Neurodegenerative diseases and cancer: sharing common mechanisms in complex interactions.

Several epidemiological studies support low cancer rates in patients with neurodegenerative disorders, including Parkinson's disease, Huntington's disease, and Alzheimer's disease. Different mechanisms were raised as possible causes, from mutated tumor suppressor genes (PARKIN, PINK1) to small interfering RNA based on the CAG trinucleotide repeat expansions located in introns or untranslated regions. However, as every rule has an exception, some tumors have an increased incidence in these neurodegenerative diseases such as breast and skin cancer (melanoma). This mini-review aims to establish the epidemiology between these neurodegenerative disorders and cancer to determine the possible mechanisms involved and therefore set eventual therapeutic applications. According to our findings, we conclude the presence of an inverse relationship among most cancers and the aforementioned neurodegenerative disorders. However, this concept needs to be considered cautiously considering specific genetic and extra-genetic linkage factors for particular tumors.

Pseudoagoraphobia, a Diagnostic Clue in Stiff-Limb Syndrome.

BACKGROUND: Stiff-limb syndrome is part of stiff person spectrum, presenting with fluctuating gait disorders attributed to leg stiffness, spasms, and posturing. It could also manifest with anxiety and specific phobias such as pseudoagoraphobia. We aimed to describe the importance of specific gait phobia as a diagnostic clue to anti-glutamic acid decarboxylase stiff-limb syndrome. CASES: We reported on 2 cases of stiff-limb syndrome sharing a similar diagnostic path and phenomenology. Both were featured by pseudoagoraphobia, which has documented to typically cover organic conditions, and a remarkable diagnostic delay attributed to misdiagnoses. Presence of pseudoagoraphobia should not point to the diagnosis of a functional disorder-although a negative instrumental workup is documented. CONCLUSIONS: Both cases are emblematic of the high misdiagnosis rate affecting stiff person syndrome patients. A proper diagnostic process, including the identification of a pseudoagoraphobia, should help in reaching a diagnosis and providing an early and effective treatment.

Late Onset Huntington Disease: Phenotypic and Genotypic Characteristics of 10 Cases in Argentina.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder that includes motor, psychiatric and cognitive manifestations with typical onset of symptoms is in the forties. A percentage of patients (4.4% - 11.5%) may be exceptions to this and manifest symptoms later (>60 years old). Diagnosis of Late onset HD (LoHD) can be a challenge, due to the low suspicion of the disease at this age. OBJECTIVE: To review the genotype and phenotype of LoHD in an Argentinian cohort. METHODS: We reviewed the medical records and genetic testing of a total of 95 individuals with clinical and molecular diagnosis of Huntington's disease, based on 2 institution's registry. RESULTS: Among our HD cohort, 10 patients (10.52%) had LoHD, with variable results regarding family history. The average of repetitions of the expanded allele was 40 (range 38-44). All cases had mild motor symptoms at onset. CONCLUSIONS: Late onset HD can be a diagnostic challenge, due to its slow progression, unawareness of manifestations among patients and in many cases, mild symptomatology that does not warrant medical attention.

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.

Holmes Tremor Partially Responsive to Topiramate: A Case Report.

Background: Holmes tremor is a rare symptomatic movement disorder, characterized by a combination of resting, postural, and intention tremor. It is usually caused by lesions in the brainstem, thalamus, and cerebellum. Despite pharmacological advances, its treatment remains a challenge; many medications have been used with various degrees of effectiveness. Stereotactic thalamotomy and deep brain stimulation in the ventralis intermedius nucleus have been effective surgical procedures in cases refractory to medical treatment. Case Report: Here we report a young woman with topiramate-responsive Holmes tremor secondary to a brainstem cavernoma. Discussion: Herein we report a Holmes tremor responsive to Topiramate.

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.

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.

Pseudodystonic Posture Secondary to Klippel-Feil Syndrome and Diastematomyelia.

BACKGROUND: Dystonic postures possess a great number of differential diagnoses. PHENOMENOLOGY SHOWN: We describe a pseudodystonic posture in a 61-year-old woman with skeletal and extra-skeletal abnormalities. EDUCATIONAL VALUE: Klippel-Feil syndrome represents an unusual cause of pseudodystonic posture to be considered in the differential diagnosis of dystonia.

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.

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.

Vascular hemichorea/hemiballism and topiramate.

Although vascular hemichorea/hemiballism (HC/HB) has been reported to be self-limited, in some cases, it can be irreversible and severely disabling. The standard treatment includes typical and atypical neuroleptics and GABA-mimetic drugs. Topiramate is a new antiepileptic drug possessing a complex mechanism of action, including the enhancement of GABA-mediated inhibition. We describe a 71-year-old patient with HC/HB who markedly improved after topiramate treatment.

Unusual phenotypic expression of the DYT1 mutation.

