Genetic analysis of a child with Charlevoix-Saguenay spastic ataxia due to variant of SACS gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical feature and genetic variant of a child with autosomal recessive Charlevoix-Saguenay type spastic ataxia (ARSACS).@*METHODS@#Clinical data of a child who was admitted to the West China Second Hospital of Sichuan University on April 30, 2021 was collected. Whole exome sequencing (WES) was carried out for the child and his parents. Candidate variants were verified by Sanger sequencing and bioinformatic analysis based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).@*RESULTS@#The child, a 3-year-and-3-month-old female, had a complain of "walking instability for over a year". Physical and laboratory examination revealed progressive and aggravated gait instability, increased muscle tone of the right limbs, peripheral neuropathy of the lower limbs, and thickening of retinal nerve fiber layer. The results of WES revealed that she has harbored a maternally derived heterozygous deletion of exons 1 to 10 of the SACS gene, in addition with a de novo heterozygous c.3328dupA variant in exon 10 of the SACS gene. Based on the ACMG guidelines, the exons 1-10 deletion was rated as likely pathogenic (PVS1+PM2_Supporting), and the c.3328dupA was rated as a pathogenic variant (PVS1_Strong+PS2+PM2_Supporting). Neither variant was recorded in the human population databases.@*CONCLUSION@#The c.3328dupA variant and the deletion of exons 1-10 of the SACS gene probably underlay the ARSACS in this patient.

Research advance on the pathogenesis of autosomal recessive spastic ataxia of Charlevoix-Saguenay / 中华医学遗传学杂志

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare and early-onset neurodegenerative disease caused by variants of the SACS gene which maps to chromosome 13q11 and encodes sacsin protein. Sacsin is highly expressed in large motor neurons, in particular cerebellar Purkinje cells. This article has provided a review for the structure and function of sacsin protein and the mechanisms underlying abnormalities of sacsin in ARSACS disease.

Diagnosis of a patient with Spinocerebellar ataxia type 29 due to a novel variant of ITPR1 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic characteristics of a child with spinocerebellar ataxia type 29 (SCA29) due to novel variant of the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) gene.@*METHODS@#The child was subjected high-throughput sequencing, and candidate variant was verified by Sanger sequencing of his family members.@*RESULTS@#The child was found to harbor a c.800C>T (p.T267M) variant of the ITPR1 gene, which was not found in his parents and their fetus. The variant has occurred in a hotspot of the ITPR1 gene variants and was unreported before in China. Based on his clinical and genetic characteristics, the child was diagnosed with SCA29.@*CONCLUSION@#The novel heterozygous c.800C>T (p.T267M) of the ITPR1 gene probably underlay the SCA29 in this child.

Aya Kitou: Resilience capacity according to the Boris Cyrulnik biopsychosocial model / Aya Kitou: capacidade de resiliência segundo o modelo biopsicossocial de Boris Cyrulnik

Objective: Spinocerebellar ataxia type 2, an orphan disease also known as spinocerebellar degeneration, is characterized by a degenerative process of the cerebellum and spinal cord. Method Biographical review of a Japanese woman known as Aya Kitou, using a qualitative approach of discourse analysis to identify resilience capacity, based on Boris Cyrulnik's Biopsychosocial model. Results Description based on the detailed experience reported in Aya´s diary; the areas to achieve resilience are identified (internal resources, sociocultural significance and social support system) Conclusion Although the progression of the clinical condition compromised Aya"s functional capacity, limiting her autonomy and quality of life, it was evidenced that thanks to strong social networks individuals are more likely to achieve resilience, although the prevalence of social values and meanings upon the patient creates greater social anxiety and a greater feeling of inferiority and incapacity.

Objetivo A ataxia espinocerebelar tipo 2, uma doença órfã também conhecida como degeneração espinocerebelar, é caracterizada pelo processo degenerativo do cerebelo e da medula espinhal. Método Revisão biográfica de mulher japonesa conhecida como Aya Kitou, a partir de uma abordagem qualitativa, baseada na análise do discurso, para identificar a capacidade de resiliência, a partir do modelo biopsicossocial de Boris Cyrulnik. Resultados Descritos com base nas vivências detalhadas de seu diário, são identificadas as áreas para alcançar resiliência (recursos internos, significado sociocultural e sistema de suporte social). Conclusão Embora a progressão do quadro clínico tenha comprometido sua capacidade funcional, limitando sua autonomia e qualidade de vida, evidenciou-se que, graças às fortes redes sociais, tem mais chance de alcançar resiliência, embora, com a prevalência de valores e significados sociais sobre ela, haja maior ansiedade social e maiores sentimentos de inferioridade e incapacidade.

