RESUMEN

Managing genetic disease using medically assisted reproductive technology is increasingly promoted as a feasible option, given revolutionary advances in genomics. Far less attention has been directed to the issue of whether there is equitable access to this option. Context and circumstance determine equitable access; however, reporting has drawn overwhelmingly from affluent Anglo-western populations in developed countries. The experiences of poorer, less educated subpopulations within affluent countries and populations in less developed countries are underreported. The ability of consumers to understand the opportunities and risks of medically assisted reproductive technology is likewise not well described in the literature despite significant technological complexity and evidence that genetic disease may be overrepresented within some disadvantaged population groups.Equity is achieved by identifying barriers and allocating appropriate resources to enable understanding and access. In the case of utilising medically assisted technology, social and power relationships, regulations, and the presumptions of authority figures and policymakers reduce equitable access. Physical or cultural marginalisation from mainstream health services may result in reduced access to genetic and prenatal testing, in-vitro fertilisation and genetic screening of embryos necessary for medically assisted reproduction. Cost and regulatory frameworks can likewise limit opportunities to engage with services. Moreover, the quality of the information provided to prospective users of the technology and how it is received governs understanding of prevention and inhibits adequately informed choice.Best practice care and adequately informed choice can only be achieved by conscientiously attending to these accessibility issues. Deep engagement with at-risk people and critical reflection on mainstream accepted standpoints is required. This paper outlines issues associated with engaging with medically assisted reproduction encountered by Aboriginal families living with Machado-Joseph Disease in some of the most remote areas of Australia. It is the right of these families to access such technologies regardless of where they live. Current barriers to access raise important questions for service providers with implications for practice as new technologies increasingly become part of standard medical care.

Asunto(s)

Accesibilidad a los Servicios de Salud , Técnicas Reproductivas Asistidas , Femenino , Humanos , Australia , Enfermedades Genéticas Congénitas , Equidad en Salud , Disparidades en Atención de Salud , Población Rural , Aborigenas Australianos e Isleños del Estrecho de Torres

RESUMEN

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a neurodegenerative disorder caused by the ATXN3 CAG repeat expansion. Preimplantation genetic testing for monogenic disorders (PGT-M) of SCA3/MJD should include reliable repeat expansion detection coupled with high-risk allele determination using informative linked markers. One couple underwent SCA3/MJD PGT-M combining ATXN3 (CAG)n triplet-primed PCR (TP-PCR) with customized linkage-based risk allele genotyping on whole-genome-amplified trophectoderm cells. Microsatellites closely linked to ATXN3 were identified and 16 markers were genotyped on 187 anonymous DNAs to verify their polymorphic information content. In the SCA3/MJD PGT-M case, the ATXN3 (CAG)n TP-PCR and linked marker analysis results concurred completely. Among the three unaffected embryos, a single embryo was transferred and successfully resulted in an unaffected live birth. A total of 139 microsatellites within 1 Mb upstream and downstream of the ATXN3 CAG repeat were identified and 8 polymorphic markers from each side were successfully co-amplified in a single-tube reaction. A PGT-M assay involving ATXN3 (CAG)n TP-PCR and linkage-based risk allele identification has been developed for SCA3/MJD. A hexadecaplex panel of highly polymorphic microsatellites tightly linked to ATXN3 has been developed for the rapid identification of informative markers in at-risk couples for use in the PGT-M of SCA3/MJD.

Asunto(s)

Ataxina-3 , Enfermedad de Machado-Joseph , Repeticiones de Microsatélite , Diagnóstico Preimplantación , Expansión de Repetición de Trinucleótido , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/diagnóstico , Humanos , Ataxina-3/genética , Expansión de Repetición de Trinucleótido/genética , Femenino , Repeticiones de Microsatélite/genética , Diagnóstico Preimplantación/métodos , Pruebas Genéticas/métodos , Alelos , Genotipo , Embarazo , Masculino , Proteínas Represoras

RESUMEN

Spinocerebellar ataxia type 3 (SCA3) is the most common type of disease related to poly-glutamine (polyQ) repeats. Its hallmark pathology is related to the abnormal accumulation of ataxin 3 with a longer polyQ tract (polyQ-ATXN3). However, there are other mechanisms related to SCA3 progression that require identifying trait and state biomarkers for a more accurate diagnosis and prognosis. Moreover, the identification of potential pharmacodynamic targets and assessment of therapeutic efficacy necessitates valid biomarker profiles. The aim of this review was to identify potential trait and state biomarkers and their potential value in clinical trials. Our results show that, in SCA3, there are different fluid biomarkers involved in neurodegeneration, oxidative stress, metabolism, miRNA and novel genes. However, neurofilament light chain NfL and polyQ-ATXN3 stand out as the most prevalent in body fluids and SCA3 stages. A heterogeneity analysis of NfL revealed that it may be a valuable state biomarker, particularly when measured in plasma. Nonetheless, since it could be a more beneficial approach to tracking SCA3 progression and clinical trial efficacy, it is more convenient to perform a biomarker profile evaluation than to rely on only one.

