Ataxia-telangiectasia: una revisión desde la etiopatogenia al manejo actual con descripción de casos reportados en Perú / Ataxia telangiectasia: A review from etiopathogenesis to current management with a description of reported cases in Peru

La Ataxia-Telangiectasia (AT) es una rara enfermedad de herencia autosómica recesiva y de afección multisistémica, caracterizada por ataxia progresiva, inmunodeficiencia variable con infecciones recurrentes, riesgo incrementado de neoplasias con o sin telangiectasias óculo-cutáneas. La AT es causada por variantes patogénicas bialélicas en el gen ATM. Su diagnóstico se basa en la sospecha de un cuadro clínico compatible, niveles elevados de alfafetoproteína, atrofia cerebelosa y estudios genéticos. No existe tratamiento curativo de AT y su manejo se basa en medidas de soporte y prevención de complicaciones y asesoramiento genético. En esta revisión, actualizamos la epidemiología, manifestaciones clínicas, diagnóstico y tratamiento de AT incluyendo una búsqueda de casos publicados en el Perú.

Ataxia-Telangiectasia (AT) is a rare autosomal recessive disease with multisystemic involvement, characterized by slowly progressive ataxia, variable immunodeficiency with recurrent infections, increased risk of neoplasms with or without oculocutaneous telangiectasias. AT is caused by biallelic pathogenic variants within the ATM gene. Its diagnosis is based on suspicion of a compatible clinical symptomatology, increased levels of alpha-fetoprotein, cerebellar atrophy, and genetic testing. There is no curative treatment for AT and its management is based on supportive and preventive measures of eventual complications and genetic counseling. This review updates the epidemiology, clinical manifestations, diagnosis, and treatment of AT, including a search for cases published in Peru.

Ataxia de Friedreich, revisión y actualización de la literatura con búsqueda sistemática de casos en Latinoamérica / Friedreich's ataxia, review and literature update with a systematic search for cases in Latin America

La Ataxia de Friedreich (AF) es una enfermedad neurodegenerativa autosómica recesiva con compromiso multisistémico. En esta revisión, se actualizan aspectos epidemiológicos, fisiopatológicos y clínico-terapéuticos y se conduce una búsqueda sistemática de casos de AF reportados en Latinoamérica. La prevalencia de AF en poblaciones caucásicas es estimada entre 2 y 5 casos por 100 000 habitantes. En Latinoamérica se han publicado 35 estudios que reúnen 1481 casos en 6 países. Causada por la expansión anormal de repeticiones GAA en el gen FXN, la etiopatogenia está asociada a una reducción en los niveles de la proteína frataxina (que altera el metabolismo energético) y el acúmulo de hierro mitocondrial. El fenotipo clásico de AF suele comenzar antes de los 25 años, aunque hay otros de inicio tardío y retención de reflejos. La sintomatología se caracteriza por ataxia progresiva, alteración sensitiva, arreflexia, disartria, y alteraciones oculomotoras, además de compromiso cardiaco, endocrino y musculoesquelético. El diagnóstico requiere evaluación neurológica detallada, estudios neurofisiológicos, neuroimágenes y pruebas bioquímicas pero el enfoque determinante es el estudio genético que demuestre variantes genéticas bialélicas en el gen FXN. El manejo es multidisciplinario, orientado a aminorar los síntomas, prevenir complicaciones y brindar asesoramiento genético apropiado. Recientemente se ha aprobado el primer tratamiento farmacológico para AF con varios más en fases de experimentación.

SUMMARY Friedreich Ataxia (FA) is an autosomal recessive neurodegenerative disease with multisystemic involvement. This update of epidemiological, pathophysiological, and clinico-therapeutic aspects of FA, includes a systematic review of cases in Latin America. The estimated FA prevalence in Caucasian populations is between 2 to 5 cases per 100 000. In Latin America, 1481 cases have been published in 35 articles from six different countries. Caused by an abnormally repeated expansion of GAA trinucleotide inside the FXN gene, FA's etiopathogenesis is associated with reduced levels of the frataxin protein, which disturb the energy metabolism and result in mitochondrial iron accumulation. The classic phenotype usually shows symptoms before the age of 25, although there are others with a later onset. The main symptoms of AF are progressive ataxia, sensory disturbances, areflexia, dysarthria, and oculomotor alterations, in addition to cardiac, endocrine, and musculoskeletal compromise. Diagnostic workup requires a detailed neurological examination, neuroconduction studies, neuroimaging, and biochemical tests. The definitive diagnosis is provided by genetic testing showing biallelic variants within the FXN gene. The management is multidisciplinary, aimed at reducing symptoms, preventing complications, and providing an appropriate genetic counseling. Recently, the first pharmacological treatment for AF has been approved, with several others in clinical assessment trials.