Functionality and disease severity in spinocerebellar ataxias / Relação entre a função e a gravidade nas ataxias espinocerebelares

ABSTRACT Background: Spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases characterized by deterioration of balance and functionality that tends to follow disease progression. There is no established link between formal clinical markers for severity and functional/balance scores that could guide rehabilitation teams. Objective: To evaluate the relationship between functional scales and ataxia severity in order to identify cutoff landmarks for functional loss and estimate the mean SARA (Scale for Assessment and Rating of Ataxia) score for the risk ratings for falls on the BBS (Berg Balance Scale). Methods: Consecutive patients with a molecular diagnosis of SCA (total 89: 31 with SCA2 and 58 with SCA3) were assessed for functionality FIM-ADL (Functional Independence Measure-activities of daily living and Lawton-IADL (instrumental activities of daily living), balance (BBS) and disease severity (SARA). Results: The main disability cutoff landmarks were that the need for supervision for FIM-ADL starts with 12 points on SARA and the need for supervision for Lawton-IADL starts with 14 points on SARA. The first items to require assistance were "expression" and "shopping", respectively. At 20 points on SARA, patients were dependent on all FIM and Lawton items. The item with the greatest impact on distinguishing dependents from independents was "means of transport" in Lawton-IADL and the domain "locomotion" in FIM-ADL. The mean SARA score for patients classified as low risk in the BBS was 9.9 points, and it was 17.4 for medium risk and 25.2 for high risk. Conclusions: Analysis on the correlation between the severity of ataxia and functional scales can form an important guide for understanding the progression of functional dependence among individuals with SCAs.

RESUMO Antecedentes: As ataxias espinocerebelares (SCA) são um grupo de doenças neurodegenerativas caracterizadas pela deterioração do equilíbrio e da funcionalidade, que tende a acompanhar a progressão da doença. Não existe uma ligação estabelecida entre os marcadores clínicos formais de gravidade e escores funcionais e de equilíbrio que possam orientar as equipes de reabilitação. Objetivo: Avaliar a relação entre escalas funcionais e de gravidade da ataxia, buscando identificar pontos de corte para a perda funcional relacionados aos escores de gravidade e aos patamares de Risco de Quedas. Métodos: Uma amostra consecutiva de 89 pacientes com diagnóstico molecular de SCA (31-SCA2 e 58-SCA3) foram avaliados para funcionalidade MIF-AVDs (Medida de independência funcional-Atividades da vida diária) e Lawton-AIVDs (Atividades instrumentais da vida diária), equilíbrio (EEB-escala de Equilíbrio de Berg), e gravidade da ataxia (SARA-escala para avaliação e graduação de ataxia). Resultados: Os principais pontos de corte de deficiência foram: com 12 pontos no SARA começa a necessidade de supervisão para MIF-AVDs e com 14 pontos no SARA começa a necessidade de supervisão para Lawton-AIVDs. Os primeiros itens a necessitar de assistência foram "expressão" e "compras", respectivamente. Com 20 pontos no SARA os pacientes eram dependentes em todos os itens MIF/LAWTON. O item com maior impacto na discriminação entre dependentes e independentes foi "meio de transporte" na Lawton e o domínio "locomoção" na MIF. O escore médio no SARA foi de 9,9 pontos para pacientes classificados com baixo risco na EEB, 17,4 para médio risco e 25,2 para alto risco. Conclusões: A análise da correlação entre a gravidade da ataxia e as escalas funcionais pode ser um importante guia no entendimento da progressão da dependência funcional em indivíduos com SCA.

Investigation on the growth factor regulatory network of dermal fibroblasts in mouse full-thickness skin defect wounds based on single-cell RNA sequencing / 中华烧伤杂志

