El difícil camino al diagnóstico del paciente con atrofia muscular espinal / The difficult path to diagnosis of the patient with spinal muscular atrophy

Introducción. Con las nuevas terapias, el diagnóstico temprano de la atrofia muscular espinal (AME) es esencial. El objetivo de este estudio es analizar los distintos componentes que influyen en el retraso diagnóstico. Población y métodos. Se incluyeron pacientes con un diagnóstico molecular de AME tipo I, II y III. Se estudiaron varios parámetros, como la edad al momento de la aparición del primer signo, qué signo fue y el intervalo entre este y el diagnóstico confirmado. Neurólogos especialistas realizaron entrevistas que se complementaron con la revisión de historias clínicas cuando fue necesario. Resultados. Se entrevistaron 112 pacientes. AME I n = 40, AME II n = 48, AME III n = 24. La mediana de edad en meses al momento del reporte del primer signo fue AME I: 1,5 (R 0-7), AME II: 9 (R 2-20), AME III: 18 (R 8-180). Los primeros signos fueron reconocidos por los padres en el 75 % al 85 % de las veces en todos los subtipos. La mediana del tiempo transcurrido entre el primer signo y la primera consulta médica fue menor a un mes en los tres tipos. La mediana de tiempo transcurrido en meses entre el primer signo y el diagnóstico molecular confirmado fue en AME I: 2 (R 0-11), en AME II: 10 (3-46) y en AME III: 31,5 (R 4-288). Conclusiones. Existe un significativo retraso en el diagnóstico de la AME relacionado fundamentalmente a la falta de sospecha clínica. La demora es menor en AME I y mayor en AME III. Otros factores incluyen deficiencias en el sistema de salud.

Introduction. News treatments, make early diagnosis of spinal muscular atrophy (SMA) critical. The objective of this study is to analyze the different factors that influence delay in diagnosis. Population and methods. Patients with a molecular diagnosis of types I, II, and III SMA were included. Several parameters were studied, such as age at onset of first sign, what sign it was, and the time from recognition of first sign to confirmed diagnosis. Neurologists specialized in SMA conducted interviews, supported by the review of medical records when deemed necessary. Results. A total of 112 patients were interviewed. SMA I n = 40, SMA II n = 48, SMA III n = 24. The median age in months at the time of reporting the first sign was SMA I: 1.5 (R: 0­7), SMA II: 9 (R: 2­20), SMA III: 18 (R: 8­180). In all subtypes, first signs were identified by parents from 75% to 85% of the times. The median time from first sign to first medical consultation was less than a month in all 3 types. The median time in months, from first sign to confirmed molecular diagnosis in SMA I was: 2 (R: 0­11), in SMA II: 10 (R: 3­46), in SMA III: 31.5 (R: 4­288). Conclusions. There is a significant delay in SMA diagnosis mainly related to the absence of clinical suspicion. The delay is shorter in SMA I and longer in SMA III. Other factors include deficiencies in the health care system.

Hirayama Disease: Case Report / Doença de Hirayama: Relato de caso

Abstract A 26-year-old previously healthy patient who, at the age of 18 years, began progressive loss of distal strength, rest tremor, and muscle atrophy in the left upper limb. Upon examination, the patient presented moderate distal atrophy, degree 4 in muscular strength, and minipolymioclonus. Electromyoneurography revealed (EMNG) chronic preganglionic bilateral involvement of bilateral C7/C8/T1, worse on the left, with signs of active C8/T1 denervation. A cervical spine magnetic resonance imaging (MRI) scan showed spondylodiscal degenerative changes with central protrusions in C4-C5, C6-C7, and right central in C5-C6, which touched the dural sac. The anteroposterior diameter of the medulla in neutral position, in the C5-C6 plane, was of 5.1 mm. There was a reduction of the spinal cord caliber to 4.0 mm after the dynamic maneuver of forced flexion of the spine, as well as signal increase in the anterior horns. The clinical findings and those of the complementary tests were compatible with Hirayama disease (HD), a rare benign motor neuron disease that affects cervical spinal segments and is most prevalent in men, with onset in the early 20s. Unilateral and slowly progressive weakness is typical, but self-limited. Sensory disturbances, and autonomic and upper motor neuron signals are rare. Management is usually conservative, with the use of a soft cervical collar. Although rare, HD should be considered in young patients with focal asymmetric atrophy in the upper limbs. The early diagnosis of HD depends on the degree of suspicion, as well as on the cooperation and communication among the various specialties involved in the investigation.