Asunto(s)

Biomarcadores , Enfermedad de Machado-Joseph , Humanos , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/metabolismo , Enfermedad de Machado-Joseph/patología , Ataxina-3/genética , Ataxina-3/metabolismo , Proteínas de Neurofilamentos/metabolismo , Péptidos/metabolismo , Progresión de la Enfermedad , Estrés Oxidativo

RESUMEN

BACKGROUND: The age at onset (AO) of Machado-Joseph disease (SCA3/MJD), a disorder due to an expanded CAG repeat (CAGexp) in ATXN3, is quite variable and the role of environmental factors is still unknown. Caffeine was associated with protective effects against other neurodegenerative diseases, and against SCA3/MJD in transgenic mouse models. We aimed to evaluate whether caffeine consumption and its interaction with variants of caffeine signaling/metabolization genes impact the AO of this disease. METHODS: a questionnaire on caffeine consumption was applied to adult patients and unrelated controls living in Rio Grande do Sul, Brazil. AO and CAGexp were previously determined. SNPs rs5751876 (ADORA2A), rs2298383 (ADORA2A), rs762551 (CYP1A2) and rs478597 (NOS1) were genotyped. AO of subgroups were compared, adjusting the CAGexp to 75 repeats (p < 0.05). RESULTS: 171/179 cases and 98/100 controls consumed caffeine. Cases with high and low caffeine consumption (more or less than 314.5 mg of caffeine/day) had mean (SD) AO of 35.05 (11.44) and 35.43 (10.08) years (p = 0.40). The mean (SD) AO of the subgroups produced by the presence or absence of caffeine-enhancing alleles in ADORA2A (T allele at rs5751876 and rs2298383), CYP1A2 (C allele) and NOS1 (C allele) were all similar (p between 0.069 and 0.516). DISCUSSION: Caffeine consumption was not related to changes in the AO of SCA3/MJD, either alone or in interaction with protective genotypes at ADORA2A, CYP1A2 and NOS1.

RESUMEN

We aimed to produce a mouse model of spinocerebellar ataxia type 3 (SCA3) using the mouse blood-brain barrier (BBB)-penetrating adeno-associated virus (AAV)-PHP.B. Four-to-five-week-old C57BL/6 mice received injections of high-dose (2.0 × 1011 vg/mouse) or low-dose (5.0 × 1010 vg/mouse) AAV-PHP.B encoding a SCA3 causative gene containing abnormally long 89 CAG repeats [ATXN3(Q89)] under the control of the ubiquitous chicken ß-actin hybrid (CBh) promoter. Control mice received high doses of AAV-PHP.B encoding ATXN3 with non-pathogenic 15 CAG repeats [ATXN3(Q15)] or phosphate-buffered saline (PBS) alone. More than half of the mice injected with high doses of AAV-PHP.B encoding ATXN3(Q89) died within 4 weeks after the injection. No mice in other groups died during the 12-week observation period. Mice injected with low doses of AAV-PHP.B encoding ATXN3(Q89) exhibited progressive motor uncoordination starting 4 weeks and a shorter stride in footprint analysis performed at 12 weeks post-AAV injection. Immunohistochemistry showed thinning of the molecular layer and the formation of nuclear inclusions in Purkinje cells from mice injected with low doses of AAV-PHP.B encoding ATXN3(Q89). Moreover, ATXN3(Q89) expression significantly reduced the number of large projection neurons in the cerebellar nuclei to one third of that observed in mice expressing ATXN3(Q15). This AAV-based approach is superior to conventional methods in that the required number of model mice can be created simply by injecting AAV, and the expression levels of the responsible gene can be adjusted by changing the amount of AAV injected. Moreover, this method may be applied to produce SCA3 models in non-human primates.

