A novel mutation in PSEN1 (p.Arg41Ser) in an Argentinian woman with early onset Parkinsonism.

INTRODUCTION: Mutations in presenilin-1 (PSEN1) account for the majority of cases of familial autosomal dominant early-onset Alzheimer's disease (AD) as well as in sporadic forms. Atypical presentations are reported including extrapyramidal signs. In the last years, a pleiotropic effect of some PSEN1 variants has been reported in Parkinson's disease (PD). OBJECTIVE: to report a new PSEN1 mutation characterized by early-onset Parkinsonism (EOPD) without dementia or classical AD biomarkers phenotype. PATIENT AND METHODS: An Argentinian 46 years old woman was diagnosed with EOPD at 35 years old with no family history of neurodegenerative disorders. Her medical history included iron deficiency and anemia since childhood. A brain MRI showed moderate frontal atrophy. 18FDG-PET and PiB-PET as well as CSF biomarkers were inconclusive for AD. Two neuropsychological examinations were compatible with a mild non amnestic cognitive impairment. Whole blood DNA was extracted and whole exome sequencing and analysis was performed. RESULTS AND CONCLUSION: A heterozygous novel missense PSEN1 mutation (position 14:73637540, A > T, pArg41Ser) was identified as a likely causative mutation in this patient. To the best of our knowledge, this case is the first PSEN1 mutation with a l-dopa responsive Parkinsonism lacking distinctive classical AD biomarkers. This case opens a new window to explore the pathophysiological link among PSEN1 and EOPDs and contributes to increase the phenotypes of PSEN1 variants.

Biological and clinical manifestations of juvenile Huntington's disease: a retrospective analysis.

BACKGROUND: Huntington's disease is a rare, neurodegenerative disease caused by an expanded CAG repeat mutation in the huntingtin gene. Compared with adult-onset Huntington's disease, juvenile Huntington's disease (onset ≤20 years) is even rarer and has not been studied extensively. We aimed to further characterise juvenile Huntington's disease by examining the effect of CAG repeat size on disease presentation, progression, and survival. METHODS: We did a retrospective analysis of patients with juvenile Huntington's disease aged 20 years or younger, according to the length of their CAG repeat and who had disabling psychiatric symptoms (with motor symptoms) or motor symptoms alone, and of patients with adult-onset Huntington's disease manifesting aged 30-60 years with 40 or more CAG repeats, from the REGISTRY and ENROLL-HD platforms and from two institutional databases (Lega Italiana Ricerca Huntington Foundation and the Instituto Neurociencias de Buenos Aires and the Sanatorio de la Trinidad Mitre). Patients with psychiatric but no motor symptoms were excluded. We compared symptoms at onset and longitudinally in patients with juvenile Huntington's disease with highly expanded (HE subgroup) or low expansion (LE subgroup) mutations, grouped by hierarchical clustering analysis. We also compared disease progression (longitudinal change in Unified Huntington's Disease Rating Scale-Total Motor Score) and survival of patients with juvenile and adult-onset Huntington's disease. FINDINGS: We extracted medical records from 580 patients entered into the studies or databases between June 23, 2004, and March 31, 2018, of whom 36 patients met our definition of juvenile Huntington's disease and 197 for adult-onset Huntington's disease. According to caregiver reports, gait disturbance was more often a first presenting symptom in the HE subgroup (eight [80%] of 10 patients) than in the LE subgroup (seven [27%] of 26 patients; p=0·0071), whereas loss of hand dexterity was more common in the LE subgroup (11 [42%] of 26 patients) than in the HE subgroup (0 [0%] of 10 patients; p=0·0160). Compared with the LE subgroup, development delay (0 [0%] in the LE subgroup vs nine [90%] in the HE subgroup; p<0·0001), severe gait impairment (nine [35%] in the LE subgroup vs nine [90%] in the HE subgroup; p=0·0072), and seizures (three [11%] in the LE subgroup vs eight [80%] in the HE subgroup; p<0·0001) prevailed over time in the HE subgroup. Disease progression was more rapid in juvenile Huntington's disease (n=14) than in adult-onset Huntington's disease (n=52; generalised estimating equation model, p=0·0003). Of 121 deceased patients, median survival was shorter in the juvenile Huntington's disease (n=17) cohort than in adult-onset Huntington's disease (n=104) cohort (hazard ratio 2·18 [95% CI 1·08-4·40]; p=0·002). INTERPRETATION: Patients with HE juvenile Huntington's disease differ clinically from patients with LE juvenile Huntington's disease or adult-onset Huntington's disease, suggesting reclassification of this particularly aggressive form of Huntington's disease might be required. FUNDING: Lega Italiana Ricerca Huntington Foundation and IRCCS Ospedale Casa Sollievo della Sofferenza.