Resumo Paciente de 26 anos, previamente hígido, que, aos 18 anos, iniciou perda progressiva de força distal, tremor de repouso, e atrofia muscular no membro superior esquerdo. Ao exame, apresentou atrofia moderada, distal, força muscular de grau 4, e minipolimioclonus. A eletroneuromiografia (ENMG) revelou comprometimento pré-ganglionar crônico de C7/C8/T1 bilateral pior à esquerda, com sinais de desnervação ativa em C8/T1. A ressonância magnética (RM) de coluna cervical mostrou alterações degenerativas espondilodiscais com protrusões centrais em C4-C5, C6-C7, e central direita em C5-C6, que tocavam o saco dural. O diâmetro anteroposterior da medula na posição neutra, no plano de C5-C6, era de 5,1 mm. Houve redução do calibre da medula para 4,0 mm após a manobra dinâmica de flexão forçada da coluna, e aumento de sinal nos cornos anteriores. Os achados clínicos e os dos exames complementares eram compatíveis com doença de Hirayama (DH), uma doença benigna rara dos neurônios motores, que afeta os segmentos espinhais cervicais e é mais prevalente em homens e de início próximo aos 20 anos. É típica a fraqueza unilateral e lentamente progressiva, porém autolimitada. Perturbações sensoriais, sinais autonômicos e do neurônio motor superior são raras. O manejo geralmente é conservador, com uso de colar cervical macio. Apesar de rara, a DH deve ser considerada em pacientes jovens que apresentam atrofias assimétricas focais de membros superiores. O diagnóstico precoce de DH depende do grau de suspeição, e da cooperação e comunicação entre as diversas especialidades envolvidas na investigação.

Calidad de vida en niños y adolescentes con Atrofia Muscular Espinal / Quality of life in children and adolescents with Spinal Muscular Atrophy

INTRODUCCIÓN: La calidad de vida (CV) es un aspecto fundamental del tratamiento en pacientes con Atrofia Muscular Espinal (AME). Existe escasa información a nivel local e internacional. OBJETIVO: Caracterizar la CV en una muestra de niños y adolescentes chilenos con AME. SUJETOS Y MÉTODO: Estudio observacional, transversal. Se aplicó un cuestionario y el módulo neuromuscular 3.0 de la encuesta PedsQLtm, a padres de niños con AME de 2-18 años. Ésta consta de 3 ámbitos: Enfermedad, Comunicación y Familia. Se consideró el puntaje >60 como CV buena, 30-60 regular y <30, deficiente. Se utilizó el programa MINITAB-17®, considerando significativo p ≤ 0,05. RESULTADOS: Se reclutaron 38 pacientes, con edad mediana 8 años (2-18), 52,7% hombres, y 17 (44,7%) AME I. Todos con confirmación genética. El puntaje total fue 51,92 ± 17, correspondiendo 31% a CV buena, 55% regular y 14% baja. En AME I fue 46,5 ± 15,2 y en AME II-III, 56,3 ± 17,4 (p = 0,071). Para el ámbito de Enfermedad fue 53,83 ± 18,1, de Familia 48,6 ± 23,14 y Comunicación 33,3 (RIC: 0,0-83,33). En este último, tuvieron mayor puntaje los pacientes con AME II o III, los mayores de 6 años, los con menor apoyo ventilatorio y los residentes en regiones. Sin embargo, en el análisis multivariado solamente el tipo de AME fue significativo, explicando 40,9% de la variación del puntaje del área de comunicación. Conclusiones: En esta muestra de pacientes con AME, la calidad de vida fue regular a buena en la mayoría. El área más baja fue la de Comunicación, con mayor puntaje en aquellos con mayor capacidad motora funcional.