Bibliometría y mapeo de redes de la producción científica internacional de Cuba sobre ataxias (1993-2020) / Bibliometrics and network mapping of Cuban international scientific production on ataxias (1993-2020)

El objetivo del estudio fue caracterizar el potencial investigador cubano en el ámbito de las ataxias y su evolución temporal. Se realizó una búsqueda en la base de datos Web of Science y se obtuvieron todos los documentos publicados entre 1993 y 2020. Se aplicaron indicadores bibliométricos para explorar la producción, dispersión, distribución y crecimiento anual de los documentos (ley de Price, ley de Lotka, índice de transitoriedad y modelo de Bradford). Se calculó el índice de participación y colaboración de países e instituciones y, por cartografía bibliométrica, se exploraron las redes de coocurrencia de los términos más utilizados. La producción científica de Cuba sobre ataxias hereditarias es alta (219 documentos) y se ajusta a un crecimiento lineal (r= 0,7580). El período estudiado concentra el 47,95 por ciento de los registros con un ritmo anual de publicaciones del 6,6 por ciento y tiempo de duplicidad de 10,8 años. El total de citas fue de 3807 (índice medio: 131,27; índice -h: 31). Se concluye que el crecimiento de la literatura científica cubana sobre ataxias fue lineal para el período estudiado, lo que confirma el incumplimiento de la ley de Price de crecimiento de la literatura científica. El estudio también corrobora la importante red de integración y cooperación internacional entre los diferentes autores y la interdisciplinariedad de los trabajos, evidencia del éxito del Centro para la Investigación y Rehabilitación de las Ataxias Hereditarias (CIRAH), al planificar una estrategia de colaboración científica con objetivos definidos(AU)

The objective of this study was to characterize the Cuban research potential in the field of ataxias and its temporal evolution. A search was carried out in the Web of Science database and all the documents published from 1993 to 2020 were retrieved. Bibliometric indicators were applied to explore the production, dispersion, distribution and annual growth of the documents (Price's law, Lotka's law, transience index and Bradford model). The participation and collaboration index of countries and institutions was calculated and, through bibliometric cartography, the co-occurrence networks of the most used terms were explored. The Cuban scientific production on hereditary ataxias is high (219 documents) and it adjusts to a linear growth (r = 0.7580). The period studied concentrates 47.95percent of the records with an annual publication rate of 6.6percent and 10.8 years' duplication time. The total number of citations was 3807 (mean index: 131.27; h-index: 31). Growth of the Cuban scientific literature on ataxias was concluded to be linear for the period studied, which confirms the non-compliance with Price's law of growth of scientific literature. The study also corroborates the important network of integration and international cooperation among the different authors and the interdisciplinarity of the papers, marking the success of the Center for Research and Rehabilitation of Hereditary Ataxias (CIRAH), when planning a strategy of scientific collaboration with objectives defined(AU)

Clinical and genetics characteristics of adult-onset cerebrotendinous xanthomatosis: analysis of a Chinese pedigree / 中华内科杂志

Objective: Clinical manifestations, imaging findings, pathologic features, and genetic mutations of Chinese adult patients with cerebrotendinous xanthomatosis (CTX) were analyzed in order to achieve a greater understanding of CTX that can improve early detection, diagnosis, and treatment. Methods: Clinical data including medical history, neurologic and auxiliary examinations, imaging findings, and genetic profile were collected for an adult patient with CTX admitted to the Sixth Medical Center of Chinese People's Liberation Army General Hospital in August 2020. Additionally, a systematic review of genetically diagnosed Chinese adult CTX cases reported in major databases in China and other countries was performed and age of onset, first symptoms, common signs and symptoms, pathologic findings, imaging changes, and gene mutations were analyzed. Results: The proband was a 39-year-old female with extensive, early-onset nervous system manifestations including cognitive dysfunction and ataxia. Systemic lesions included juvenile cataract and a tendon mass. Cranial magnetic resonance imaging revealed cerebral atrophy, symmetric white matter changes predominantly in the pyramidal tract, and lesions in the cerebellar dentate nucleus. A novel homozygous mutation in the sterol-27-hydroxylase (CYP27A1) gene (c.1477-2A>C) was identified. There were no family members with similar clinical presentation although some were carriers of the c.1477-2A>C mutation. The patient showed a good response to deoxycholic acid treatment. Totally there were 56 cases of adult CTX patients in China, mostly in East China (31/56, 55.4%), at a male-to-female ratio of 1.8 to 1. Multiple organs and tissues including nervous system, tendon, lens, lung, and skeletal muscle were affected in these cases. The most common neurologic manifestations were cognitive dysfunction (44/52, 84.6%) and ataxia (44/51, 86.3%). The cases were characterized by early onset, chronic progressive damage of multiple systems, long disease course, and delayed diagnosis, making the disease difficult to manage clinically and resulting in poor prognosis. The 2 most common genetic mutations in Chinese adult CTX patients were c.1263+1G>A and c.379C>T. Exon 2 of the CYP27A1 gene was identified as a mutation hot spot. Conclusions: Chinese adult patients with CTX have complex clinical characteristics, a long diagnostic cycle, and various CYP27A1 gene mutations. Early diagnosis and intervention can improve the prognosis of these patients.

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.

Clinical features and genetic analysis of a child with EAST/SeSAME syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a EAST/SeSAME syndrome child featuring epilepsy, ataxia, sensorineural deafness and intellectual disability.@*METHODS@#A child with EAST/SeSAME syndrome who had presented at the Third Affiliated Hospital of Zhengzhou University in January 2021 was selected as the study object. Peripheral blood samples of the child and her parents were collected and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing.@*RESULTS@#Genetic testing revealed that the child has harbored compound heterozygous variants of the KCNJ10 gene, namely c.557T>C (p.Val186Ala) and c.386T>A (p.Ile129Asn), which were inherited from her mother and father, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted as likely pathogenic (PM1+PM2_Supporting+PP3+PP4; PM1+PM2_Supporting+PM3+PP3+PP4).@*CONCLUSION@#The patient was diagnosed with EAST/SeSAME syndrome due to the compound heterozygous variants of the KCNJ10 gene.