Asunto(s)

Ataxina-3 , Dependovirus , Modelos Animales de Enfermedad , Vectores Genéticos , Enfermedad de Machado-Joseph , Ratones Endogámicos C57BL , Animales , Dependovirus/genética , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/terapia , Enfermedad de Machado-Joseph/metabolismo , Enfermedad de Machado-Joseph/patología , Ratones , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Ataxina-3/genética , Ataxina-3/metabolismo , Inyecciones Intravenosas , Barrera Hematoencefálica/metabolismo , Regiones Promotoras Genéticas

RESUMEN

Spinocerebellar ataxias (SCA) are most frequently due to (CAG)n (coding for polyglutamine, polyQ) expansions and, less so, to expansion of other oligonucleotide repeats (non-polyQ) or other type of variants (non-repeat expansion SCA). In this study we compared polyQ and non-repeat expansion SCA, in a cohort of patients with hereditary ataxia followed at a tertiary hospital. From a prospective study, 88 patients (51 families) with SCA were selected, 74 (40 families) of whom genetically diagnosed. Thirty-eight patients (51.4%, 19 families) were confirmed as having a polyQ (no other repeat-expansions were identified) and 36 (48.6%, 21 families) a non-repeat expansion SCA. Median age-at-onset was 39.5 [30.0-45.5] for polyQ and 7.0 years [1.00-21.50] for non-repeat expansion SCA. PolyQ SCA were associated with cerebellar onset, and non-repeat expansion forms with non-cerebellar onset. Time to diagnosis was longer for non-repeat expansion SCA. The most common polyQ SCA were Machado-Joseph disease (MJD/SCA3) (73.7%) and SCA2 (15.8%); whereas in non-repeat expansion SCA ATX-CACNA1A (14.3%), ATP1A3-related ataxia, ATX-ITPR1, ATX/HSP-KCNA2, and ATX-PRKCG (9.5% each) predominated. Disease duration (up to inclusion) was significantly higher in non-repeat expansion SCA, but the difference in SARA score was not statistically significant. Cerebellar peduncles and pons atrophy were more common in polyQ ataxias, as was axonal neuropathy. SCA had a wide range of genetic etiology, age-at-onset and presentation. Proportion of polyQ and non-repeat expansion SCA was similar; the latter had a higher genetic heterogeneity. While polyQ ataxias were typically linked to cerebellar onset in adulthood, non-repeat expansion forms associated with early onset and non-cerebellar presentations.

RESUMEN

Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar ataxia (SCA) caused by a polyglutamine expansion in the ataxin-3 protein, which initiates a cascade of pathogenic events, including transcriptional dysregulation. Genotype-phenotype correlations in MJD are incomplete, suggesting an influence of additional factors, such as epigenetic modifications, underlying the MJD pathogenesis. DNA methylation is known to impact the pathophysiology of neurodegenerative disorders through gene expression regulation and increased methylation has been reported for other SCAs. In this work we aimed to analyse global methylation in MJD carriers. Global 5-mC levels were quantified in blood samples of 33 MJD mutation carriers (patients and preclinical subjects) and 33 healthy controls, matched by age, sex, and smoking status. For a subset of 16 MJD subjects, a pilot follow-up analysis with two time points was also conducted. No differences were found in median global 5-mC levels between MJD mutation carriers and controls and no correlations between methylation levels and clinical or genetic variables were detected. Also, no alterations in global 5-mC levels were observed over time. Our findings do not support an increase in global blood methylation levels associated with MJD.

Asunto(s)

Metilación de ADN , Heterocigoto , Enfermedad de Machado-Joseph , Mutación , Humanos , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/sangre , Masculino , Femenino , Adulto , Persona de Mediana Edad , Estudios de Casos y Controles , Ataxina-3/genética , 5-Metilcitosina/metabolismo , 5-Metilcitosina/sangre , Anciano , Epigénesis Genética

RESUMEN

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is reported to be the most common type of autosomal dominant cerebellar ataxia (ADCA). SCA3 patients suffer from a progressive decline in motor coordination and other disease-associated symptoms. Moreover, recent studies have reported that SCA3 patients also exhibit symptoms of cerebellar cognitive affective syndrome (CCAS). We previously observed signs of CCAS in mouse model of SCA3. Particularly, SCA3-84Q mice suffer from anxiety, recognition memory decline, and also exhibit signs of low mood and aversion to activity. Here we studied the effect of long-term injections of SK channels activator chlorzoxazone (CHZ) together and separately with the folic acid (FA) on the cerebellar Purkinje cell (PC) firing and histology, and also on the motor and cognitive functions as well as mood alterations in SCA3-84Q hemizygous transgenic mice. We realized that both CHZ and CHZ-FA combination had similar positive effect on pure cerebellum impairments including PC firing precision, PC histology, and motor performance in SCA3-84Q mice. However, only the CHZ-FA combination, but not CHZ, had significantly ameliorated the signs of anxiety and depression, and also noticeably improved recognition memory in SCA3-84Q mice. Our results suggest that the combination therapy for both ataxia and non-motor symptoms is required for the complex treatment of ADCA.