INTRODUCTION: Quality of life (QoL) is a key aspect in the treatment of patients with Spinal Muscular Atrophy (SMA). International information regarding QoL in SMA is scarce, and is not available in our country. OBJECTIVE: To characterize QoL in a sample of Chilean children and adolescents with SMA. SUBJECTS AND METHOD: Observational, cross-sectional study. A general questionnaire and the PedsQLTM 3.0 Neuromuscular Module Inventory were applied to parents of children with SMA aged 2 to 18 years. It has three areas: Disease, Communication, and Family. A score >60 was considered as good QoL, 30-60 as regular, and <30 as low. MINITAB-17® software was used, considering significant a p <0.05 value. RESULTS: We recruited 38 patients, with median age 8 years (2-18), 52.63% were male, and 17 (44.7%) with SMA I. All had genetic confirmation. The total score of QoL was 51.92 ± 17, representing 31% good, 55% regular, and 14% low. Regarding SMA I, it was 46.5 ± 15.2 and SMA II-III, 56.3 ± 17.4 (p = 0.071). Concerning the area of Disease, it was 53.83 ± 18.1, Family 48.6 ± 23.14, and Communication 33.3 (IQR: 0.0; 83.33). In this last area, children with SMA II-III, older than 6 years., with non-invasive ventilatory support, or living out of the metropolitan area had hig her scores, however, in multivariate analysis, only SMA type was significant, which explained 40,9% of the variation in the communication area score. CONCLUSIONS: In this sample of SMA pediatric patients, the QoL was regular or good in most of them. The lowest area was communication, with a higher score in those children with higher motor function.

Observations from a nationwide vigilance program in medical care for spinal muscular atrophy patients in Chile / Atrofia muscular espinal en Chile, resultados de un programa de atención médica nacional

ABSTRACT Spinal muscular atrophy (SMA) has gained much attention in the last few years because of the approval of the first intrathecal treatment for this neurodegenerative disease. Latin America needs to develop the demographics of SMA, timely access to diagnosis, and appropriate following of the standards of care recommendations for patients. These are essential steps to guide health policies. Methods This was a descriptive study of a cohort of SMA patients from all over Chile. We analyzed the clinical, motor functional, and social data, as well as the care status of nutritional, respiratory and skeletal conditions. We also measured the SMN2 copy number in this population. Results We recruited 92 patients: 50 male; 23 SMA type-1, 36 SMA type-2 and 33 SMA type-3. The median age at genetic diagnosis was 5, 24 and 132 months. We evaluated the SMN2 copy number in 57 patients. The SMA type-1 patients were tracheostomized and fed by gastrostomy in a 69.6 % of cases, 65% of SMA type-2 patients received nocturnal noninvasive ventilation, and 37% of the whole cohort underwent scoliosis surgery. Conclusion Ventilatory care for SMA type-1 is still based mainly on tracheostomy. This Chilean cohort of SMA patients had timely access to genetic diagnosis, ventilatory assistance, nutritional support, and scoliosis surgery. In this series, SMA type-1 is underrepresented, probably due to restrictions in access to early diagnosis and the high and early mortality rate.

La Atrofia Muscular Espinal (AME) ha concitado mucha atención en los últimos 2 años debido a la aprobación del primer tratamiento intratecal para esta enfermedad neurodegenerativa. América Latina necesita desarrollar la demografía de AME, un acceso oportuno al diagnóstico y un seguimiento apropiado de los pacientes que incorporen los estándares de atención recomendados por expertos. Estos son pasos esenciales para orientar las futuras políticas de salud en esta enfermedad. Métodos Este es un estudio descriptivo de una cohorte de pacientes con AME de todo el país. Se analizaron los datos clínicos, motores, funcionales, sociales y el estado nutricional, respiratorio y esquelético de los pacientes. También medimos el número de copias del gen SMN2 en esta población. Resultados se reclutaron 92 pacientes, 50 varones; 23 AME tipo 1, 36 AME tipo 2 y 33 AME tipo 3. La edad media al diagnóstico genético fue de 5, 24 y 132 meses respectivamente. Evaluamos el número de copias de SMN2 en 57 pacientes. Un 69,6% de los pacientes con AME tipo 1 estaban traqueostomízados y gastrostomizados , un 65% de los pacientes con AME tipo 2 usaban ventilación nocturna no invasiva y el 37% de toda la cohorte presentaba una cirugía de escoliosis. Conclusión Esta cohorte chilena de pacientes con AME tuvo acceso oportuno al diagnóstico genético, asistencia ventilatoria, apoyo nutricional y cirugía de escoliosis, sin embargo, la atención ventilatoria para AME tipo 1 continúa aun basándose principalmente en la traqueostomía. En esta serie, AME tipo 1 está subrepresentada, probablemente debido a las restricciones en el acceso al diagnóstico temprano y la tasa de mortalidad alta y temprana.