Causas de ataxia aguda en un hospital de tercer nivel de complejidad / Causes of acute ataxia at a tertiary level hospital

La ataxia es una alteración de la coordinación motora voluntaria y del control postural. Es una entidad poco frecuente en la infancia, siendo la principal causa de ataxia aguda descripta en la bibliografía, de origen inmunológico (post infecciosa), seguida de las intoxicaciones. Para el diagnóstico es fundamental una anamnesis detallada, cronología de los síntomas, antecedentes infecciosos o de contacto con sustancias tóxicas y un examen neurológico completo. El objetivo de nuestro estudio fue analizar retrospectivamente la causa de ataxia aguda como signo neurológico predominante en pacientes que consultaron en el Hospital Juan P. Garrahan. Diseño: Se trata de un estudio descriptivo, observacional, retrospectivo y de corte transversal. Población: niños de 1 a 18 años, con o sin patología previa conocida, que consultaron al servicio de emergencias del hospital por ataxia entre enero de 2013 y octubre de 2018. Método: recolección y análisis de historias clínicas comprendidas en esa fecha, con alteración en la marcha como síntoma de consulta. Resultados: de un total de 237 pacientes, la causa más frecuente de ataxia aguda fue la inmunológica (incluyendo en este grupo a las postinfecciosas y a las no asociadas a infección). Conclusión: En nuestro hospital con tercer nivel de atención, la causa más frecuente de ataxia aguda fue la inmunológica. En segundo lugar, las intoxicaciones y, en tercer lugar, las enfermedades neurológicas. (AU)

Ataxia is a disorder of voluntary motor coordination and postural control, which is rare in childhood. The main cause of acute ataxia described in the literature is immune-mediated inflammation (postinfectious), followed by intoxication. A detailed anamnesis, chronology of symptoms, history of infection or contact with toxic substances, and a complete neurological examination are essential in the diagnostic work-up. The aim of our study was to retrospectively analyze the cause of acute ataxia as a predominant neurological sign in patients who consulted at Hospital Juan P. Garrahan. Study design: A descriptive, observational, retrospective, cross-sectional study was conducted. Study population: children aged 1 to 18 years, with or without known previous disease, who presented to the hospital emergency department for ataxia between January 2013 and October 2018. Method: collection and analysis of medical records from that period of patients with gait disturbance as the reason for consultation. Results: out of a total of 237 patients, the most frequent cause of acute ataxia was immune-mediated inflammation (both post-infectious and noninfectious). Conclusion: In our tertiary care hospital, the most frequent cause of acute ataxia was immune-mediated inflammation. The second most frequent cause was intoxication and the third neurological diseases (AU)

Diagnosis of a child with mitochondrial myopathy and cerebellar atrophy with ataxia due to compound heterozygous variants of MSTO1 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child with myopathy and cerebellar atrophy with ataxia.@*METHODS@#Clinical examinations and laboratory testing were carried out for the patient. The proband and the parents' genomic DNA was extracted from peripheral blood samples and subjected to trio whole-exome sequencing. Candidate variant was validated by Sanger sequencing.@*RESULTS@#The 1-year-and-8-month-old boy manifested motor developmental delay, ataxia, hypomyotonia, increased serum creatine kinase. Cranial MRI showed cerebellar atrophy with progressive aggravation. Genetic testing revealed that the patient has harbored compound heterozygous variants of the MSTO1 gene, namely c.13delG (p.Ala5ProfsTer68) and c.971C>T (p.Thr324Ile), which were respectively inherited from his mother and father. The former was unreported previously and was predicted to be likely pathogenic, whilst the latter has been reported previously and was predicted to be of uncertain significance.@*CONCLUSION@#The compound heterozygous c.13delG (p.Ala5ProfsTer68) and c.971C>T (p.Thr324Ile) variants probably underlay the disease in the proband. Above finding has enriched the spectrum of MSTO1 gene variants underlying mitochondrial myopathy and cerebellar atrophy with ataxia.

Clinical and genetic spectrum of SCN2A gene associated epilepsy and episodic ataxia / 中华儿科杂志

Objective: To explore the clinical manifestations and genetic characteristics of patients with epilepsy and episodic ataxia caused by SCN2A gene variation. Methods: The clinical data of seizure manifestation, imaging examination and genetic results of 5 patients with epilepsy and (or) episodic ataxia because of SCN2A gene variation admitted to the Department of Pediatrics, the Third Affiliated Hospital of Zhengzhou University from July 2017 to January 2021 were analyzed retrospectively. Results: Among 5 patients, 4 were female and 1 was male. The onset age of epilepsy ranged from 4 days to 8 months. There were 2 cases of benign neonatal or infantile epilepsy and 3 cases of epileptic encephalopathy, in whom 1 case had development retardation,1 case transformed from West syndrome to infantile spasm and another one transformed from infantile spasm to Lennox-Gastaut syndrome. One case of benign neonatal-infantile epilepsy was characterized by neonatal onset seizures and episodic ataxia developed at the age of 78 months. Electroencephalograms at first visit of 5 cases showed that 2 cases were normal, 1 case had focal epileptic discharge, and 2 cases had multi-focal abnormal discharge with peak arrhythmia. The brain magnetic resonance imaging (MRI) of 3 cases were nomal, 1 case was abnormal (brain atrophy with decreased white matter) and the results of 1 case was unknown. The follow-up time ranged from 17 months to 89 months. Four cases of epilepsy were controlled and 1 case died at 2 years of age. Two cases had normal intelligence and motor development, 2 had moderate to severe intelligence retardation and motor critical state, and 1 had moderate to severe intelligence and motor development retardation. SCN2A gene variations were identified in all cases. There were 4 missense variations and 1 frameshift variation. Three variations had not been reported so far, including c.4906A>G,c.3643G>T,c.638delT. Conclusions: Variations in SCN2A gene can cause benign neonatal or infantile epilepsy and epileptic encephalopathy. Some children develop episodic ataxia with growing age. The variation of SCN2A gene is mainly missense variation.