Asunto(s)

Ansiedad , Clorzoxazona , Depresión , Modelos Animales de Enfermedad , Ácido Fólico , Enfermedad de Machado-Joseph , Ratones Transgénicos , Animales , Ratones , Ansiedad/tratamiento farmacológico , Ansiedad/fisiopatología , Depresión/tratamiento farmacológico , Depresión/genética , Depresión/fisiopatología , Ácido Fólico/farmacología , Ácido Fólico/administración & dosificación , Enfermedad de Machado-Joseph/tratamiento farmacológico , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/fisiopatología , Enfermedad de Machado-Joseph/patología , Clorzoxazona/farmacología , Células de Purkinje/efectos de los fármacos , Células de Purkinje/metabolismo , Células de Purkinje/patología , Memoria/efectos de los fármacos , Humanos , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Masculino , Ataxina-3/genética , Ataxina-3/metabolismo

RESUMEN

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is the most common subtype of hereditary ataxia (HA), which is characterized by motor deficits and a lack of effective treatments, and imposes a huge physical, mental, and financial burden on patients and their families. Therefore, it is important to study the early pathogenesis of spinal cerebellar ataxia type 3 based on a mouse model for subsequent preventive treatment and seeking new therapeutic targets.

Asunto(s)

Modelos Animales de Enfermedad , Enfermedad de Machado-Joseph , Enfermedad de Machado-Joseph/terapia , Enfermedad de Machado-Joseph/fisiopatología , Animales , Ratones , Humanos , Ataxina-3/genética

RESUMEN

Introduction: The vestibulo-ocular reflex (VOR) stabilizes vision during head movements. VOR disorders lead to symptoms such as imbalance, dizziness, and oscillopsia. Despite similar VOR dysfunction, patients display diverse complaints. This study analyses saccades, balance, and spatial orientation in chronic peripheral and central VOR disorders, specifically examining the impact of oscillopsia. Methods: Participants involved 15 patients with peripheral bilateral vestibular loss (pBVL), 21 patients with clinically and genetically confirmed Machado-Joseph disease (MJD) who also have bilateral vestibular deficit, and 22 healthy controls. All pBVL and MJD participants were tested at least 9 months after the onset of symptoms and underwent a detailed clinical neuro-otological evaluation at the Dizziness and Eye Movements Clinic of the Meir Medical Center. Results: Among the 15 patients with pBVL and 21 patients with MJD, only 5 patients with pBVL complained of chronic oscillopsia while none of the patients with MJD reported this complaint. Comparison between groups exhibited significant differences in vestibular, eye movements, balance, and spatial orientation. When comparing oscillopsia with no-oscillopsia subjects, significant differences were found in the dynamic visual acuity test, the saccade latency of eye movements, and the triangle completion test. Discussion: Even though there is a significant VOR gain impairment in MJD with some subjects having less VOR gain than pBVL with reported oscillopsia, no individuals with MJD reported experiencing oscillopsia. This study further supports that subjects experiencing oscillopsia present a real impairment to stabilize the image on the retina, whereas those without oscillopsia may utilize saccade strategies to cope with it and may also rely on visual information for spatial orientation. Finding objective differences will help to understand the causes of the oscillopsia experience and develop coping strategies to overcome it.