Objective: To explore the heterogeneity and growth factor regulatory network of dermal fibroblasts (dFbs) in mouse full-thickness skin defect wounds based on single-cell RNA sequencing. Methods: The experimental research methods were adopted. The normal skin tissue from 5 healthy 8-week-old male C57BL/6 mice (the same mouse age, sex, and strain below) was harvested, and the wound tissue of another 5 mice with full-thickness skin defect on the back was harvested on post injury day (PID) 7. The cell suspension was obtained by digesting the tissue with collagenase D and DNase Ⅰ, sequencing library was constructed using 10x Genomics platform, and single-cell RNA sequencing was performed by Illumina Novaseq6000 sequencer. The gene expression matrices of cells in the two kinds of tissue were obtained by analysis of Seurat 3.0 program of software R4.1.1, and two-dimensional tSNE plots classified by cell group, cell source, and gene labeling of major cells in skin were used for visual display. According to the existing literature and the CellMarker database searching, the expression of marker genes in the gene expression matrices of cells in the two kinds of tissue was analyzed, and each cell group was numbered and defined. The gene expression matrices and cell clustering information were introduced into CellChat 1.1.3 program of software R4.1.1 to analyze the intercellular communication in the two kinds of tissue and the intercellular communication involving vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF) signal pathways in the wound tissue, the relative contribution of each pair of FGF subtypes and FGF receptor (FGFR) subtypes (hereinafter referred to as FGF ligand receptor pairs) to FGF signal network in the two kinds of tissue, and the intercellular communication in the signal pathway of FGF ligand receptor pairs with the top 2 relative contributions in the two kinds of tissue. The normal skin tissue from one healthy mouse was harvested, and the wound tissue of one mouse with full-thickness skin defect on the back was harvested on PID 7. The multiple immunofluorescence staining was performed to detect the expression and distribution of FGF7 protein and its co-localized expression with dipeptidyl peptidase 4 (DPP4), stem cell antigen 1 (SCA1), smooth muscle actin (SMA), and PDGF receptor α (PDGFRα) protein. Results: Both the normal skin tissue of healthy mice and the wound tissue of full-thickness skin defected mice on PID 7 contained 25 cell groups, but the numbers of cells in each cell group between the two kinds of tissue were different. Genes PDGFRα, platelet endothelial cell adhesion molecule 1, lymphatic endothelial hyaluronic acid receptor 1, receptor protein tyrosine phosphatase C, keratin 10, and keratin 79 all had distinct distributions on two-dimensional tSNE plots, indicating specific cell groups respectively. The 25 cell groups were numbered by C0-C24 and divided into 9 dFb subgroups and 16 non-dFb groups. dFb subgroups included C0 as interstitial progenitor cells, C5 as adipose precursor cells, and C13 as contractile muscle cells related fibroblasts, etc. Non-dFb group included C3 as neutrophils, C8 as T cells, and C18 as erythrocytes, etc. Compared with that of the normal skin tissue of healthy mice, the intercellular communication in the wound tissue of full-thickness skin defected mice on PID 7 was more and denser, and the top 3 cell groups in intercellular communication intensity were dFb subgroups C0, C1, and C2, of which all communicated with other cell groups in the wound tissue. In the wound tissue of full-thickness skin defected mice on PID 7, VEGF signals were mainly sent by the dFb subgroup C0 and received by vascular related cell groups C19 and C21, PDGF signals were mainly sent by peripheral cells C14 and received by multiple dFb subgroups, EGF signals were mainly sent by keratinocyte subgroups C9 and C11 and received by the dFb subgroup C0, and the main sender and receiver of FGF signals were the dFb subgroup C6. In the relative contribution rank of FGF ligand receptor pairs to FGF signal network in the normal skin tissue of healthy mice and the wound tissue of full-thickness skin defected mice on PID 7, FGF7-FGFR1 was the top 1, and FGF7-FGFR2 or FGF10-FGFR1 was in the second place, respectively; compared with those in the normal skin tissue, there was more intercellular communication in FGF7-FGFR1 signal pathway, while the intercellular communication in FGF7-FGFR2 and FGF10-FGFR1 signal pathways decreased slightly or did not change significantly in the wound tissue; the intercellular communication in FGF7-FGFR1 signal pathway in the wound tissue was stronger than that in FGF7-FGFR2 or FGF10-FGFR1 signal pathway; in the two kinds of tissue, FGF7 signal was mainly sent by dFb subgroups C0, C1, and C2, and received by dFb subgroups C6 and C7. Compared with that in the normal skin tissue of healthy mouse, the expression of FGF7 protein was higher in the wound tissue of full-thickness skin defected mouse on PID 7; in the normal skin tissue, FGF7 protein was mainly expressed in the skin interstitium and also expressed in the white adipose tissue near the dermis layer; in the two kinds of tissue, FGF7 protein was co-localized with DPP4 and SCA1 proteins and expressed in the skin interstitium, co-localized with PDGFRα protein and expressed in dFbs, but was not co-localized with SMA protein, with more co-localized expression of FGF7 in the wound tissue than that in the normal skin tissue. Conclusions: In the process of wound healing of mouse full-thickness skin defect wound, dFbs are highly heterogeneous, act as potential major secretory or receiving cell populations of a variety of growth factors, and have a close and complex relationship with the growth factor signal pathways. FGF7-FGFR1 signal pathway is the main FGF signal pathway in the process of wound healing, which targets and regulates multiple dFb subgroups.

Aproximación a la ingesta nutricional en pacientes con Ataxia Espinocerebelosa tipo 2 / An approach to nutritional intake in patients with Spinocerebellar Ataxia type 2

Introducción: La Ataxia Espinocerebelosa tipo 2 (SCA2) es una enfermedad neurodegenerativa y hereditaria. No se ha realizado ningún estudio para la caracterización de la ingesta nutricional en pacientes cubanos con SCA2. Objetivo: Comprobar la reproducibilidad y fiabilidad del método de recordatorio de 24 horas para la evaluación de la ingesta nutricional en pacientes cubanos con SCA2, y obtener una caracterización preliminar de la misma en estos pacientes. Material y Métodos: Se realizó un estudio transversal con test-retest que incluyó 35 pacientes con diagnóstico de SCA2. Se empleó el cuestionario dietético de recordatorio de 24 horas incorporado al sistema CERES+. Resultados: Se obtuvieron correlaciones altamente significativas entre la primera y segunda mediciones para la ingesta estimada de energía, nutrientes y según grupos de alimentos. En la mayoría de los elementos relativos a la ingesta estimada de energía y nutrientes, y en todos los grupos de alimentos, se obtuvieron coeficientes de correlación intraclase (0,75. Se obtuvieron diferencias significativas entre pacientes de sexo masculino o femenino en cuanto a la ingesta de proteínas, carbohidratos, cobalamina, hierro, sodio y cinc. Se obtuvo un incremento en la ingesta de sodio y una disminución en la ingesta de ácido fólico y cobre, con respecto a las recomendaciones de ingesta nutricional diaria para la población cubana. Conclusiones: Se comprobó la elevada reproducibilidad y fiabilidad del cuestionario dietético recordatorio de 24 horas para la evaluación de la ingesta nutricional en pacientes con SCA2 y se logró una caracterización preliminar de la ingesta nutricional en estos pacientes(AU)