Clinical features and CACNA1A gene mutation in a family with episodic ataxia type 2 / 中南大学学报(医学版)

Episodic ataxia (EA) is a group of disorders characterized by recurrent spells of vertigo, truncal ataxia, and dysarthria. Episodic ataxia type 2 (EA2), the most common subtype of EA, is an autosomal dominant disease caused by mutation of the CACNA1A gene. EA2 has been rarely reported in the Chinese population. Here we present an EA2 family admitted to Xiangya Hospital in October 2018. The proband was a 22-year-old male who complained of recurrent spells of vertigo, slurred speech, and incoordination for 4 years. Brain magnetic resonance imaging (MRI) showed cerebellar atrophy. He had neuropsychological development disorder in childhood, and cognitive assessment in adulthood showed cognitive impairment. The proband's mother and grandmother had a similar history. Peripheral blood samples from the proband and family members were collected, and genomic DNA was isolated. Whole exome sequencing of the proband detected a heterozygous frameshift mutation c.2042_2043del (p.Q681Rfs*100) of CACNA1A gene. This mutation was verified in the proband and 2 family members using Sanger sequencing. One family member carrying this mutation was free of symptoms and signs, suggesting an incomplete penetrance of the mutation. We reported a variant c.2042_2043del of CACNA1A gene as the pathogenic mutation in a Chinese EA2 family for the first time. This case enriched the clinical spectrum of CACNA1A related EA2, and contributed to the understanding of clinical and genetic characteristics of EA2 to reduce misdiagnosis.

The evaluation of cerebellum gross morphometric measurements in subjects having migraine, ataxia, dementia and vertigo / Evaluación de las medidas morfométricas macroscópicas del cerebelo en sujetos con migraña, ataxia, demencia, vértigo

SUMMARY: This paper was aimed to determine the morphometric measurements of cerebellum using MRI in subjects having migraine, ataxia, dementia and vertigo. Three hundred twenty six (326 subjects; 80 migraine subjects; 85 vertigo subjects; 83 dementia subjects; 78 ataxia subjects) subjects ranging from 20 up to 85 years were included in this study. Cerebellum morphometric measurements were taken from subjects having brain MRI in the Radiology Department. The means and standard deviations of the measurements were: Sagittal section cerebellum superior inferior length, 56.21±5.16 mm; sagittal section cerebellum anteroposterior length, 86.36 ±5.36 mm; axial section cerebellum antereoposterior length, 66.53±5.41 mm; axial section bi-cerebellar length, 100.48±5.14 mm; coronal section cerebellum supero-inferior length,53.60±3.84 mm; coronal section bi-cerebellar length, 99.77±6.24 mm in subjects with migraine, whereas the corresponding values were 62.33±8.66 mm; 93.31±9.89 mm; 60.26±7.98 mm; 99.89±6.41 mm; 54.35±4.64 mm; 85.58±14.74 mm in subjects with vertigo, respectively. The same values were found as 58.82±8.34 mm; 86.74±13.22 mm; 58.93±8.89 mm; 97.93±6.07 mm; 50.66±4.92 mm; 84.96±14.93 mm in patients having dementia, respectively, while the same measurements were as 60.83±8.59 mm; 92.18±9.12 mm; 57.76±7.85 mm; 97.71±5.82 mm; 52.48±4.85 mm; 81.49±14.38 mm in ataxia patients, respectively. Also, ages were divided into seven groups as decades. There were found significant difference in all parameters according to sex and ages (p<0.05). The cerebellum morphometry provides important and useful knowledge in terms of comparison of abnormalities clinicians and data will be valuable for the determination of pathologies for clinical disciplines.