RESUMEN

Spinocerebellar ataxia (SCA) results in balance and coordination impairment, and current treatments have limited efficacy. Recent evidence suggests that combining postural training with cerebellar transcranial direct current stimulation (ctDCS) can improve these symptoms. However, the combined effects of ctDCS and postural training on individuals with spinocerebellar ataxia remain underexplored. Ten volunteers with (SCA type 3) participated in a triple-blind, randomized, crossover study to receive a single session of ctDCS (2 mA for 20 min) and a sham ctDCS session separated by at least one week. The Biodex Balance System was used to assess balance at each session, measuring overall stability index, anteroposterior stability index, and medial-lateral stability index. As secondary outcomes, cerebellar ataxia symptoms were evaluated using the 8-item Scale for Assessment and Rating of Ataxia. The assessments were conducted before and after each session. The results indicated that ctDCS enhanced the overall stability index when compared to sham ctDCS (Z = -2.10, p = 0.03), although it did not significantly affect the anteroposterior or medial-lateral stability indices. Compared to the baseline, a single session of ctDCS reduced appendicular symptoms related to cerebellar ataxia, as evidenced by improvements in the nose-finger test (Z = -2.07, p = 0.04), fast alternating hand movements (Z = -2.15, p = 0.03), and heel-to-shin slide (Z = -1.91, p = 0.05). In conclusion, our study suggests that a single session of ctDCS, in combination with postural training, can enhance balance and alleviate ataxia symptoms in individuals with cerebellar ataxia. This study was approved by the local research ethics committee (No. 2.877.813) and registered on clinicaltrials.org (NCT04039048 - https://www.clinicaltrials.gov/study/NCT04039048 ) on 2019-07-28.

RESUMEN

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a fatal neurodegenerative disease that causes loss of balance and motor co-ordination, eventually leading to paralysis. It is caused by the autosomal dominant inheritance of a long CAG trinucleotide repeat sequence within the ATXN3 gene, encoding for an expanded polyglutamine (polyQ) repeat sequence within the ataxin-3 protein. Ataxin-3 containing an expanded polyQ repeat is known to be highly prone to intraneuronal aggregation, and previous studies have demonstrated that protein quality control pathways, such as autophagy, are impaired in MJD patients and animal models of the disease. In this study, we tested the therapeutic potential of spermidine on zebrafish and rodent models of MJD to determine its capacity to induce autophagy and improve functional output. Spermidine treatment of transgenic MJD zebrafish induced autophagy and resulted in increased distances swum by the MJD zebrafish. Interestingly, treatment of the CMVMJD135 mouse model of MJD with spermidine added to drinking water did not produce any improvement in motor behaviour assays, neurological testing or neuropathology. In fact, wild type mice treated with spermidine were found to have decreased rotarod performance when compared to control animals. Immunoblot analysis of protein lysates extracted from mouse cerebellar tissue found little differences between the groups, except for an increased level of phospho-ULK1 in spermidine treated animals, suggesting that autophagy was indeed induced. As we detected decreased motor performance in wild type mice following treatment with spermidine, we conducted follow up studies into the effects of spermidine treatment in zebrafish. Interestingly, we found that in addition to inducing autophagy, spermidine treatment also induced apoptosis, particularly in wild type zebrafish. These findings suggest that spermidine treatment may not be therapeutically beneficial for the treatment of MJD, and in fact warrants caution due to the potential negative side effects caused by induction of apoptosis.

Asunto(s)

Enfermedad de Machado-Joseph , Enfermedades Neurodegenerativas , Humanos , Animales , Ratones , Espermidina/farmacología , Espermidina/uso terapéutico , Pez Cebra , Apoptosis , Autofagia , Modelos Animales de Enfermedad

RESUMEN

Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia. Currently, no preventive or disease-modifying treatments exist for this progressive neurodegenerative disorder, although efforts using gene silencing approaches are under clinical trial investigation. The disease is caused by a CAG repeat expansion in the mutant gene, ATXN3, producing an enlarged polyglutamine tract in the mutant protein. Similar to other paradigmatic neurodegenerative diseases, studies evaluating the pathogenic mechanism focus primarily on neuronal implications. Consequently, therapeutic interventions often overlook non-neuronal contributions to disease. Our lab recently reported that oligodendrocytes display some of the earliest and most progressive dysfunction in SCA3 mice. Evidence of disease-associated oligodendrocyte signatures has also been reported in other neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Here, we assess the effects of anti-ATXN3 antisense oligonucleotide (ASO) treatment on oligodendrocyte dysfunction in premanifest and symptomatic SCA3 mice. We report a severe, but modifiable, deficit in oligodendrocyte maturation caused by the toxic gain-of-function of mutant ATXN3 early in SCA3 disease that is transcriptionally, biochemically, and functionally rescued with anti-ATXN3 ASO. Our results highlight the promising use of an ASO therapy across neurodegenerative diseases that requires glial targeting in addition to affected neuronal populations.