Introduction: Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative and inherited disorder. No study has been conducted to characterize nutritional intake in Cuban SCA2 patients. Objective: To test the reproducibility and reliability of the 24-hour dietary recall method for the assessment of nutritional intake in Cuban patients with SCA2, as well as to obtain a preliminary characterization of nutritional intake in these patients. Material and Methods: A cross-sectional test-retest study was conducted on 35 SCA2 patients. The 24-hour dietary recall questionnaire in the CERES+ system was used. Results: Highly significant correlations between the first and second measurements were obtained for energy and nutrients intake, and according to food groups. Intraclass correlation coefficients higher than 0.75 were obtained for energy and most of the nutrients and according to food groups. Significant differences were obtained between male and female patients in terms of proteins, carbohydrates, cobalamin, iron, sodium, and zinc intake. An increase in sodium intake and a decrease in folic acid and copper intake were obtained. SCA2 patients showed increased sodium intake, and decreased folic acid and copper intake relative to nutritional intake recommendations for the Cuban population. Conclusions: The 24-hour recall dietary questionnaire is reproducible and reliable for the assessment of nutritional intake in SCA2 patients. Preliminary characterization of nutritional intake in SCA2 patients was obtained(AU)

Nystagmus may be the first neurological sign in early stages of spinocerebellar ataxia type 3 / Nistagmo pode ser o primeiro sinal neurológico nos estágios precoces da ataxia espinocerebelar tipo 3

Abstract Background: Spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant spinocerebellar ataxia worldwide. Almost all patients with SCA3 exhibit nystagmus and/or saccades impairment. Objective: To investigate the presence of nystagmus as an early neurological manifestation, before ataxia, in some patients with SCA3 in the first six months of the disease. Methods: We evaluated a series of 155 patients with clinically and molecularly proven SCA3 between 2013 and 2020. Data regarding sex, age, age at onset, disease duration, CAG repeat expansion length, first symptom, presence of ataxia, scores on SARA and ICARS scales, and presence and characteristics of nystagmus were collected. Results: We identified seven patients with symptomatic SCA3 who presented with isolated nystagmus. In these seven individuals the age at onset ranged from 24 to 57 years, and disease duration from four to six months. Conclusions: Our study showed that nystagmus may be the first neurological sign in SCA3. This clinical observation reinforces the idea that the neurodegenerative process in SCA3 patients may start in vestibular system connections or in flocculonodular lobe. This study adds relevant information about pre-symptomatic features in SCA3 that may work as basis for a better understanding of brain degeneration and for future therapeutic clinical trials.

RESUMO Antecedentes: A ataxia espinocerebelar tipo 3 (SCA3) é a ataxia espinocerebelar de herança autossômica dominante mais comum em todo o mundo. Quase todos os pacientes com SCA3 têm nistagmo e/ou comprometimento das sácades. Objetivo: Investigar a presença de nistagmo como manifestação neurológica precoce, antes do surgimento da ataxia, em alguns pacientes com SCA3 nos primeiros seis meses de doença. Métodos: Foram avaliados 155 pacientes com diagnóstico clínico e molecular de SCA3, entre 2013 e 2020, em relação a sexo, idade, idade de início, duração da doença, expansão da repetição CAG, primeiro sintoma, presença de ataxia, pontuações nas escalas SARA e ICARS, e presença e caracterização de nistagmo. Resultados: Identificamos sete pacientes com SCA3 que apresentavam nistagmo isolado. A idade de início da doença nesses pacientes variou de 24 a 57 anos e a duração da doença variou de quatro a seis meses. Conclusões: O nosso estudo mostrou que o nistagmo pode ser o primeiro sinal neurológico na SCA3. Essa observação clínica reforça a ideia de que o processo neurodegenerativo nos pacientes com SCA3 pode se iniciar nas conexões do sistema vestibular ou no lobo floculonodular. Este estudo adiciona informações relevantes sobre características pré-sintomáticas na SCA3 e que podem servir de base para melhor entendimento da degeneração cerebral e para futuras terapias.