RESUMEN: Este trabajo tuvo como objetivo determinar las medidas morfométricas del cerebelo mediante resonancia magnética en sujetos con migraña, ataxia, demencia y vértigo. Trescientos veintiseis sujetos (80 con migraña; 85 con vértigo; 83 con demencia y 78 con ataxia) entre los 20 y los 85 años de edad se incluyeron en este estudio. Se tomaron medidas morfométricas del cerebelo de sujetos sometidos a resonancia magnética en el Departamento de Radiología. Las medias y desviaciones estándar de las medidas fueron: sección sagital longitud superoinferior del cerebelo, 56,21±5,16 mm; sección sagital longitud anteroposterior del cerebelo, 86,36 ±5,36 mm; sección axial longitud anteroposterior del cerebelo, 66,53±5,41 mm; sección axial longitud bicerebelosa, 100,48±5,14 mm; sección coronal longitud superoinferior del cerebelo, 53,60±3,84 mm; longitud bicerebelosa de la sección coronal, 99,77±6,24 mm en sujetos con migraña, mientras que los valores correspondientes fueron 62,33±8,66 mm; 93,31±9,89mm; 60,26±7,98 mm; 99,89±6,41 mm; 54,35±4,64 mm; 85,58±14,74 mm en sujetos con vértigo, respectivamente. Se encontraron los mismos valores para pacientes con demencia 58,82±8,34 mm; 86,74±13,22 mm; 58,93±8,89 mm; 97,93±6,07 mm; 50,66±4,92 mm; 84,96±14,93 mm , respectivamente, mientras que las mismas medidas fueron de 60,83±8,59 mm; 92,18±9,12 mm; 57,76±7,85 mm; 97,71±5,82 mm; 52,48±4,85 mm; 81,49±14,38 mm en pacientes con ataxia, respectivamente. Las edades se dividieron en siete grupos, cada uno en década. Se encontraron diferencias significativas en todos los parámetros según sexo y edad (p<0,05). La morfometría del cerebelo proporciona un conocimiento importante y útil en términos de comparación de anormalidades clínicas y los datos serán valiosos para la determinación de patologías para las disciplinas clínicas.

Mutação missense de novo patogênica c. 2415C G (p. Asp805Glu) no gene ATP1A3 em paciente com hemiplegia alternante da infância com resposta favorável ao cloridrato de biperideno / A de novo missense pathogenic mutation c.2415C> G (p.Asp805Glu) in ATP1A3 gene in a patient with alternating hemiplegia of childhood with favorable response to biperiden hydrochloride

A Hemiplegia Alternante da Infância é um distúrbio neurológico grave e uma doença rara (1 em cada 100.000 recém-nascidos), caracterizado por ataques repetidos transitórios de hemiplegia episódica ou tetraplegia que podem durar minutos a horas, acompanhados por outros sintomas paroxísticos como anormalidades oculomotoras e autonômicas, distúrbios do movimento como ataxia, comprometimento cognitivo progressivo, convulsões, distonia e coreia. Os tratamentos atuais são amplamente sintomáticos. Neste relato de caso, apresentamos paciente do sexo feminino, 18 anos, na qual aos 10 meses apresentou o primeiro episódio aparente de crise convulsiva com versão ocular. O eletroencefalograma e tomografia computadorizada não revelaram anormalidades e foram administradas diversas medicações como fenobarbital, carbamazepina, valproato de sódio, topiramato, dicloridrato de flunarizina, clonazepam, cipro-heptadina e pizotifeno, todos sem resultado. Devidos aos sintomas extrapiramidais, paciente passou a utilizar biperideno, apresentando não só melhora da distonia, mas também no número de crises hemiplégicas. Aos 13 anos, ela foi diagnosticada com Hemiplegia Alternante da Infância na mutação patogênica missense de novo c.2415C G (p.Asp805Glu) no gene ATP1A3 apresentando boa resposta ao tratamento com cloridrato de biperideno. (AU)

Alternating hemiplegia of childhood is a severe neurological disorder and a rare disease (1 in 100,000 newborns), characterized by repeated transient attacks of episodic hemiplegia or tetraplegia that can last minutes to hours, accompanied by other paroxysmal symptoms such as oculomotor and autonomic abnormalities, movement disorders such as ataxia, progressive cognitive impairment, seizures, dystonia, and chorea. Current treatments are largely symptomatic. In this case report, we present a female patient, 18 years old, who presented the first apparent episode of seizure with ocular version at ten months of age. The electroencephalogram and CT scan revealed no abnormalities, and several medications such as phenobarbital, carbamazepine, sodium valproate, topiramate, flunarizine dihydrochloride, clonazepam, cyproheptadine and pizotifen were administered, all without result. Due to the extrapyramidal symptoms, the patient started using biperidene, showing improvement in dystonia and the number of hemiplegic seizures. At age 13, she was diagnosed with Alternating hemiplegia of Childhood in the pathogenic missense de novo mutation c.2415C>G (p.Asp805Glu) in the ATP1A3 gene showing a good response to treatment with biperidene hydrochloride. (AU)

Enfermedad de Creutzfeldt-Jakob: experiencia de 5 años en un hospital terciario de Chile / Creutzfeldt-Jakob disease, experience in 17 patients

Background: Creutzfeldt-Jakob disease (CJD) is a prion affection that typically produces a rapidly progressive dementia with different neurologic and extra-neurologic manifestations. Aim: To characterize clinical, imaging and electroencephalography findings in patients with a probable CJD. Patients and Methods: A case series study of patients admitted in the Neurology department at a public hospital, between 2014 and 2019. Demographic, clinical, imaging, and electroencephalographic data of patients with probable CJD were analyzed. Results: Seventeen patients aged 63 ± 11 years (53% women) with a probable CJD were gathered. The incidence was 4.7 cases/year per million inhabitants. Twenty four percent of patients had a family history of CJD. The median time between the onset of symptoms and the hospital admission was three months with a survival of four months. The most common clinical manifestations were an amnesic syndrome in 88%, myoclonus in 76%, frontal syndrome and ataxia in 71%. Brain MRI was abnormal in all patients. The preponderant finding was the involvement of the caudate nucleus in 82% of cases. In the EEG, 94% of patients had abnormalities. All had a theta-delta slowing as a base rhythm. The pseudo-periodic pattern was observed in the 29% and status epilepticus in 18%. Conclusions: In this group of patients we observed the heterogeneity of the clinical manifestations of the disease, the frequent imaging and electroencephalographic alterations and the short evolution time leading to death.