Asunto(s)

Ataxina-3 , Modelos Animales de Enfermedad , Enfermedad de Machado-Joseph , Oligodendroglía , Oligonucleótidos Antisentido , Animales , Oligodendroglía/metabolismo , Ratones , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/terapia , Enfermedad de Machado-Joseph/patología , Enfermedad de Machado-Joseph/metabolismo , Ataxina-3/genética , Ataxina-3/metabolismo , Humanos , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Ratones Transgénicos

RESUMEN

Spinocerebellar ataxia type 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the ATXN3/MJD gene. Mutation of ATXN3 causes formation of ataxin-3 protein aggregates, neurodegeneration, and motor deficits. Here we investigated the therapeutic potential and mechanistic activity of sodium butyrate (SB), the sodium salt of butyric acid, a metabolite naturally produced by gut microbiota, on cultured SH-SY5Y cells and transgenic zebrafish expressing human ataxin-3 containing 84 glutamine (Q) residues to model SCA3. SCA3 SH-SY5Y cells were found to contain high molecular weight ataxin-3 species and detergent-insoluble protein aggregates. Treatment with SB increased the activity of the autophagy protein quality control pathway in the SCA3 cells, decreased the presence of ataxin-3 aggregates and presence of high molecular weight ataxin-3 in an autophagy-dependent manner. Treatment with SB was also beneficial in vivo, improving swimming performance, increasing activity of the autophagy pathway, and decreasing the presence of insoluble ataxin-3 protein species in the transgenic SCA3 zebrafish. Co-treating the SCA3 zebrafish with SB and chloroquine, an autophagy inhibitor, prevented the beneficial effects of SB on zebrafish swimming, indicating that the improved swimming performance was autophagy-dependent. To understand the mechanism by which SB induces autophagy we performed proteomic analysis of protein lysates from the SB-treated and untreated SCA3 SH-SY5Y cells. We found that SB treatment had increased activity of Protein Kinase A and AMPK signaling, with immunoblot analysis confirming that SB treatment had increased levels of AMPK protein and its substrates. Together our findings indicate that treatment with SB can increase activity of the autophagy pathway process and that this has beneficial effects in vitro and in vivo. While our results suggested that this activity may involve activity of a PKA/AMPK-dependent process, this requires further confirmation. We propose that treatment with sodium butyrate warrants further investigation as a potential treatment for neurodegenerative diseases underpinned by mechanisms relating to protein aggregation including SCA3.

Asunto(s)

Enfermedad de Machado-Joseph , Neuroblastoma , Enfermedades Neurodegenerativas , Humanos , Animales , Ácido Butírico/farmacología , Ataxina-3/genética , Enfermedad de Machado-Joseph/tratamiento farmacológico , Enfermedad de Machado-Joseph/genética , Pez Cebra , Proteínas Quinasas Activadas por AMP , Agregado de Proteínas , Proteómica , Autofagia , Animales Modificados Genéticamente , Proteínas Quinasas Dependientes de AMP Cíclico

RESUMEN

Spinocerebellar ataxias (SCAs) have a worldwide average prevalence of 2.7 cases per 100,000 individuals, with significant geographic variability. This study aimed to develop resource-limited strategies to detect and characterize the frequency and genetic-clinical profile of SCAs in an unexplored population from Alagoas State, a low Human Development Index state in northeastern Brazil. Active search strategies were employed to identify individuals with a diagnosis or clinical suspicion of SCAs, and a protocol for clinical and molecular evaluation was applied in collaboration with a reference center in Neurogenetics. A total of 73 individuals with SCAs were identified, with a minimum estimated prevalence of 2.17 cases per 100,000 inhabitants. SCA3 was the most common type (75.3%), followed by SCA7 (15.1%), SCA1 (6.8%), and SCA2 (2.7%). Patients with SCA3 subphenotype 2 were the most predominant. Detailed analysis of patients with SCA3 and SCA7 revealed age at onset and clinical features congruent with other studies, with gait disturbance and reduced visual capacity in SCA7 as the main initial manifestations. The study also identified many asymptomatic individuals at risk of developing SCAs. These findings demonstrate that simple and collaborative strategies can enhance the detection capacity of rare diseases such as SCAs in resource-limited settings and that Alagoas State has a minimum estimated prevalence of SCAs similar to the world average.

