , Estudos Retrospectivos , Xantomatose Cerebrotendinosa/tratamento farmacológico , Xantomatose Cerebrotendinosa/genética , Xantomatose Cerebrotendinosa/fisiopatologiaRESUMO
Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p.G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.
Assuntos
Tremor Essencial/genética , Mitocôndrias/enzimologia , Proteínas Mitocondriais/genética , Doença de Parkinson/genética , Serina Endopeptidases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Serina Peptidase 2 de Requerimento de Alta Temperatura A , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto JovemRESUMO
The Westphal variant of Huntington's disease (HD) is a progressive neurodegenerative disease characterized by a rigid-hypokinetic syndrome rather than choreiform movements. This variant is a distinct clinical entity of HD and is often associated with a juvenile onset of the disease. We present the case of a 13-year-old patient diagnosed with the Westphal variant with an onset at approximately 7 years of age and primarily exhibited developmental delay and psychiatric symptoms. In the light of findings from both physical and clinical examinations, possible difficulties in the diagnosis and treatment of juvenile HD are discussed in here.
RESUMO
The objective of this study was to determine the prevalence of blepharospasm (BSP), with and without apraxia of eyelid opening (AEO), in patients with parkinsonism, cervical dystonia (CD), and essential tremor (ET). BSP, with or without AEO, is associated with parkinsonism. There have been several reports of BSP in other dystonic conditions, but few looked at the incidence of BSP in ET patients. This study included 659 patients of which 357 had parkinsonism (276 idiopathic Parkinson's disease (IPD) and 81 atypical parkinsonism (57 progressive supranuclear palsy; 11 multiple system atrophy 13 corticobasal degeneration)), 274 had ET, 22 had CD, and 6 had spinocerebellar ataxia. Our results indicate that BSP (with or without AEO) was more prevalent in atypical parkinsonism (6 out of 81, 7.41%) than IPD (9 out of 276, 3.26%). The study also followed 10 (of the 28) patients with BSP to screen for the development of other movement disorders - of these, 2 developed Parkinson's disease. We conclude then that BSP is common in parkinsonism and that BSP is more prevalent in atypical parkinsonism. We also conclude that BSP is not a common feature in ET patients (0 out of 274 patients reported BSP symptoms).
Assuntos
Apraxias/epidemiologia , Blefarospasmo/epidemiologia , Tremor Essencial/complicações , Pálpebras/fisiopatologia , Doença de Parkinson/epidemiologia , Torcicolo/complicações , Apraxias/etiologia , Blefarospasmo/complicações , Blefarospasmo/diagnóstico , Blefarospasmo/etiologia , Feminino , Humanos , Masculino , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Prevalência , Paralisia Supranuclear Progressiva/complicaçõesRESUMO
Parkinson's disease (PD) is a neurodegenerative disease with a rapidly increasing incidence and prevalence. Although it affects more than 6 million people worldwide, it is predicted to be doubled by 2040. Current criteria used in the diagnosis of PD include the presence of bradykinesia as well as the presence of rest tremor and/or rigidity, but the clinic is multifaceted and includes many non-motor symptoms. Non-motor symptoms may occur in the prodromal period, years before clinically evident Parkinson's disease. During this period, diagnosing the disease will likely be even more important when disease-modifying treatments are available. Currently, there is no single biomarker that can be used in the diagnosis of PD and no disease-modifying treatment is available. Identification of biomarkers in early diagnosis will enable the most effective use of disease-modifying therapies and will shed light on possible underlying pathologies, studies in this area have gained momentum in recent years. Molecular imaging methods, genetic studies, salivary gland and skin biopsies, metabolomics, lysosomal pathway are some of them. In this article, besides the current diagnosis and treatment methods of the disease, biomarkers and treatments that are expected to be better understood in the near future will be mentioned.
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BACKGROUND: Aerobic exercise training contributes to improvement of cardiopulmonary capacity, mobility, neurological function, and quality of life. AIMS: To investigate the effects of arm crank ergometer training on aerobic capacity, quality of life, and Parkinson's disease (PD)-related disability METHODS: Seventeen patients with PD were recruited to study. Assessments were performed at baseline and at the end of an 8-week arm crank ergometer (ACE) training program (3 days/week; 1 h per session, 50-70% VO2peak) with patients acting as their own control. Outcome measures included aerobic capacity assessment, 6-min walk test (6MWT), timed up and go test (TUG), Unified Parkinson's Disease Rating Scale (UPDRS), Parkinson's Disease Questionnaire-39 (PDQ-39), Beck Depression Index (BDI), the Falls Efficacy Scale (FES), and Montreal Cognitive Assessment (MoCA). RESULTS: At the end of the study, an increase of 30.49% in aerobic capacity was observed. Statistically significant improvements were found for the 6MWT (p = 0.001), TUG test (p = 0.001), UPDRS total score (p = 0.002), quality of life assessed with PDQ-39 (p = 0.006), BDI (p = 0.001), and FES scores (p = 0.002) after an 8-week ACE training. No significant effect on MoCA was found (p = 0.264). CONCLUSION: An 8-week ACE training led to significant improvement in aerobic capacity, physical performance, and PD-related disabilities.