El cerebelo y sus afecciones en los niños / The cerebellum and its conditions in children

Introducción: Cuando se piensa en estudiar el cerebelo es posible que lo primero que viene a la mente sean las siguientes preguntas: ¿cuáles son sus enfermedades?, ¿cómo se expresan clínicamente? y quizás, ¿cómo es su estructura y cuáles las funciones de este órgano? Objetivo: Examinar las principales características anatómicas y funcionales del cerebelo y relacionarlas con su expresión clínica cuando enferma, así como comentar sobre su abanico de etiologías en el niño. Métodos: Las fuentes de búsquedas fueron las bases de datos computarizadas: PubMed, Ebsco y SciELO. Se utilizaron las palabras clave: cerebelo, ataxia, erores congénicos del metabolismo y ataxias, ataxias episódicas, enfermedades progresivas del sistema nervioso y ataxias; en idioma español e inglés. Resultados: El cerebelo recepciona múltiples informaciones y las envía a diversas estructuras cerebrales por medio de las cuales modula la excitabilidad de estas estructuras y sus sistemas descendentes. Este órgano organiza, dirige, coordina múltiples funciones que se traducen en fuerza, tiempo y secuencia. El cerebelo enfermo impide que la persona ejecute sus funciones y movimientos de forma uniforme y coordinada; puede resultar afectado por un amplio abanico de posibilidades etiológicas, genéticas o adquiridas y enfermarse todo o parte de él. Consideraciones finales: El cerebelo cumple importantes funciones dentro del sistema nervioso, tiene una expresividad muy típica cuando está enfermo. El uso adecuado de las nuevas técnicas de estudios por imágenes y genéticas, entre otras, permiten al pediatra clínico estar en mejores condiciones para el diagnóstico de sus afecciones y tratamiento oportuno(AU)

Introduction: When we think about studying the cerebellum, the first thing that comes to mind may be the following questions: Which are its diseases? How they are clinically expressed? , and perhaps: What is its structure and what functions do this organ has? Objective: Examine the main anatomical and functional characteristics of the cerebellum and relate them to its clinical expression when it becomes ill, as well as comment on its range of etiologies in the child. Methods: Search sources were computerized databases like: PubMed, Ebsco, and SciELO. Keywords used were: cerebellum, ataxia, metabolism congenital errors and ataxias, episodic ataxias, progressive diseases of the nervous system and ataxias; in Spanish and English. Results: The cerebellum receives information and sends it to various brain structures through which it modulates the excitability of these structures and their downstream systems. This organ organizes, directs, and coordinates multiple functions that translate into strength, time and sequence. An ill cerebellum prevents the person from performing their functions and movements in a uniform and coordinated way; it can be affected by a wide range of etiological, genetic or acquired possibilities and make all or part of it ill. Final considerations: The cerebellum performs important functions within the nervous system; it has a very typical expressiveness when it is ill. Proper use of new imaging and genetic study techniques, among others, allows the clinical pediatricians to be better able to diagnose its conditions and timely treatment(AU)

Paraparesia espástica complicada como fenótipo neurológico em OPA1 / Complex spastic paraplegia as a neurological phenotype in an opa1 patient

RESUMO: A atrofia óptica autossômica dominante (ADOA) é uma das formas mais comuns de atrofias ópticas hereditárias, e causada por mutações no gene OPA1. Os pacientes afetados por essa doença geralmente apresentam perda visual na primeira década de vida, podendo apresentar manifestações extraoftalmológicas no decorrer dos anos, configurando uma síndrome chamada OPA1 plus ou ADOA-plus. Objetivos: Relatar caso de paciente portadora da síndrome ADOA-plus, estabelecendo correlações com casos descritos na literatura. Relato de caso: Paciente feminino, 30 anos, foi encaminhada para avaliação de quadro de atrofia óptica progressiva associada a sintomas de neuropatia periférica. Aos dois anos, foi diagnosticada com perda visual parcial em consulta de puericultura. Não relatou outros sintomas associados durante a infância e a adolescência. Aos 20 anos, apresentou dificuldades de deambular, fraqueza em membros inferiores e falta de equilíbrio. Aos 25 anos, após extensa investigação, foi identificada, através de sequenciamento de exoma, mutação patológica no gene OPA1 confirmando o diagnóstico ADOA-plus e iniciado tratamento com Coenzima Q10. Atualmente a paciente relata ataxia sensitiva, diminuição da acuidade visual progressiva, fasciculações e câimbras em MMII, disfagia e dispneia. Discussão: Muitos pacientes com ADOA-plus apresentam surdez neurossensorial como sintoma extraoftalmológico mais comum, além de quadros de parkinsonismo e demência, ataxia e ptose. Paciente relatada constitui um caso de atrofia óptica associado à neuropatia periférica, ataxia e miopatia. Devido à ampla variabilidade clínica dessa doença, deve-se investigar mutações no OPA1 em casos de paraparesia espástica progressiva associada à atrofia óptica, visto que possibilidade de tratamento com Coenzima Q10. (AU)