Asunto(s)

Configuración de Recursos Limitados , Ataxias Espinocerebelosas , Humanos , Brasil/epidemiología , Epidemiología Molecular , Ataxias Espinocerebelosas/diagnóstico , Ataxias Espinocerebelosas/epidemiología , Ataxias Espinocerebelosas/genética

RESUMEN

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant hereditary disorder, caused by an expansion of polyglutamine in the ataxin-3 protein. SCA3 symptoms include progressive motor decline caused by an atrophy of the cerebellum and brainstem. However, it was recently reported that SCA3 patients also suffer from the cerebellar cognitive affective syndrome. The majority of SCA3 patients exhibit cognitive decline and approximately half of them suffer from depression and anxiety. The necessity to find a combined therapy for both motor and cognitive deficits in a SCA3 mouse model is required for the development of SCA3 treatment. Here, we demonstrated that the SCA3-84Q transgenic mice exhibited anxiety over the novel brightly illuminated environment in the open field, novelty suppressed feeding, and light-dark place preference tests. Moreover, SCA3-84Q mice also suffered from a decline in recognition memory during the novel object recognition test. SCA3-84Q mice also demonstrated floating behavior during the Morris water maze that can be interpreted as a sign of low mood and aversion to activity, i.e. depressive-like state. SCA3-84Q mice also spent more time immobile during the forced swimming and tail suspension tests which is also evidence for depressive-like behavior. Therefore, the SCA3-84Q mouse model may be used as a model system to test the possible treatments for both ataxia and non-motor symptoms including depression, anxiety, and memory loss.

Asunto(s)

Enfermedad de Machado-Joseph , Humanos , Ratones , Animales , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/metabolismo , Depresión/genética , Cerebelo/metabolismo , Ataxina-3/genética , Ataxina-3/metabolismo , Ratones Transgénicos , Ansiedad/genética

RESUMEN

BACKGROUND: Cognitive deficits were related to Spinocerebellar Ataxia type 3/Machado-Joseph Disease (SCA3/MJD), but the Cerebellar Cognitive Affective Syndrome (CCAS) needs further investigation in this disorder. We aimed to characterize cognitive-affective deficits in manifest and premanifest SCA3/MJD carriers. METHODS: Subjects at 50% risk, manifest carriers and unrelated controls were evaluated in-person or in virtual settings with CCAS Scale (CCAS-S), Stroop Color-Word Test (SCWT), Trail-Making Test (TMT), and Reading the Mind in the Eyes Test (RMET). Scale for Assessment and Rating of Ataxia (SARA) >2.5 or Friedreich Ataxia Rating Scale/Activities of Daily Living (FARS-adl) >4 divided carriers into manifest and premanifest. Time after onset or time left to gait ataxia onset (TimeToAfterOnset) were estimated. Differences between groups and correlations with TimeToAfterOnset, SARA and FARS-adl were checked. RESULTS: After random selection to balance groups, 23 manifest and 35 premanifest carriers, and 58 controls were included. CCAS-S, semantic fluency, phonemic fluency, category switching, affect, SCWT, and RMET showed significant differences between manifest carriers and controls; premanifest carriers mostly displayed intermediate values between controls and manifest carriers. These variables correlated with TimeToAfterOnset and SARA scores of the carriers. Correlations with SARA were stronger in the pre-ataxic group. CCAS-S had the strongest correlations with time and SARA. DISCUSSION: Cognitive-affective deficits in SCA3/MJD involve executive function, language, affect, and social cognition, which seem to be altered prior to the ataxia onset, and correlate with markers of motor progression. CCAS-S was the most promising biomarker and should be evaluated in longitudinal studies.

Asunto(s)

Ataxia Cerebelosa , Enfermedad de Machado-Joseph , Ataxias Espinocerebelosas , Humanos , Enfermedad de Machado-Joseph/genética , Actividades Cotidianas , Ataxias Espinocerebelosas/genética , Ataxia , Cognición

