Genetic heterogeneity within a consanguineous family involving TTPA and SETX genes.

Autosomal recessive cerebellar ataxias (ARCA) constitute a highly heterogeneous group of progressive neurodegenerative disorders that typically occur prior to adulthood. Despite some clinical resemblance between these disorders, different genes are involved. We report in this study four Tunisian patients belonging to the same large consanguineous family, sharing autosomal recessive cerebellar ataxia phenotypes but with clinical, biological, electrophysiological, and radiological differences leading to the diagnosis of two distinct ARCA caused by two distinct gene defects. Two of our patients presented ataxia with the vitamin E deficiency (AVED) phenotype, and the other two presented ataxia with oculo-motor apraxia 2 (AOA2). Genetic testing confirmed the clinical diagnosis by the detection of a frameshift c.744delA pathogenic variant in the TTPA gene, which is the most frequent in Tunisia, and a new variant c.1075dupT in the SETX gene. In Tunisia, data suggest that genetic disorders are common. The combined effects of the founder effect and inbreeding, added to genetic drift, may increase the frequency of detrimental rare disorders. The genetic heterogeneity observed in this family highlights the difficulty of genetic counseling in an inbred population. The examination and genetic testing of all affected patients, not just the index patient, is essential to not miss a treatable ataxia such as AVED, as in the case of this family.

Ataxias in Brazil: 17 years of experience in an ataxia center.

BACKGROUND: Cerebellar ataxias comprise sporadic and genetic etiologies. Ataxia may also be a presenting feature in hereditary spastic paraplegias (HSPs). OBJECTIVE: To report a descriptive analysis of the frequency of different forms of cerebellar ataxia evaluated over 17 years in the Ataxia Unit of Universidade Federal de São Paulo, Brazil. METHODS: Charts of patients who were being followed from January 2007 to December 2023 were reviewed. We used descriptive statistics to present our results as frequencies and percentages of the overall analysis. Diagnosed patients were classified according to the following 9 groups: sporadic ataxia, spinocerebellar ataxias (SCAs), other autosomal dominant cerebellar ataxias, autosomal recessive cerebellar ataxias (ARCAs), mitochondrial ataxias, congenital ataxias, X-linked ataxias, HSPs, and others. RESULTS: There were 1,332 patients with ataxias or spastic paraplegias. Overall, 744 (55.85%) of all cases were successfully diagnosed: 101 sporadic ataxia, 326 SCAs, 20 of other autosomal dominant cerebellar ataxias, 186 ARCAs, 6 X-linked ataxias, 2 mitochondrial ataxias, 4 congenital ataxias, and 51 HSPs. CONCLUSION: This study describes the frequency of cerebellar ataxias in a large group of patients followed for the past 17 years, of whom 55% obtained a definitive clinical or molecular diagnosis. Future demographic surveys in Brazil or Latin American remain necessary.

ANTECEDENTES: Ataxias cerebelares compreendem as etiologias esporádicas e genéticas. Ataxia também pode ser uma característica das paraplegias espásticas hereditárias (HSPs). OBJETIVO: Relatar uma análise descritiva da frequência das diferentes formas de ataxias cerebelares avaliadas ao longo de 17 anos no Setor da Ataxias da Universidade Federal de São Paulo, Brasil. MéTODOS: Prontuários de pacientes acompanhados de janeiro de 2007 a dezembro de 2023 foram revisados. Usamos análise descritiva para apresentar nossos resultados como frequências e percentuais. Os pacientes foram classificados de acordo com os 9 grupos seguintes: ataxias esporádicas, ataxias espinocerebelares (SCA), outras ataxias cerebelares autossômicas dominantes, ataxias cerebelares autossômicas recessivas (ARCA), ataxias mitocondriais, ataxias congênitas, ataxias ligadas ao X, PEH e outros. RESULTADOS: Foram avaliados 1.332 pacientes. Desse total, 744 tiveram um diagnóstico definitivo: 101 ataxias esporádicas, 326 SCA, 20 outras ataxias cerebelares autossômicas dominantes, 186 (ARCA), 6 ataxias ligadas ao X, 2 ataxias mitocondriais, 4 ataxias congênitas e 51 HSP. CONCLUSãO: Esse estudo descreve a frequência e a etiologia das ataxias em um grande grupo de pacientes acompanhados nos últimos 17 anos, dos quais 55% obtiveram diagnóstico clínico ou molecular definitivos. Estudos demográficos futuros do Brasil ou da América Latina continuam sendo necessários.

Spinocerebellar ataxia 27B: a frequent and slowly progressive autosomal-dominant cerebellar ataxia-experience from an Italian cohort.