Assuntos
Doença de Parkinson , Braço , Terapia por Exercício , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/psicologia , Desempenho Físico Funcional , Equilíbrio Postural , Qualidade de Vida , Estudos de Tempo e MovimentoRESUMO
In the present study, we focused on investigating the contribution of functional dopamine D2 and D3 receptor variants to motor and/or non-motor symptoms of early onset Parkinson's disease (EOPD). Three functional single nucleotide polymorphisms (SNPs), DRD3 rs6280, DRD2 rs2283265 and DRD2 rs1076560, were genotyped in 128 Turkish EOPD patients and then, statistical analysis was conducted for the potential impacts of SNPs on clinical parameters. All three SNPs were found to be statistically significant in terms of PD-related pain: DRD3 [rs6280; risk allele "T" for pain; pâ¯=â¯0.031; odds ratio (OR)=4.25], DRD2 [rs2283265; risk allele "A" for pain; pâ¯=â¯0.001; OR=8.47] and, DRD2 [rs1076560; risk allele "A" for pain; pâ¯=â¯0.022; OR=4.58]. Additionally, bilateral disease [pâ¯=â¯0.011; OR=5.10] and gender [risk group "female"; pâ¯=â¯0.003; OR=8.53] were also identified as significant univariate risk factors for PD-related pain. Based on logistic regression analysis conducted with the significant univariate risk factors, this the first report to clarify that a female patient with bilateral PD and DRD2 rs2283265 polymorphism has a significant risk for PD-related pain. Our findings might contribute to improve life quality by offering treatment options for pain in PD patients with these clinical and genetic features.
Assuntos
Variação Genética/genética , Transtornos das Habilidades Motoras/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/genética , Adulto , Idade de Início , Estudos de Coortes , Feminino , Seguimentos , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos das Habilidades Motoras/diagnóstico , Transtornos das Habilidades Motoras/epidemiologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/epidemiologiaRESUMO
Essential tremor (ET) still remains a clinical diagnosis. Nonetheless, it is misdiagnosed in 30 to 50% of cases. There are a number of areas of diagnostic uncertainty. One of these is isolated head tremor, on which published data are limited and at variance. We studied the prevalence of isolated head (i.e., neck) tremor in ET in two population-based studies (Turkey and New York) and a large clinical sample (New York); these 583 ET cases all received the same detailed tremor examination. Head tremor with mild arm tremor occurred in a very small percentage of cases in each sample (1.9-3.1%, overall 2.7%). Nearly all of them were women. Head tremor in the complete absence of arm tremor was not observed in any cases (0.0%). These clinical data may be of value to clinicians in practice settings and researchers in phenotyping efforts in the emerging field of ET genetics.
Assuntos
Tremor Essencial/diagnóstico , Tremor Essencial/epidemiologia , Cabeça/fisiopatologia , Adulto , Idoso , Planejamento em Saúde Comunitária , Avaliação da Deficiência , Tremor Essencial/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , New York/epidemiologia , Prevalência , Índice de Gravidade de Doença , Turquia/epidemiologiaRESUMO
BACKGROUND: Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Unified Dyskinesia Rating Scale (UDysRS) were developed as standard tools to rate Parkinson's disease (PD) and drug-induced dyskinesias of PD. As these scales have become widely used, there is a need for translation to non-English languages. Here we present the standardization for the Turkish translations. METHODS: The scales were translated into Turkish and then back-translated to English. These back-translations were reviewed by the MDS team. After cognitive pretesting, movement disorder specialists from nine centers tested 352 patients for MDS-UPDRS, and 250 patients for UDysRS. Confirmatory factor analyses (CFAs) were used to determine if the factor structures for the reference standards could be confirmed in the Turkish data. The comparative fit indexes (CFIs) for the scales were required to be 0.90 or higher. Exploratory factor analyses (EFAs) were conducted to explore the underlying factor structure without the constraint of a pre-specified factor structure. RESULTS: For both scales, the CFIs were 0.94 or greater as compared to the reference standard factor structures. The factor structures were consistent with that of reference standards, although there were some differences in some areas as compared to the EFA of the reference standard dataset. This may be due to the inclusion of patients with different stages of PD and different cultural properties of raters and patients. CONCLUSIONS: These results demonstrate that the Turkish translations of MDS-UPDRS and UDysRS have adequate clinimetric properties. They are established as the official translations and can be reliably used in Turkish speaking populations.