ABSTRACT: Introduction: Autosomal dominant optic atrophy (ADOA) is one of the most common forms of inherited optic atrophies and is caused by mutations in the OPA1 gene. Patients affected by this disease usually present visual loss in the first decade of life, and may present extra-ophthalmologic manifestations over the years, configuring a syndrome called OPA1 plus or ADOA-plus. Objectives: to report the case of a patient with ADOA-plus syndrome, establishing correlations with cases described in the literature, Case report: a 30-year-old female patient was referred for evaluation of progressive optic atrophy associated with symptoms of peripheral neuropathy. At two years of age, she was diagnosed with partial visual loss during a childcare visit. She reported no other associated symptoms during childhood and adolescence. At the age of 20, she presented with difficulty walking, lower limb weakness, and poor balance. At 25, after extensive investigation, a pathological mutation in the OPA1 gene was identified through exome sequencing, confirming the diagnosis of ADOA-plus, and treatment with Coenzyme Q10 was initiated. Currently the patient reports sensory ataxia, progressive decrease in visual acuity, fasciculations and cramps in the lower limbs, dysphagia and dyspnea. Discussion: Many patients with ADOA-plus present sensorineural deafness as the most common extra-ophthalmologic symptom, in addition to parkinsonism and dementia, ataxia and ptosis. The patient reported is a case of optic atrophy associated with peripheral neuropathy, ataxia and myopathy. Due to the wide clinical variability of this disease, OPA1 mutations should be investigated in cases of progressive spastic paraparesis associated with optic atrophy, since the possibility of treatment with Coenzyme Q10. (AU)

Pediculectomy and fenestration for spinal cord decompression of the lumbar spine of a bush dog (Speothos venaticus) - case report / [Pediculectomia e fenestração para descompressão medular da coluna lombar em um cachorro-vinagre (Speothos venaticus) - relato de caso]

A captive adult male bush dog (Speothos venaticus) was referred to our Veterinary Medical Teaching Hospital from a local zoo due to a two-week history of progressive hind limb gait impairment and ataxia, non-responsive to clinical management. Computed tomography revealed decreased disc space at L3 - L4 level, with probable disc extrusion narrowing the right side of the spinal canal, compressing the spinal cord. We opted to surgically remove the disc material using both fenestration and right lateral pediculectomy (mini-hemilaminectomy) techniques. Twelve days after surgery there was mild residual proprioceptive ataxia. Gait was fully regained with remission of the neurological deficits around the 30th postoperative day. This is - to the best of our knowledge - the first successful report of a lumbar intervertebral disc extrusion in a bush dog (Speothos venaticus) surgically treated by pediculectomy and disc fenestration.(AU)

Um cachorro-vinagre (Speothos venaticus), macho, adulto, mantido em cativeiro, foi encaminhado ao Hospital Veterinário Universitário pelo zoológico local com histórico de duas semanas de comprometimento progressivo da marcha dos membros posteriores e ataxia, que não responderam ao tratamento clínico. Tomografia computadorizada revelou diminuição do espaço em disco no nível L3 - L4, com provável extrusão de disco estreitando o lado direito do canal vertebral, comprimindo a medula espinhal. Optamos por remover cirurgicamente esse material do disco usando técnicas de fenestração e pediculectomia lateral direita (mini-hemilaminectomia). Doze dias após a cirurgia, houve melhora na deambulação, com ataxia proprioceptiva residual leve. A marcha foi totalmente recuperada com remissão dos déficits neurológicos por volta do trigésimo dia de pós-operatório. Este é - até onde sabemos - o primeiro relato bem-sucedido de uma extrusão de disco intervertebral lombar em um cachorro-vinagre (Speothos venaticus) tratado cirurgicamente por pediculectomia e fenestração de disco.(AU)

Neurofibromatosis tipos 1 y 2 / Neurofibromatosis type 1 and 2

La neurofibromatosis (NF) comprende un grupo de enfermedades genéticas de herencia autosómica dominante, que se clasifican de la siguiente manera: neurofibromatosis tipo 1 (NF1), neurofibromatosis tipo 2 (NF2) y schwannomatosis (también conocida como neurofibromatosis tipo 3). Esta última es una enfermedad muy infrecuente, con una prevalencia aproximada de 1/126 000 personas, por lo que solo profundizaremos las dos primeras. La NF1, también conocida como la enfermedad de Von Recklinghausen, es la más frecuente de las tres y afecta principalmente la piel y el sistema nervioso periférico. Se caracteriza por la presencia de máculas "café con leche", pecas axilares o inguinales, nódulos de Lisch (hamartomas en el iris) y neurofibromas (tumores de la vaina de nervios periféricos). Otras manifestaciones menos frecuentes, aunque de mayor gravedad, incluyen gliomas del nervio óptico, meningiomas, neurofibromas malignos, escoliosis y displasia de la tibia. Su diagnóstico se suele realizar al nacimiento o durante los primeros años de vida, y se estima que un 50% de quienes la padecen presenta dificultades cognitivas. No hay datos concluyentes sobre la mortalidad en los pacientes con NF1, aunque se sabe que la expectativa de vida es menor que en la población general. La NF2 tiene una prevalencia considerablemente menor que la NF1 y su inicio es más tardío, afectando principalmente a adultos jóvenes. La presentación clínica típica se caracteriza por acúfenos, hipoacusia y ataxia en contexto de la presencia de schwannomas vestibulares bilaterales. Otros hallazgos menos frecuentes incluyen schwannomas de nervios periféricos, meningiomas, ependimomas o astrocitomas. La esperanza de vida es de unos 36 años, con una supervivencia media desde el momento del diagnóstico de 15 años. (AU)