Optical coherence tomography (OCT) study in Argentinean Huntington's disease patients.

BACKGROUND: Huntington's disease (HD) is a genetic, rare and progressive neurodegenerative disorder that causes motor and cognitive impairment in midlife patients. Although retinal damage was observed in animal HD models and in patients with other neurodegenerative diseases, we still need confirmation of impairment in HD patients. Optical coherence tomography (OCT) is a non-invasive methodology that analyses the retinal nerve fibre layers (RNFL) and could reflect processes of neurodegeneration. METHODS: A cross-sectional study with 14 HD patients who underwent a spectral domain OCT. Results were compared with a control group. Demographic data were also obtained. RESULTS: Temporal and superior RNFL sectors in HD showed a significant RNFL thinning compared with a control group. However, no differences were identified in mean total RNFL thickness between HD patients and controls. CONCLUSIONS: OCT is a rapid and non-invasive technique that can be investigated in larger cohorts of patients to assess its potential role as a biomarker in HD patients.

Sertraline-induced Hemichorea.

Background: Hemichorea-hemiballism is a syndrome secondary to different etiologies. Drug-induced hemichorea is a rare syndrome related to selective serotonin reuptake inhibitors. To the best of our knowledge, no previous cases of hemichorea associated with sertraline have been reported. Case Report: A 65-year-old female noticed hemichorea 1 week after initiation of sertraline. After extensive investigations, other causes of hemichorea were excluded. Hemichorea remitted after sertraline withdrawal. Discussion: In our patient, temporal association and the negative clinical assessment supported a diagnosis of likely drug-induced involuntary movement. We hypothesized that enhanced serotonergic transmission in the ventral tegmental area or nigrostriatum may be involved in sertraline-induced hemichorea.

Juvenile Huntington disease in Argentina / Doença de Huntington juvenil na Argentina

ABSTRACT We analyzed demographic, clinical and genetic characteristics of juvenile Huntington disease (JHD) and it frequency in an Argentinean cohort. Age at onset was defined as the age at which behavioral, cognitive, psychiatric or motor abnormalities suggestive of JHD were first reported. Clinical and genetic data were similar to other international series, however, in this context we identified the highest JHD frequency reported so far (19.72%; 14/71). Age at onset of JHD is challenging and still under discussion. Our findings reinforce the hypothesis that clinical manifestations, other than the typical movement disorder, may anticipate age at onset of even many years. Analyses of JHD cohorts are required to explore it frequency in populations with different backgrounds to avoid an underestimation of this rare phenotype. Moreover, data from selected populations may open new pathways in therapeutic approaches and may explain new potential correlations between HD presentations and environmental or biological factors.

RESUMO Foram analisadas as características demográficas, clínicas e genéticas de doença de Huntington juvenil (JHD) e na freqüência em uma coorte argentino. A idade de início foi definida como a idade em que distúrbios comportamentais, cognitivos, psiquiátricos ou anormalidades motoras sugestivas de JHD foram relatada pela primeira vez. Os dados clínicos e genéticos foram semelhantes aos de outras séries internacionais, no entanto, neste contexto identificamos a maior freqüência de JHD relatados até agora (19,72%; 14/71). A idade de início de JHD é um desafio ainda em discussão. Nossos resultados reforçam a hipótese de que as manifestações clínicas, além do transtorno de movimento típico, pode antecipar a idade de início em muitos anos. As análises de coortes de JHD são obrigados a explorar frequências em populações com diferentes formações, para evitar uma subestimação deste fenótipo raro. Além disso, os dados de populações selecionadas podem abrir novos caminhos em abordagens terapêuticas e pode explicar novas correlações potenciais entre apresentações de HD e fatores ambientais ou biológicas.

Juvenile Huntington disease in Argentina.