Relevancia del metabolismo del folato en el contexto de enfermedades neurodegenerativas / Relevance of folate metabolism in neurodegenerative disorders

Introducción: Varias enfermedades neurodegenerativas están asociadas a alteraciones en el metabolismo del folato, lo que tiene sustanciales implicaciones fisiopatológicas, clínicas y terapéuticas potenciales. Objetivo: Reflejar la relevancia del metabolismo del folato para enfermedades neurodegenerativas, destacando su significación fisiopatológica y clínica, y sus implicaciones terapéuticas. Material y métodos: Se consultaron las bases de datos especializadas en busca de artículos publicados hasta marzo de 2020. Se emplearon descriptores específicos y operadores booleanos. Se empleó la estrategia de búsqueda avanzada para la selección de los artículos, teniendo en cuenta la calidad metodológica o validez de los estudios. Desarrollo: Fueron identificadas evidencias de asociación entre alteraciones del metabolismo del folato y enfermedades neurodegenerativas. Se han identificado variantes en genes que codifican enzimas involucradas en el metabolismo del folato, y modificaciones en patrones de metilación de ADN, asociadas al riesgo o a la gravedad clínica de las enfermedades de Alzheimer, Parkinson, Huntington, Temblor Esencial y Ataxia Espinocerebelosa tipo 2. Fueron encontradas asociaciones entre enfermedades neurodegenerativas y alteraciones en los niveles de metabolitos del folato, y la frecuencia de micronúcleos. Se han realizado varios estudios observacionales o experimentales que indican que la suplementación con ácido fólico y vitaminas B6 y B12, tiene utilidad terapéutica potencial en el contexto de enfermedades neurodegenerativas. Conclusiones: El metabolismo del folato es de relevancia fisiopatológica, clínica y terapéutica para enfermedades neurodegenerativas. El uso de estrategias dirigidas a restaurar los niveles normales de folatos o de co-factores enzimáticos involucrados en el metabolismo del folato, o a reducir la acumulación de homocisteína, tiene potenciales aplicaciones terapéuticas en el contexto de estas enfermedades(AU)

Introduction: Several neurodegenerative disorders are associated with alterations in folate metabolism, having essential physiopathological, clinical and therapeutic implications. Objective: To assess the relevance of folate metabolism in neurodegenerative disorders, highlighting its physiopathological, clinical and therapeutic significance. Material and Methods: Specialized biomedical databases were searched for studies published up to March 2020. Descriptors and Boolean operators were used. Advanced search strategy was used for the selection of articles, taking into account the methodological quality and validity of the studies. Results: Strong evidence of the association between folate metabolism and neurodegenerative disorders were identified. Enzyme-coding genes involved in folate metabolism and epigenetic DNA modifications associated with increased risk or disease severity in Alzheimer´s, Parkinson´s, and Huntington´s diseases, Essential Tremor, and Spinocerebellar ataxia type 2 were also identified. Associations between neurodegenerative disorders and altered levels of folate metabolites and the frequency of micronuclei were found. A number of observational and experimental studies have demonstrated that the supplementation with folic acid and vitamin B6 and B12 has therapeutic potential in the context of neurodegenerative disorders. Conclusions: Folate metabolism is of physiopathological, clinical and therapeutic relevance for neurodegenerative disorders. The use of strategies to normalize folate levels or enzyme cofactors involved in folate metabolism or to reduce homocysteine levels has potential therapeutic applications for these disorders(AU)

Evidence and practices of the use of next generation sequencing in patients with undiagnosed autosomal dominant cerebellar ataxias: a review / Evidências e práticas do uso do sequenciamento de nova geração em pacientes com ataxias cerebelares autossômicas dominantes não diagnosticadas: uma revisão

ABSTRACT Autosomal dominant cerebellar ataxias (ADCA) are heterogeneous diseases with a highly variable phenotype and genotype. They can be divided into episodic ataxia and spinocerebellar ataxia (SCA); the latter is considered the prototype of the ADCA. Most of the ADCA are caused by polyglutamine expansions, mainly SCA 1, 2, 3, 6, 7, 17 and Dentatorubral-pallidoluysian atrophy (DRPLA). However, 30% of patients remain undiagnosed after testing for these most common SCA. Recently, several studies have demonstrated that the new generation of sequencing methods are useful for the diagnose of these patients. This review focus on searching evidence on the literature, its usefulness in clinical practice and future perspectives.

RESUMO As ataxias cerebelares autossômicas dominantes (ACAD) são doenças heterogêneas com fenótipo e genótipo altamente variáveis. Podem ser divididas em ataxia episódica e ataxia espinocerebelar (SCA), sendo este último considerado o protótipo do ACAD. A maior parte das ACAD são causadas por expansões de poliglutaminas, principalmente SCA 1, 2, 3, 6, 7, 17 e atrofia dentatorubro-palidoluisiana (DRPLA). No entanto, 30% dos pacientes permanecem sem diagnóstico após o teste para essas SCA mais comuns. Recentemente, vários estudos têm demonstrado que a nova geração de métodos de sequenciamento são ferramentas úteis para o diagnóstico desses pacientes. Esta é uma revisão sistemática da literatura, com foco em sua utilidade na prática clínica e em perspectivas futuras.