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BACKGROUND: Essential tremor (ET) is one of the most common neurologic disorders. Aside from underlying susceptibility genes, recent studies have also begun to focus on environmental toxic factors. Yet there remains a paucity of information on such factors, making studies of environmental factors important. A recent study in New York City found blood lead concentrations to be elevated in ET cases compared with matched controls. Chronic exposure to lead produces cerebellar damage, and this could predispose individuals to develop ET. OBJECTIVE: The aim of this study was to determine whether the elevation in blood lead concentrations observed in a single study in New York was similarly present in ET cases sampled from a completely different geographic region. METHODS: Blood lead concentrations were measured in 105 ET cases and 105 controls at Mersin University, Mersin, Turkey. RESULTS: The median blood lead concentration was 2.7 microg/dL in ET cases compared with 1.5 microg/dL in controls (p < 0.001). In an unadjusted logistic regression model, blood lead concentration was associated with diagnosis: odds ratio (OR) = 4.01; 95% confidence interval (CI), 2.53-6.37; p < 0.001 (i.e., each 1-microg/dL increase in blood lead concentration was associated with a 4-fold increased odds of ET). This association was more robust when cases were compared with a subsample of controls who did not share the same home environment (OR = 8.13; 95% CI, 3.05-21.65; p < 0.001). In adjusted models, results were similar. CONCLUSIONS: These data replicate those of a previous study in New York and demonstrate an association between the environmental toxicant lead and a common neurologic disorder.
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Tremor Essencial/fisiopatologia , Intoxicação por Chumbo/complicações , Chumbo/sangue , Adulto , Estudos de Casos e Controles , Tremor Essencial/diagnóstico , Tremor Essencial/etiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Turquia , Gravação de VideoteipeRESUMO
BACKGROUND/AIMS: The distribution of age of onset of essential tremor (ET) is unclear, with discrepancies in the literature. Some data suggest a bimodal distribution and other data 1 late-life peak. We studied age of ET onset in 2 distinct settings: a population-based study and a tertiary referral center. METHODS: Age of onset data were collected. RESULTS: In the population, there was only a small peak at the age of Assuntos
Tremor Essencial/epidemiologia
, Adulto
, Fatores Etários
, Idade de Início
, Idoso
, Idoso de 80 Anos ou mais
, Comparação Transcultural
, Tremor Essencial/etiologia
, Feminino
, Inquéritos Epidemiológicos
, Humanos
, Masculino
, Pessoa de Meia-Idade
, Cidade de Nova Iorque
, Encaminhamento e Consulta/estatística & dados numéricos
, Fatores de Risco
, Turquia
RESUMO
Background and aim The effect of epigenetic modifications in the genes related to Parkinson's disease (PD) is still unclear. In the present study, we investigated methylation status of SNCA and PARK2 genes in patients with early-onset Parkinson's disease (EOPD). Materials and methods The promoter region methylation status of SNCA and PARK2 genes was evaluated by methylation specific-PCR (MSP) in 91 patients with EOPD and 52 healthy individuals. Results The methylation of SNCA and PARK2 promoter regions were significantly lower in EOPD patients compared to the control group (P = 0.013 and P = 0.03, respectively). We also found that the methylation status of the SNCA might be associated with positive family history of PD (P = 0.042). Conclusion Although it should be supported by further analysis, based on the results of the present study, the methylation status of SNCA and PARK2 genes might contribute to EOPD pathogenesis.
Assuntos
Metilação de DNA , Doença de Parkinson/genética , Regiões Promotoras Genéticas , Ubiquitina-Proteína Ligases/genética , alfa-Sinucleína/genética , Idade de Início , Ilhas de CpG , Epigênese Genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , LinhagemRESUMO
INTRODUCTION: Mutations in the C19orf12 gene cause mitochondrial membrane protein associated neurodegeneration (MPAN), an autosomal recessive form of neurodegeneration with brain iron accumulation (NBIA). A limited number of patients with C19orf12 mutations, particularly those with adult onset of symptoms, have been reported. METHODS: We sequenced the entire coding region of C19orf12 in 15 Turkish adult probands with idiopathic NBIA. We also performed haplotype analysis in families with a recurrent C19orf12 mutation. Clinical features were collected using a standardized form. RESULTS: Nine of our 15 probands (60%) carried the homozygous c.32C > T mutation in C19orf12 (predicted protein effect: p.Thr11Met). This homozygous mutation co-segregated with the disease in all affected relatives available for testing (16 homozygous subjects). Haplotypes across the C19orf12 locus were identical for a very small region, closest to the mutation, suggesting an old founder, or, two independent founders. The clinical phenotype was characterized by adult onset in most cases (mean 24.5 years, range 10-36), and broad spectrum, including prominent parkinsonism, pyramidal signs, psychiatric disturbances, cognitive decline, and motor axonal neuropathy, in various combinations. On T2- or susceptibility weighted-MRI images, all patients displayed bilateral hypointensities in globus pallidus and substantia nigra, without an eye-of-the-tiger sign; however, hyperintense streaking of the medial medullary lamina between the external and internal parts of globus pallidus was observed frequently. CONCLUSION: The C19orf12 p.Thr11Met mutation is frequent among adult Turkish patients with MPAN. These findings contribute to the characterization of this important NBIA form, and have direct implications for genetic testing of patients of Turkish origin.