We analyzed demographic, clinical and genetic characteristics of juvenile Huntington disease (JHD) and it frequency in an Argentinean cohort. Age at onset was defined as the age at which behavioral, cognitive, psychiatric or motor abnormalities suggestive of JHD were first reported. Clinical and genetic data were similar to other international series, however, in this context we identified the highest JHD frequency reported so far (19.72%; 14/71). Age at onset of JHD is challenging and still under discussion. Our findings reinforce the hypothesis that clinical manifestations, other than the typical movement disorder, may anticipate age at onset of even many years. Analyses of JHD cohorts are required to explore it frequency in populations with different backgrounds to avoid an underestimation of this rare phenotype. Moreover, data from selected populations may open new pathways in therapeutic approaches and may explain new potential correlations between HD presentations and environmental or biological factors.

[Rational use of psychotropic medications and sedative load in older adults with and without dementia]. / Uso de psicofármacos y carga sedativa en pacientes adultos con y sin demencia.

Sedative drugs use has been associated with more cognitive impairment and increased mortality. Sedative load refers to cumulative exposure to multiple drugs with sedative properties. OBJECTIVE: Describe the use of psychotropic drugs and sedative load in older adults with and without dementia. MATERIAL AND METHODS: We conducted a cross-sectional study from 2014-2015 (Sanatorio Trinidad Mitre), in hospitalized patients older than 65 years old. Drugs were classified according to the WHO ATC system. The sedative load of drugs was calculated using the Linjakumpu model. RESULTS: 152 PsD and 35 PcD patients were registered, mean age 80.8±8.42. Polypharmacy was present in 44.39% being higher in patients with dementia than without dementia (62.80% vs 40.13%, p=0.0147). In 40.64% at least one psychotropic/sedative medication was used, greater in PcD (60% vs 36.18%, p=0.0097). The CS was: 1.32±1.59; 2.14 in PcD and 1.13 in PsD (p<0.001). Atypical antipsychotics and benzodiazepines were the most common (51.43 and 40% respectively) in patients without dementias. CONCLUSION: we evidenced a high level of prescription psychotropic or sedative drugs, mostly in patients with dementia. In those, the sedative load was greater. This finding highlights the importance of implementing strategies to optimize sedative drug use among older people.

Focal Task-specific Dystonia among Professional Musicians in Latin America.

In Response To: Frucht SJ. Focal task-specific dystonia-from early descriptions to a new, modern formulation. Tremor Other Hyperkinet Mov. 2014; 4. doi: 10.7916/D8VD6WHP.

Inverse association between yerba mate consumption and idiopathic Parkinson's disease. A case-control study.

Yerba mate tea is a very common beverage in some countries of South America. We conducted a case-control study on an individual basis using hospital records to investigate the association between Parkinson's disease (PD) and yerba mate intake. A case was defined as an age of ≥ 40 years with ≥ 1 year of PD. Each case was individually matched by two controls. Exposure was measured by yerba mate consumption, coffee, tea, and alcohol intake and smoking status. The sample consisted of 223 PD patients (mean age 68 years and mean disease duration 7.3 years) and 406 controls. There was an inverse association between yerba mate "bombilla" consumption and PD (OR 0.64, 95% CI: 0.54-0.76, p=0.00001). A multivariate analysis with a logistic regression adjusted by sex, alcohol intake and smoking provided the following results: yerba mate (OR 0.63, 95% CI: 0.53-0.76), tea (OR 0.60, 95% CI: 0.42-0.86), coffee (OR 0.51, 95% CI: 0.35-0.73). We found an inverse association between yerba mate consumption and PD. These results led us to hypothesize that yerba mate may have a potential protective role in the development of PD.

Cognition in a multiple system atrophy series of cases from Argentina.

UNLABELLED: Cognitive dysfunction may occur in 17-40% of patients with multiple system atrophy (MSA). It has been suggested a milder cognitive impairment in cerebellar (MSA-C) than in parkinsonian variant (MSA-P). However, differences in cognitive profiles remain under discussion. OBJECTIVE: To evaluate cognitive features in a series of patients with "probable MSA" from Argentina. METHOD: After informed consent was obtained, an extensive cognitive tests battery was administered. Nine patients (6 MSA-P and 3 MSA-C) composed the sample. RESULTS: Depression was detected in 43% of patients. Seven patients showed at least one cognitive domain impairment. Temporospatial orientation, visuospatial abilities, executive and attentional functions, episodic memory and language were compromised in MSA-P, while MSA-C dysfunction was restricted to attentional and executive domains. CONCLUSION: Despite the small sample size, our findings could suggest a more widespread cognitive impairment in MSA-P than MSA-C.