Pure-Tone Hearing Thresholds and Brainstem Auditory Evoked Potentials in Sporadic Ataxia

Abstract Introduction Spinocerebellar ataxia (SCA) is part of a genetic and clinical heteroge- neous group of neurodegenerative diseases characterized by progressive cerebellar ataxia. Objective To describe the results of audiological and electrophysiological hearing evaluations in patients with sporadic ataxia (SA). Methods A retrospective cross-sectional study was carried out with 11 patients submitted to the following procedures: anamnesis, otorhinolaryngological evaluation, tonal and vocal audiometry, acoustic immittance and brainstem auditory evoked potential (BAEP) tests. Results The patients presented with a prevalence of gait imbalance, of dysarthria, and of dysphagia; in the audiometric and BAEPs, four patients presented with alterations; in the acoustic immittance test, five patients presented with alterations, predominantly bilateral. Conclusion The most evident alterations in the audiological evaluation were the prevalence of the descending audiometric configuration between the frequencies of 2 and 4 kHz and the absence of the acoustic reflex between the frequencies of 3 and 4 kHz bilaterally. In the electrophysiological evaluation, the patients presented changes with a prevalence of increased I, III and V wave latencies and the interval in the interpeak I-III, I-V and III-V. In the present study, it was observed that auditory complaints did not have a significant prevalence in this type of ataxia, which does not occur in some types of autosomal recessive and dominant ataxia.

Assessment of ventilatory function in patients with spinocerebellar ataxia type 2 / Avaliação da função ventilatória em pacientes com ataxia espinocerebelar tipo 2

Abstract Subclinical ventilatory dysfunction is observed in individuals with spinocerebellar ataxias (SCA). No studies have correlated ventilatory dysfunction to clinical and functional decline in SCA2. Objective: To evaluate the relationship between the values of peak expiratory flow (PEF), maximum inspiratory pressure (MIP), and presence of respiratory complaints with age, disease duration, age at onset of symptoms, balance scores, independence in basic (ADL) and instrumental (IADL) Activities of Daily Living (ADLs), and severity of ataxia (SARA) in individuals with SCA2. Methods: Cross-sectional study evaluating age, disease duration, age at onset of symptoms, scores in the Berg Balance Scale and in the SARA, Functional Independence Measure and Lawton's scale, values of PEF and MIP, and the presence of respiratory complaints. Results: The study included 36 individuals with SCA2, with a mean age of 42.5±2.4 years, disease duration of 7.6±8.2 years, age 33.7±11.5 years at onset of symptoms, and 9.9±10.3 points in the SARA scale. The lowest PEF values correlated with the longer disease duration (p=0.021). The lowest values of PEF and MIP correlated with greater balance impairment (p=0.019 and p=0.045, respectively), increased degree of dependence in the ADL (p=0.006 and p=0.050, respectively) and IADL (p=0.003 and p=0.001, respectively) scales, and highest severity of ataxia (p=0.00 and p=0.017, respectively). Respiratory complaints were observed in 12 (33.3%) individuals and were not related to age, disease duration, age at onset of symptoms, balance, independence, ataxia severity, or PEF and MIP values. Conclusion: Ventilatory dysfunction, even when asymptomatic, is related to balance impairment, independence, and ataxia severity in individuals with SCA2.

Resumo Disfunção ventilatória subclínica tem sido observada em indivíduos com ataxias espinocerebelares (SCA). Não existem estudos relacionando disfunção ventilatória ao declínio clínico e funcional na SCA2. Objetivo: Avaliar a relação dos valores de Pico de Fluxo Expiratório (PFE), Pressão Inspiratória Máxima (PIMAX) e presença de queixas respiratórias com idade, tempo de doença, idade de início dos sintomas, escore de equilíbrio, independência para atividades básicas (AVD) e instrumentais (AIVD) de vida diária e gravidade da ataxia (SARA) em indivíduos com SCA2. Métodos: Estudo transversal, considerando: idade, tempo de doença, idade de início dos sintomas, escores nas Escalas SARA, Equilíbrio de Berg, Medida da Independência Funcional e de Lawton, valores de PFE, PIMAX e queixas respiratórias. Resultados: Foram avaliados 36 indivíduos com SCA2 com média de 42,5±2,4) anos de idade, 7,6±8,2 anos de tempo de doença, 33,7±11,5 anos de idade de início dos sintomas e 9,9±10,3 pontos na escala SARA. Os menores valores de PFE estiveram relacionados ao maior tempo de doença (p=0,021). Os menores valores de PFE e PIMAX estiveram relacionados ao maior comprometimento do equilíbrio (p=0,019; p=0,045, respectivamente), maior dependência para ADV (p=0,006; p=0,050, respectivamente) e AIVD (p=0,003; p=0,001, respectivamente) e maior gravidade da ataxia (p=0,006; p=0,017, respectivamente). Foram observadas queixas respiratórias em 12 (33,3%) indivíduos que não estiveram relacionadas à idade, idade de início dos sintomas, tempo de doença, equilíbrio, independência, gravidade da ataxia, ou valores de PFE e PIMAX. Conclusão: A disfunção ventilatória, mesmo quando assintomática, está relacionada ao comprometimento do equilíbrio, à independência e à gravidade da ataxia em indivíduos com SCA2.