Assuntos
Predisposição Genética para Doença/genética , Proteínas Mitocondriais/genética , Mutação/genética , Doenças Neurodegenerativas/genética , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Saúde da Família , Feminino , Haplótipos , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Metionina/genética , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/diagnóstico por imagem , Treonina/genética , Turquia , Adulto JovemRESUMO
OBJECTIVE: Variations in PARK genes (PRKN, PINK1, DJ-1, and SNCA) cause early-onset Parkinson's disease (EOPD) in different populations. In the current study, we aimed to evaluate the frequencies of variations in PARK genes and the effects of these variations on the phenotypes of Turkish EOPD patients. METHODS: All coding regions and exon-intron boundaries of the PRKN, PINK1, DJ-1, and SNCA genes were screened by heteroduplex analysis followed by direct sequencing of the detected variants in 50 Turkish EOPD patients. These variants were evaluated using SIFT, PolyPhen, HSF, and LOVD web-based programs. RESULTS: The frequency of EOPD-associated variations in the PRKN gene was 34%. Among these variations, p.A82E in exon 3 and p.Q409X in exon 11 was determined to be pathogenic. We also defined previously unknown cryptic variations, including c.872-35 G>A and c.872-28T>G in exon 8 of PRKN and c.252+30 T>G and c.322+4 A>G in exons 4 and 5 of DJ1, respectively, that were associated with EOPD. Although no significant association was observed between the PARK gene mutations and clinical features (P>0.05), the alterations were related to the clinical symptoms in each patient. CONCLUSION: An increasing number of studies report that PRKN, PINK1, DJ1 and SNCA mutations are associated with early-onset Parkinson's disease; however, a limited number of studies have been conducted in Turkey. Additionally, our study is the first to evaluate the frequency of SNCA mutations in a Turkish population. The aim of this study was determine the frequency distributions of the PRKN, PINK1, DJ1, and SNCA gene mutations and to analyze the relationships between these genetic variations and the clinical phenotype of EOPD in Turkish patients.
Assuntos
Doença de Parkinson/genética , Doença de Parkinson/fisiopatologia , Proteína Desglicase DJ-1/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , alfa-Sinucleína/genética , Adulto , Idade de Início , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , TurquiaRESUMO
OBJECTIVE: To describe the clinical features of essential tremor (ET) in a population. BACKGROUND: With few exceptions, clinical data on ET are derived from patients who attend specialty clinics. Most (> 90%) population-dwelling ET cases do not seek neurological attention. METHODS: 89 ET cases living in the Mersin province, Turkey were matched to 89 controls from the same population. All were examined by neurologists. Standardized scales included the Hamilton Depression Scale (HDS) and Hamilton Anxiety Scale (HAS). RESULTS: Eight-one (91%) of 89 cases previously had not been diagnosed as ET and 96.6% were untreated. Despite this,more than half (51.7%) of the cases answered "yes" to the question "are you disabled in some way by your tremor". Cases had more psychiatric symptomatology than controls (mean HDS scores = 11.4 +/- 8.2 vs. 7.9 +/- 6.1, p = 0.003 and mean HAS scores = 12.0 +/- 8.8 vs. 6.9 +/- 7.1, p < 0.001). Among ET cases, HDS scores (r = 0.24, p = 0.03) and HAS scores (r = 0.27, p = 0.01) were correlated with tremor severity. CONCLUSIONS: We present the clinical findings of a group of largely undiagnosed and untreated population-dwelling ET cases that would not otherwise have come to neurological attention. Approximately one-half reported functional difficulty and psychiatric symptoms were over-represented in these ET cases compared with matched controls. These findings suggest that ET, as it exists in the population, is not a completely benign entity.
Assuntos
Tremor Essencial/epidemiologia , Tremor Essencial/patologia , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Turquia/epidemiologiaRESUMO
We recently reported here that SNCA triplication results in a doubling in the amount of alpha-synuclein protein in blood from cases with hereditary Lewy body disease. This observation shows that alpha-synuclein levels in blood accurately reflect gene dosage, which we assume drives pathogenesis in these individuals. A previous report has suggested that parkin can affect alpha-synuclein metabolism in human brain. Here we have tested whether there is also an increase of alpha-synuclein in autosomal recessive juvenile Parkinsonism (ARJP). We find there is not and discuss this result in terms of the putative relationships between alpha-synuclein and parkin.