Cognition in a multiple system atrophy series of cases from Argentina / Cognição em uma série dos casos de atrofia de múltiplos sistemas da Argentina

Cognitive dysfunction may occur in 17-40% of patients with multiple system atrophy (MSA). It has been suggested a milder cognitive impairment in cerebellar (MSA-C) than in parkinsonian variant (MSA-P). However, differences in cognitive profiles remain under discussion. Objective To evaluate cognitive features in a series of patients with “probable MSA” from Argentina. Method After informed consent was obtained, an extensive cognitive tests battery was administered. Nine patients (6 MSA-P and 3 MSA-C) composed the sample. Results Depression was detected in 43% of patients. Seven patients showed at least one cognitive domain impairment. Temporospatial orientation, visuospatial abilities, executive and attentional functions, episodic memory and language were compromised in MSA-P, while MSA-C dysfunction was restricted to attentional and executive domains. Conclusion Despite the small sample size, our findings could suggest a more widespread cognitive impairment in MSA-P than MSA-C. .

Disfunção cognitiva pode ocorrer em 17-40 % dos pacientes com atrofia de múltiplos sistemas (AMS). Alguns estudos têm sugerido a presença de disfunção cognitiva mais leve nos pacientes com AMS do tipo cerebelar (AMS-C) do que na variante parkinsoniana (AMS-P). Objetivo Avaliar os perfis cognitivos de uma série de pacientes argentinos com “Provável AMS”. Método Foram selecionados 6 AMS-P e 3 AMS–C aos quais foi aplicada uma extensa bateria de testes cognitivos. Resultados Depressão foi detectada em 43% dos pacientes. Sete pacientes apresentaram comprometimento de pelo menos um domínio cognitivo. As funções de orientação temporo-espacial, habilidades visuo-espaciais, função executiva e de atenção, memória episódica e linguagem foram comprometidas em pacientes com AMS-P. Nos pacientes com AMS-C as dificuldades cognitivas ficaram restritas às funções executivas e de atenção. Conclusão Apesar do pequeno tamanho da amostra, nossos achados sugerem que pacientes com AMS-P apresentam um comprometimento cognitivo mais amplo do que pacientes com AMS-C. .

Pan-American Consortium of Multiple System Atrophy (PANMSA). A Pan-American multicentre cohort study of multiple system atrophy.

BACKGROUND: Multiple system atrophy (MSA) is an adult-onset and rapidly progressive, neurodegenerative condition that presents with autonomic dysfunction, parkinsonism, cerebellar ataxia and corticospinal deficits. Clinical, demographic and epidemiological data from different regions have provided valuable information concerning the natural history of MSA. There are no published data of Multiple System Atrophy (MSA) in Latin American countries. OBJECTIVE: To describe clinical and epidemiological data of patients with "possible" MSA from seven referral movement disorders centers from Argentina, Chile, Mexico, Peru and United States. METHODS: We conducted a retrospective, observational, cross-sectional Pan-American multicentre cohort study of MSA. RESULTS: The sample was composed of 82 females and 77 men with the diagnosis of "possible" MSA with a mean age at onset of 65 ± 10 years. 67.29% of the individuals had a MSA-P variant with a mean age at onset of 61.47 ± 10.28 years, whereas the mean age at onset in the MSA-C patients was 57.44 ± 10.58 years. Interestingly, MSA-C-was more prevalent in Non-Caucasian (50-Mestizo and 2 Asian patients) than Caucasians (51.92% vs. 20.79%, p = 0.0001). Dysautonomic symptoms were present in 95.6% of the patients, parkinsonism in 85.5%, pyramidal signs in 25.8% and depression in 48.4% of the patients. CONCLUSIONS: Our epidemiological and clinical data appears to be similar to other Western international series, however, of note, the MSA-C phenotype was predominant in Non-Caucasians, more specifically the Mestizo population. This observation opens a new path to explore. Larger prospective epidemiologic studies in Latin America may provide valuable information concerning MSA in the region.

The LRRK2 G2019S mutation in a series of Argentinean patients with Parkinson's disease: clinical and demographic characteristics.