Obsessive-compulsive disorder in a patient with SCA type 1 / Transtorno obsessivo compulsivo em um paciente com SCA tipo 1

For many years, the cerebellum was thought to be only responsible for balance, movement, planning and execution. Nowadays, it is well accepted that most cerebellar connections are involved in non-motor functions. Herein, we provide a case report in which a 27-year-old Brazilian male, diagnosed with Obsessive-Compulsive Disorder (OCD), has demonstrated cerebellar features that could be connected to Spinocerebellar ataxia type 1 (SCA-1), an autosomal dominant polyglutamine neurodegenerative disorder that had been previously ruled out. Since obsessive compulsive symptoms (OCS) are known to correlate with alterations in the cortico-striato-thalamo-cortical circuitry, we propose a possible association between OCS and SCA onset.

Durante muitos anos, o cerebelo foi considerado responsável exclusivamente pelo controle das funções de equilíbrio, movimento, planejamento e execução. Atualmente, já está consagrada a participação das conexões cerebelares em funções não-motoras. Apresentamos um relato de caso de um paciente de 27 anos de idade, diagnosticado com Transtorno Obsessivo-Compulsivo (TOC). O paciente apresentava sintomas cerebelares compatíveis com o diagnóstico de ataxia espinocerebelar tipo 1 (SCA-1), um distúrbio da poliglutamina, autossômico dominante neurodegenerativo, que havia sido previamente descartado. Como os sintomas obsessivos compulsivos (SOC) são conhecidos por correlacionar-se com alterações nos circuitos cortico-estriato-tálamo-cortical, propomos uma possível associação entre o SOC e o início da SCA.

Assessment of Bone Mineral Density of Patients with Spinocerebellar Ataxia Type 3

OBJECTIVE: Machado-Joseph disease (MJD) is a spinocerebellar ataxia, and osteoporosis is a multifactor disease that may affect patients with neurologic conditions. The frequency of osteoporosis among MJD patients, however, has not been studied. The purpose of this study is to evaluate bone mineral density (BMD) and identify correlations between clinical factors and frequency of vertebral fractures in patients with MJD. METHODS: Clinical data, lumbar X-rays and BMD data were obtained in 30 patients with MJD. RESULTS: Ten patients (33.3%) showed low BMD in at least one of the sites studied based on Z-scores. The Z-score correlated directly with body mass index, and the femoral neck Z-score was inversely correlated with cytosine-adenine-guanine (CAG) expansion. There was no correlation between BMD and other clinical factors. Forty-three percent of the patients reported previous pathologic fractures. Five patients (16.7%) had at least one fracture detected by lumbar X-ray. CONCLUSION: Low BMD and fractures are frequent among MJD patients, and careful management of BMD may be beneficial for these patients.

Analysis of SACS mutation in a family affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay / 中华医学遗传学杂志

OBJECTIVE@#To carry out mutation analysis for a Chinese family affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).@*METHODS@#Whole exome sequencing (WES) was used to screen potential mutations within genomic DNA extracted from the proband. Suspected mutation was validated by combining clinical data and results of Sanger sequencing.@*RESULTS@#A homozygous deletional mutation c.3665_3675delGTGCTGTCTTA (p.S1222fs) was found in the proband, for which her parents were both heterozygous carriers.@*CONCLUSION@#WES is capable of detecting mutation underlying this disorder and facilitating genetic counseling and prenatal diagnosis for the affected family. A novel pathogenic mutation of the SACS gene was discovered.

Twenty-five years since the identification of the first SCA gene: history, clinical features and perspectives for SCA1 / Vinte e cinco anos desde a identificação do primeiro gene das SCAs: história, aspectos clínicos e perspectivas para a SCA1

ABSTRACT Spinocerebellar ataxias (SCA) are a clinically and genetically heterogeneous group of monogenic diseases that share ataxia and autosomal dominant inheritance as the core features. An important proportion of SCAs are caused by CAG trinucleotide repeat expansions in the coding region of different genes. In addition to genetic heterogeneity, clinical features transcend motor symptoms, including cognitive, electrophysiological and imaging aspects. Despite all the progress in the past 25 years, the mechanisms that determine how neuronal death is mediated by these unstable expansions are still unclear. The aim of this article is to review, from an historical point of view, the first CAG-related ataxia to be genetically described: SCA 1.

RESUMO As ataxias espinocerebelares (SCA) são um grupo clínico e geneticamente heterogêneo de doenças monogênicas que compartilham ataxia e herança autossômica dominante como características principais. Uma proporção importante de SCAs é causada por expansões de repetição de trinucleotídeos CAG na região de codificação de diferentes genes. Além da heterogeneidade genética, os aspectos clínicos transcendem os sintomas motores, incluindo aspectos cognitivos, eletrofisiológicos e de imagem. Apesar de todo o progresso feito nos últimos 25 anos, os mecanismos que determinam como se dá a morte neuronal mediada por essas expansões instáveis ainda não estão claros. O objetivo deste artigo é revisar, de um ponto de vista histórico, a primeira ataxia geneticamente relacionada com o CAG descrita: SCA 1.