RESUMEN

Background: Spinocerebellar ataxia types 2 (SCA2) and 3 (SCA3/MJD) are diseases due to dominant unstable expansions of CAG repeats (CAGexp). Age of onset of symptoms (AO) correlates with the CAGexp length. Repeat instability leads to increases in the expanded repeats, to important AO anticipations and to the eventual extinction of lineages. Because of that, compensatory forces are expected to act on the maintenance of expanded alleles, but they are poorly understood. Objectives: we described the CAGexp dynamics, adapting a classical equation and aiming to estimate for how many generations will the descendants of a de novo expansion last. Methods: A mathematical model was adapted to encompass anticipation, fitness, and allelic segregation; and empirical data fed the model. The arbitrated ancestral mutations included in the model had the lowest CAGexp and the highest AO described in the literature. One thousand generations were simulated until the alleles were eliminated, fixed, or 650 generations had passed. Results: All SCA2 lineages were eliminated in a median of 10 generations. In SCA3/MJD lineages, 593 were eliminated in a median of 29 generations. The other ones were eliminated due to anticipation after the 650th generation or remained indefinitely with CAG repeats transitioning between expanded and unexpanded ranges. Discussion: the model predicted outcomes compatible with empirical data - the very old ancestral SCA3/MJD haplotype, and the de novo SCA2 expansions -, which previously seemed to be contradictory. This model accommodates these data into understandable dynamics and might be useful for other CAGexp disorders.

RESUMEN

Spectral domain optical coherence tomography (SD-OCT) allows noninvasive measurements of retinal neuron layers. Here, we evaluate the relationship between clinical features and anatomical SD-OCT measurements in patients with spinocerebellar ataxia type 3 (SCA3) and how they change with time. A retrospective review was conducted on SCA3 patients. Clinical variables such as disease duration, number of CAG repeats, and the Scale for the Assessment and Rating of Ataxia (SARA) score were correlated with SD-OCT measurements, including retinal nerve fiber layer (RNFL) thickness, ganglion cell complex (GCC) thickness, macular volume (MV), and central macular thickness (CMT). Seventeen SCA3 patients with an average follow-up of 44.9 months were recruited. Clinical features with significant baseline correlations with SD-OCT measurements included disease duration (CMT r = - 0.590; GCC r = - 0.585), SARA score (CMT r = - 0.560; RNFL r = - 0.390), and number of CAG repeats (MV r = - 0.552; RNFL r = - 0.503; GCC r = - 0.493). The annual rate of change of the SARA score during follow-up was associated with that of both the MV (r = - 0.494; p = 0.005) and GCC thickness (r = - 0.454; p = 0.012). High disability (stages 2 and 3) was independently inversely associated with the annual change in MV (ß coefficient - 17.09; p = 0.025). This study provides evidence of an association between clinical features and objective anatomical measurements obtained by SD-OCT in SCA3 patients. MV and GCC thickness could serve as potential biomarkers of disease severity, as their rates of decrease seem to be related to a worsening in the SARA score. These findings highlight the potential of SD-OCT as a noninvasive tool for assessing disease severity and progression in SCA3 patients.

RESUMEN

Objective: Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a rare neurodegenerative disease for which there is no specific treatment. Very few cases have been treated with single-target deep brain stimulation (DBS), and the results were not satisfactory. We applied multi-target DBS to an SCA3/MJD patient and performed positron emission computed tomography (PET) before and after DBS to explore the short-term clinical therapeutic effect. Materials and methods: A 26-year-old right-hand-dominant female with a family history of SCA3/MJD suffered from cerebellar ataxia and dystonia. Genetic testing indicated an expanded CAG trinucleotide repeat in the ATXN3 gene and a diagnosis of SCA3/MJD. Conservative treatment had no obvious effect; therefore, leads were implanted in the bilateral dentate nucleus (DN) and the globus pallidus internus (GPi) and connected to an external stimulation device. The treatment effect was evaluated in a double-blind, randomized protocol in five phases (over a total of 15 days): no stimulation, GPi, DN, or sham stimulation, and combined GPi and DN stimulation. 18F-fluoro-2-deoxy-d-glucose and dopamine transporter PET, Scale for the Assessment and Rating of Ataxia, Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (FTM), Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), and SF-36 quality of life scores were compared before and after DBS. Results: The Total Scale for the Assessment and Rating of Ataxia scores improved by ~42% (from 24 to 14). The BFMDRS movement scores improved by ~30% (from 40.5 to 28.5). The BFMDRS disability scores improved by ~12.5% (from 16 to 14). Daily living activities were not noticeably improved. Compared with the findings in pre-DBS imaging, 18F-fluoro-2-deoxy-d-glucose uptake increased in the cerebellum, while according to dopamine transporter imaging, there were no significant differences in the bilateral caudate nucleus and putamen. Conclusion: Multi-target acute stimulation (DN DBS and GPi DBS) in SCA3/MJD can mildly improve cerebellar ataxia and dystonia and increase cerebellar metabolism.