Neurofibromatosis (NF) includes a group of genetic diseases with an autosomal-dominant inheritance pattern, and they are classified as follows: Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and Schwannomatosis (also known as neurofibromatosis type 3). This last one is a very rare disease, with an approximate prevalence of 1/126000, so we will only deepen in the first two. NF1, also known as von Recklinghausen disease, is the most frequent, and mainly affects the skin and peripheral nervous system. Its typical manifestations are the presence of café-au-lait macules, axillary or inguinal freckles, Lisch nodules (hamartomas in the iris) and neurofibromas (peripheral nerve sheath tumors). Less frequent manifestations, although more serious, include optic nerve gliomas, meningiomas, malignant neurofibromas, scoliosis and tibial dysplasia. The diagnosis is usually made at birth or during the first years of life, and approximately 50% of patients present cognitive difficulties. There is no conclusive data on mortality in patients with NF1, although it is known that life expectancy is lower than in general population. NF2 has a considerably lower prevalence than NF1, and its onset is later in life, mainly affecting young adults. Its typical clinical presentation is characterized by tinnitus, hearing loss and ataxia in the context in the presence of bilateral vestibular schwannomas. Less frequent findings include peripheral nerve schwannomas, meningiomas, ependymomas or astrocytomas. Life expectancy is about 36 years old, with a median survival from the moment of diagnosis of 15 years. (AU)

Spontaneous poisoning by Talisia esculenta in cattle / Intoxicação espontânea por Talisia esculenta em bovinos

Talisia esculenta, commonly known as pitombeira, is a tree which fruits are widely consumed by human beings in northeastern Brazil. The aim of this work is to describe the epidemiological, clinical and pathological aspects of two outbreaks of spontaneous poisoning by T. esculenta in cattle in the dry region of Pernambuco, northeastern Brazil. The cases occurred in the municipalities of São Bento do Una and Belo Jardim. From a total of 25 adult cattle, eight become sick after ingest T. esculenta leaves and fruits. Four cattle died until 72 hours after the first clinical signs; which consisted in ataxia, reluctance to walk, tottering, head tremors muscle spasms in the limbs, rigidity of the pelvic limbs with wide base stance position, ruminal atony and, when stressed, presented falls and remained in abnormal positions. Two cattle were necropsied; the only significant finding was the presence of partially digested leaves, barks and seeds of T. esculenta in ruminal contents. Microscopically no lesions were observed. There is no specific therapy for poisoning by T. esculenta leaves. Prophylaxis consists in preventing cattle from gaining access to pasture areas containing the plant.(AU)

Talisia esculenta, popularmente conhecida como pitombeira, é uma árvore cujos frutos são amplamente consumidos por seres humanos no nordeste do Brasil. O objetivo deste trabalho é descrever os aspectos epidemiológicos, clínicos e patológicos de dois surtos de intoxicação espontânea por T. esculenta em bovinos no Agreste de Pernambuco, Nordeste do Brasil. Os casos ocorreram nos municípios de São Bento do Una e Belo Jardim De um total de 25 bovinos adultos, oito adoeceram após consumirem as folhas e frutos de T. esculenta. Quatro morreram em até 72 horas após a observação dos primeiros sinais clínicos; que consistiam em ataxia, relutância em caminhar, andar cambaleante, tremores de cabeça, espasmos musculares nos membros, rigidez dos membros pélvicos com posição de ampla base, atonia ruminal e, quando excitados, apresentavam quedas e permaneciam em posições anormais. Dois bovinos foram necropsiados e o único achado significante foi a presença de folhas, cascas e sementes parcialmente digeridas de T. esculenta no conteúdo ruminal. Microscopicamente não foram observadas lesões. Não existe terapia específica para a intoxicação pelas folhas de T. esculenta. A profilaxia consiste em evitar que bovinos tenham acesso às áreas de pastagem contendo a planta.(AU)

Neuroaxonal Dystrophy in a mule: first case reported / Distrofia neuroaxonal em muar: primeiro relato de caso

A 12-month-old mule (sterile hybrid equine species) presented unspecific neurological changes (symmetric ataxia, dysmetria, conscious proprioceptive deficit and weakness). Due to poor prognosis and to the fact that a sibling from the previous generation exhibited similar clinical signs that were not definitively diagnosed, the animal was euthanized. Diagnosis of neuroaxonal dystrophy was confirmed by anatomohistopathological analysis. This is the first clinical case of neuronal dystrophy in a mule reported in the world. The clinical and histopathological characteristics of this disease were very similar to those reported for several equine breeds. Therefore, the disease should also be considered in the diagnosis of neurological conditions in mules and donkeys.(AU)

Relata-se o caso de uma mula de 12 meses que apresentou alterações neurológicas inespecíficas (ataxia simétrica, dismetria, déficit proprioceptivo consciente e fraqueza). Devido ao mau prognóstico e ao fato de um irmão da geração anterior apresentar sinais clínicos similares sem diagnóstico conclusivo, o animal foi eutanasiado. O diagnóstico de distrofia neuroaxonal foi confirmado por análise anátomo-histopatológica. Esse é o primeiro caso clínico de distrofia neuroaxonal em muar relatado no mundo. As características clínicas e histopatológicas dessa doença foram muito semelhantes às relatadas em várias raças de equinos. Portanto, a doença também deve ser considerada no diagnóstico de condições neurológicas em muares e asininos.(AU)