OBJECTIVES: To determine clinical characteristics and frequency of leucine-rich repeat kinase 2 gene (LRRK2) mutations in a cohort of patients with Parkinson's disease (PD) from Argentina. BACKGROUND: Variation in the LRRK2 gene represents the most common genetic determinant of PD, only few data are available from Latin-America. DESIGN/METHODS: Informed consent was obtained and all studies were approved by the Institutional Review Boards. Fifty five consecutive PD patients were recruited. A structured interview and neurological examination were used to collect demographic and clinical information. Blood samples were obtained and DNA extracted from patient venous blood. All LRRK2 exons from 25 exon to 51 exon were screened in all patients. RESULTS: Clinical and molecular data of 55 patients with PD were analyzed. Mean age was 68.8±10.6 years. Jewish and Basque ancestries were found positive in 9 and 7 patients, respectively; family history of PD was identified in 16 patients. The G2019S mutation was present in 3 Ashkenazi Jewish subjects (5.45%); all of them reported family history of PD in first-degree relatives. Although Argentina possesses one of the most important Basque communities outside Spain, non R1414G mutation was identified in this cohort. Eleven single polymorphisms (SNP) were identified in this cohort. The mean age at onset was higher in G2019S mutation carriers than non-carriers (66.67 vs 58.78 years). Asymmetrical tremor as initial symptom and non-motor symptoms occurred at similar frequencies in both groups. The G2019S mutation carriers showed a non significant increase in dyskinesias, and 2/3 developed Dopamine Dysregulation Syndrome and visual hallucinations. Systemic disorder identified in G2019S mutation carriers included: celiac disease, hypothyroidism, Hashimoto's Thyroiditis and arterial hypertension. CONCLUSIONS: The prevalence of LRRK2 G2019S mutation in this Argentinean cohort was similar to other international series, with a higher prevalence in Ashkenazi Jewish. The phenotype was indistinguishable from patients with idiopathic PD. Interestingly, we identified immune mediated disorders in two PD patients carrying the G2019S mutation. Within this context, recent studies have identified full-length LRRK2 as a relatively common constituent of many cell types in the immune system including human peripheral blood mononuclear cells. Nevertheless, a casual association could not be excluded and the analysis of more extensive series is required.

Clinical and genetic characteristics in patients with Huntington's Disease from Argentina.

UNLABELLED: Huntington's Disease (HD) is a neurodegenerative disease, caused by the expansion of an unstable (CAG)(n) in the HTT gene. There is scarce data about the disease in Argentina. OBJECTIVE: To describe the demographic, clinical and molecular data in patients with HD from Argentina. PATIENTS AND METHODS: 59 HD patients were recruited at our department. Comprehensive interviews, neurological examination and genetic analysis were performed in probands. Statistical analysis was conducted using G-Stat 2.0 and non-parametric tests (Wilcoxon). RESULTS: 32 women and 27 men were diagnosed with a mean age of 45.7 ± 16.2 years and a mean age at onset of 35.8 ± 14.8 years. We found no gender prevalence and an inverse correlation between size of mutant CAG repeat sequence and age at onset, r = -0.58, r(2) = 33.6, Pearson's correlation coefficient p = 0.0008. Juvenile HD in this series of patients was higher than previously reported (16.6% vs. <10%). The mean CAG repeat in the expanded allele was 45.1. The number of CAG repeats in Argentinean controls was 17.8, which is similar to the literature of the European population. CONCLUSIONS: This is the first series of Argentinean HD patients with demographic, clinical and molecular data. Our findings appear similar to the ones described in Western European populations.

Prevalence of restless legs syndrome: a community-based study from Argentina.

BACKGROUND AND PURPOSE: The number of restless legs syndrome (RLS) prevalence studies performed outside Europe and North America remains small. We conducted a community-based study to estimate the relative prevalence of RLS in Argentina. PATIENTS AND METHODS: A total sample of 471 participants from high (Buenos Aires) and low population density areas (three cities with <35,000 inhabitants), completed a self-assessment questionnaire, including the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria, to determine RLS symptoms. RESULTS: In the present study, the four RLS criteria were reported in 20.2%. In accordance with other studies, we found a female/male ratio of 3:1, with women being younger than men. However, RLS prevalence in "clinically significant" participants, that is symptoms present at least two or more times a week, were 10.8% (12.4% in participants from high population density versus 2.60% in participants from low population density areas). CONCLUSIONS: In the present study, RLS appears as a common disorder in this population. The RLS prevalence found is in agreement with some epidemiological reports from the American and European populations but it is significantly higher than the prevalence reported for Native South Americans (i.e., 0.8-3.2%). These differences could be explained by the composition of the Argentinean population with predominantly European roots. Taking into account the significant impact of RLS on health and quality of life, our study represents a preliminary approach to characterize this chronic disease in this community.