Highly variable phenotype expression has long been recognized in DYT1 carrier patients. We report here an Ashkenazi-Jewish woman who carried a DYT1 mutation and developed a predominant unilateral myoclonic-dystonia (MD) displaying a fluctuating course. The present case is the second supporting the variability of DYT1 phenotype and further illustrates its ability to mimic the MD syndrome.

Parkinsonism as a manifestation of multiple sclerosis.

We describe a 48-year-old patient, with a diagnosis of relapsing-remitting multiple sclerosis, who presented to our service with a parkinsonian syndrome that markedly improved after corticosteroid treatment. To the best of our knowledge, only 12 cases of parkinsonism have been reported from 1970 to the present, of which only 8 seemed secondary to MS, i.e., those presenting conclusive imaging evidence or unequivocal response to corticosteroids.

Neuroprotection in Parkinson's disease; a commentary.

Parkinson's disease (PD) is a worldwide neurodegenerative disorder. Although the etiology has been linked to genetic and environmental factors, curative treatment remains a challenge. Several hypotheses support different pathophysiological mechanisms related to oxidative stress, glutamate-mediated neurotoxicity, mitochondrial energetic impairment and nitric oxide (NO) over-production. Moreover, apoptotic mechanisms have been identified in PD. In this way, classical drugs such as amantadine, selegiline and dopamine agonists show only a modest neuroprotective effect. New strategies with enormous potential are now under development. These include neuroprotectants and agents that might rescue dopaminergic neurons. Glutamate receptor antagonists, neurotrophins, neuroimmunophilins, adenosine A2A receptor antagonists, iron-chelators and NO modulators, as well as caspase inhibitors have evident neuroprotective properties in experimental PD models.

Hidrosiringomielia no comunicante asociada a lesión desmielinizante / Non-communicatig hydrosyringomyelia associated to demyelinative lesion

La siringomielia no comunicante ha sido descrita en asociación con diversas patologías medulares, pero raramente ha sido reportada en relación con lesiones desmielinizantes. Presentamos un paciente de 39 años, varón, con antecedentes de herpes zoster craneal en 1996 que evolucionó con omalgia izquierda y cervicalgia persistente. La resonancia magnética (RM) de médula cervical evidenció lesión intramedular focal a nivel C4-C5 de aspecto desmielizante, y la presencia de hidrosiringomielia nivel C6. El paciente rehusó nuevos procedimientos. En 1998 agrega signo de Lhermitte. Una nueva RM espinal mostró reducción de la lesión intramedular cervical con persistencia de la siringomielia no comunicante. La RM cerebral objetivó una única lesión puntiforme en el brazo posterior de la cápsula interna derecha. Las serologías para HIV, herpes, HTLV I-II, VDRL y potenciales evocados fueron normales. En septiembre de 1998 se encontraba asistomático, con examen neurológico normal y sin cambios en el control por imágenes. La evolución clínica y hallazgos neurorradiológicos sugieren una lesión primariamente desmielinizante versus un mecanismo postinfeccioso La patogénesis de la siringomielia no comunicante asociada alesiones desmielinizantes es discutida: se postula dilatación ependimaria mécanica por obstrucción al flujo del líquido cefalorraquídeo causado por el edema de la placa espinal versus dilatación ependimaria secundaria a mielomalacia. Pese a su baja prevalencia y a la dificultad diagnóstica que plantea la ausencia de un patrón radiológico característico, la patología desmielinizante debería considerarse entre los diagnósticos diferenciales de lesiones intramedulares asociadas a hidromielia, ya que en estos casos el abordaje quirúrgico no estaría indicado

Inhibidores enzimáticos en el tratamiento de la enfermedad de Parkinson / Enzymatic inhibitors in the treatment of Parkinson's disease

La introducción de la L-DOPA en el tratamiento de los pacientes con enfermedad de Parkinson produjo un dramático impacto en la historia natural de esta enfermedad. Sin embargo su empleo crónico se asocia con la aparición de fluctuaciones motoras, describiéndose además una capacidad neurotóxica de la Dopamina. Ambos factores promueven la investigación constante de nuevos fármacos que permitan estabilizar los niveles plasmáticos de la L-DOPA y reducir las dosis útiles necesarias. Los inhibidores de la monoaminooxidasa (MAO) y de la catecol-oxi-metiltransferasa (COMT) permiten disminuir la degradación de la Dopamina contribuyendo a aumentar su biodisponibilidad y reducir las dosis de L-DOPA. Los inhibidores de la COMT aparecen como nuevos adjuvantes seguros y eficaces de la terapia antiparkinsoniana, pudiendo actuar a nivel central y periférico. Estas nuevas herramientas farmacológicas están destinadas a disminuir los efectos deletéreos que a largo plazo acarrea la L-DOPA terapia