BACKGROUND: Autosomal-dominant spinocerebellar ataxia (ADCA) due to intronic GAA repeat expansion in FGF14 (SCA27B) is a recent, relatively common form of late-onset ataxia. OBJECTIVE: Here, we aimed to: (1) investigate the relative frequency of SCA27B in different clinically defined disease subgroups with late-onset ataxia collected among 16 tertiary Italian centers; (2) characterize phenotype and diagnostic findings of patients with SCA27B; (3) compare the Italian cohort with other cohorts reported in recent studies. METHODS: We screened 396 clinically diagnosed late-onset cerebellar ataxias of unknown cause, subdivided in sporadic cerebellar ataxia, ADCA, and multisystem atrophy cerebellar type. We identified 72 new genetically defined subjects with SCA27B. Then, we analyzed the clinical, neurophysiological, and imaging features of 64 symptomatic cases. RESULTS: In our cohort, the prevalence of SCA27B was 13.4% (53/396) with as high as 38.5% (22/57) in ADCA. The median age of onset of SCA27B patients was 62 years. All symptomatic individuals showed evidence of impaired balance and gait; cerebellar ocular motor signs were also frequent. Episodic manifestations at onset occurred in 31% of patients. Extrapyramidal features (17%) and cognitive impairment (25%) were also reported. Brain magnetic resonance imaging showed cerebellar atrophy in most cases (78%). Pseudo-longitudinal assessments indicated slow progression of ataxia and minimal functional impairment. CONCLUSION: Patients with SCA27B in Italy present as an adult-onset, slowly progressive cerebellar ataxia with predominant axial involvement and frequent cerebellar ocular motor signs. The high consistency of clinical features in SCA27B cohorts in multiple populations paves the way toward large-scale, multicenter studies.

Ataxias cerebelosas e infecciones virales: caracterización clínica y mecanismos neuropatogénicos / Cerebellar ataxias and viral infections: clinical characterization and neuropathogenic mechanisms

Introducción: La ataxia constituye una alteración en la coordinación de los movimientos, resultado de una disfunción del cerebelo, sus conexiones, así como alteraciones en la médula espinal, nervios periféricos o una combinación de estas condiciones. Las ataxias se clasifican en hereditarias, esporádicas y en adquiridas o secundarias, en las cuales los virus neurotrópicos constituyen los principales causantes. Objetivo: Actualizar los conocimientos relacionados con las ataxias causadas por virus neurotrópicos y los mecanismos neurodegenerativos que pudieran tener relación con la ataxia. Métodos: Se realizó una revisión bibliográfica incluyendo artículos publicados en las principales bases de datos bibliográficas (Web of Sciences, Scopus, SciELO). Se utilizaron las palabras claves: ataxia, virus neurotrópicos, ataxias cerebelosas, ataxias infecciosas, en inglés y español. Análisis e integración de la información: Los virus más conocidos que provocan ataxias infecciosas son el virus de inmunodeficiencia humana, virus del herpes simple, virus del herpes humano tipo 6, virus de la varicela zoster, virus Epstein-Barr, virus del Nilo Occidental, y enterovirus 71, aunque existen otros virus que causan esta afectación. Los mecanismos neuropatogénicos sugeridos son la invasión directa del virus y procesos inmunopatogénicos desencadenados por la infección. Estos virus pueden causar ataxia cerebelosa aguda, ataxia aguda posinfecciosa, síndrome opsoclono-mioclono-atáxico y ataxia por encefalomielitis aguda diseminada. Aunque la mayoría de los reportes de casos informan la evolución satisfactoria de los pacientes, algunos refieren complicaciones neurológicas e incluso la muerte. Conclusiones: Actualmente existe la necesidad de profundizar en el estudio de este tipo de ataxia para favorecer su diagnóstico y tratamiento(AU)

Introduction: Ataxia is an alteration in the coordination of movements caused by a dysfunction of the cerebellum and its connections, as well as alterations in the spinal cord, the peripheral nerves, or a combination of these factors. Ataxias are classified into hereditary, sporadic and acquired or secondary, in which neurotropic viruses are the main causative agents. Objective: Update knowledge about ataxias caused by neurotropic viruses and the neurodegenerative mechanisms which could bear a relationship to ataxia. Methods: A review was conducted of papers published in the main bibliographic databases (Web of Sciences, Scopus, SciELO), using the search terms ataxia, neurotropic virus, cerebellar ataxias, infectious ataxias, in English and in Spanish. Discussion: The best known viruses causing infectious ataxias are the human immunodeficiency virus, herpes simplex virus, human herpesvirus 6, varicella zoster virus, Epstein-Barr virus, Western Nile virus and enterovirus 71, though other viruses may also cause this condition. The neuropathogenic mechanisms suggested are direct invasion of the virus and immunopathogenic processes triggered by the infection. These viruses may cause acute cerebellar ataxia, acute postinfectious ataxia, opsoclonus-myoclonus-ataxia syndrome and ataxia due to acute encephalomyelitis disseminata. Though most case reports describe a satisfactory evolution of patients, some refer to neurological complications and even death. Conclusions: There is a current need to carry out further research about this type of ataxia to improve its diagnosis and treatment(AU)