Quality of life in individuals with spinocerebellar ataxia type 10: a preliminary study / Qualidade de vida em indivíduos com ataxia espinocerebelar tipo 10: estudo preliminar

ABSTRACT Spinocerebellar ataxia type 10 (SCA10) is characterized by gait ataxia, dysarthria, nystagmus, epilepsy, reduced cognitive ability and depression, which lead to functional loss and behavioral changes. These signs gradually evolve and may interfere with the physical, emotional, and social aspects of quality of life (QoL). Objective: To assess the self-perception of quality of life and its association with disease duration, severity of ataxia, balance and functional independence. Methods: This study focused on the disease duration, ataxia severity (SARA), balance (Berg Balance Scale), functionality (FIM, Lawton IADL) and QoL (SF-36 v.2) of 15 individuals with SCA10. Results: The population sample consisted of eight females and seven males, with a mean age of 43.8 (± 8.2) years, mean age of symptom onset of 33.1 (± 8.9) years and mean disease duration of 9.8 (± 11.2) years. The mean Berg Balance Scale score was 47.2 (± 12), mean SARA score (n = 14) 11.5 (± 7.3), mean Lawton IADL score 20.4 (± 1.8) and mean FIM score 120.3 (± 5.4). Individuals with SCA10 had a greater impairment of QoL in the "role-physical" domain (p = 0.04). The longer the disease duration (p = 0.02), risk of falling (p = 0.04), severity of ataxia (p = 0.00) and functional dependence in activities of daily living (p = 0.03) and instrumental activities of daily living (p = 0.00), the worse the QoL was in the "physical functioning" domain, with a decrease of 1.62 points for each year of disease duration. Conclusion: In this sample, the greatest impairment of QoL in individuals with SCA10 was observed in "physical functioning" and "physical role".

RESUMO A Ataxia Espinocerebelar tipo 10 (SCA10) caracteriza-se pela ataxia da marcha, disartria, nistagmo, epilepsia, redução da capacidade cognitiva e depressão, causando perda funcional e alterações comportamentais. Esses sinais evoluem gradualmente e podem interferir nos aspectos físicos, emocionais e sociais da Qualidade de Vida (QV). Objetivo: Avaliar a autopercepção da qualidade de vida e sua associação com a duração da doença, gravidade da ataxia, equilíbrio e independência funcional. Método: O estudo enfoca a duração da doença, gravidade da ataxia (SARA), equilíbrio (EEB), funcionalidade (MIF, Lawton) e QV (SF-36 v.2) de 15 indivíduos com SCA10. Resultados: A amostra foi composta por oito indivíduos do sexo feminino, com média de idade de 43,8 (± 8,2), de idade de início dos sintomas 33,1 (± 8,9) e de tempo de doença de 9,8 (± 11,2) anos. A média do escore na Berg foi 47,2 (± 12,0), no SARA (n = 14) foi de 11,5 (± 7,3), na escala de LAWTON 20,4 (± 1,8) e na MIF 120,3 (± 5,4) pontos. Os Indivíduos com SCA10 apresentaram maior prejuízo na QV no domínio "Aspectos Físicos" (p = 0,04). Quanto maior a duração da doença (p = 0,02), risco de queda (p = 0,04), gravidade da ataxia (p = 0,00) e maior dependência funcional para AVD (p = 0,03) e AIVD (p = 0,00), pior a QV no domínio "Capacidade Funcional" com decréscimo de 1,62 ponto para cada ano no tempo de doença. Conclusão: Nesta amostra, o comprometimento da QV em indivíduos com SCA10 foi observado nos domínios "Capacidade Funcional" e "Aspectos Físicos".

Report on the External Quality Assessment Scheme for Molecular Diagnostics in Korea (2017)

Quality control for genetic analysis has become more important with a drastic increase in testing volume and clinical demands. The molecular diagnostics division of the Korean Association of Quality Assurance for Clinical Laboratory conducted two trials in 2017 on the basis of molecular diagnostics surveys, involving 53 laboratories. The molecular diagnostics surveys included 37 tests: gene rearrangement tests for leukemia (BCR-ABL1, PML-RARA, AML1-ETO, and TEL-AML1), genetic tests for Janus kinase 2, FMS-like tyrosine kinase 3-internal tandem duplication, FMS-like tyrosine kinase 3-tyrosine kinase domain, nucleophosmin, cancer-associated genes (KRAS, EGFR, KIT, and BRAF), hereditary breast and ovarian cancer genes (BRCA1 and BRCA2), Li-Fraumeni syndrome (TP53), Wilson disease (ATP7B), achondroplasia (FGFR3), hearing loss and deafness (GJB2), Avellino (TGFBI), multiple endocrine neoplasia 2 (RET), Huntington disease, spinocerebellar ataxia, spinal and bulbar muscular atrophy, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes, myoclonic epilepsy ragged red fibre, Leber hereditary optic neuropathy, Prader-raderd Angelman syndrome, Duchenne muscular dystrophy, spinal muscular atrophy, fragile X syndrome, apolipoprotein E genotyping, methylenetetrahydrofolate reductase genotyping, and ABO genotyping. Molecular genetic surveys revealed excellent results for most participants. The external quality assessment program for genetic analysis in 2017 proved useful for continuous education and the evaluation of quality improvement.