Manejo respiratorio en atrofia muscular espinal: cambio de paradigma en la era de las nuevas terapias específicas / Respiratory care in spinal muscular atrophy in the new therapeutic era

Resumen: La atrofia muscular espinal (AME) es la enfermedad genética mortal más frecuente en lactantes, con severidad variable. Se clasifica en cuatro subtipos: tipo 0 de inicio prenatal y recién nacido ya afecta do, con ausencia de esfuerzo respiratorio y ningún desarrollo motor, tipo 1 de inicio en menores de 3 meses que no logran sentarse, tipo 2 que logran sentarse, pero no caminar y tipo 3 que consiguen caminar. La causa más seria de morbimortalidad es la neumonía y la insuficiencia respiratoria. La información a los cuidadores debe contemplarse desde el diagnóstico, para la toma de decisiones anticipadas. Los objetivos del manejo incluyen el estímulo de la tos, evitar la deformación de la caja torácica, la hipoventilación, y tratar oportunamente las infecciones respiratorias, el trastorno de de glución, el reflujo gastroesofágico y la malnutrición. El objetivo de esta actualización es discutir los nuevos desafíos en cuidados respiratorios con un enfoque preventivo, considerando la reciente dis ponibilidad de tratamientos específicos -oligonucleótidos antisentido nusinersen- y otros que están en desarrollo, incluída la terapia génica.

Abstract: Spinal muscular atrophy (SMA) is the first inherited cause of mortality in infants, with four subtypes: SMA0 prenatal onset, SMA1 babies less than 3 months non sitters, SMA2 sitters and SMA3 walkers. Pneumonia and respiratory insufficiency are the most severe complications. Informed parental de cisions are relevant. Respiratory management includes cough assistance, prevention of lung under development due to chest deformity, prompt treatment of respiratory infections, hypoventilation, swallow problems, gastro esophageal reflux and malnutrition. In view of the FDA and EMA approval of the nonsense oligonucleotides nusinersen, the first specific treatment for SMA and the future with gene therapy and others under development, we need to optimize preventive respiratory manage ment with the new standard of care.

Dispositivos ventilatórios não invasivos em criança portadora de amiotrofia espinhal do tipo 1: relato de caso / Noninvasive ventilation devices in a child with spinal muscular atrophy type 1: a case report

Amiotrofia espinhal do tipo 1 (AME 1) é uma doença genética autossômica recessiva que promove morte celular de neurônios motores localizados no corno anterior da medula e núcleos motores do tronco cerebral. A precoce morbimortalidade está associada à disfunção bulbar e insuficiência respiratória, necessitando de internamento hospitalar e de suporte ventilatório artificial. O objetivo do estudo foi divulgar a relevância da manutenção de paciente com AME 1 sem prótese ventilatória invasiva e com protocolo de fisioterapia individualizado, proporcionando melhor qualidade de vida e integração com seus familiares. Descrição: relato de caso de menor diagnosticado com AME 1 que aos 11 meses foi submetido à ventilação mecânica invasiva (VMI) por 76 dias, obtendo sucesso no desmame após aplicação de um protocolo de fisioterapia respiratória, incluindo a utilização de tosse mecanicamente assistida e ventilação não invasiva (VNI). Discussão: apesar das dificuldades e intercorrências observadas, a assistência proposta alcançou o objetivo de retirada da VMI e transferência para internação domiciliar com dispositivos ventilatórios não invasivos. A VMI por traqueostomia é considerada tratamento de eleição no Brasil, no entanto, as famílias precisam ser esclarecidas da irreversibilidade da doença e das possibilidades estratégicas das terapêuticas atuais (VMI, VNI e paliação) para o manuseio de criança grave com AME 1...

The spinal muscular atrophy type 1 (AME1) is an autosomal recessive genetic disorder that promotes cell death of motor neurons located in the anterior horn of the spinal cord and motor nuclei of the brainstem. Early mortality is linked to the bulbar dysfunction and respiratory failure, requiring hospitalization and invasive mechanical ventilation (IMV). The purpose of this study is to promote the maintenance patients with SMA type 1 without invasive ventilation support and individualized physical therapy protocol, improving child's quality of life and integration with their families. Description: this report relates a child diagnosed with AME1, who at 11 months was admitted and underwent IMV for 76 days, succeeding extubation after respiratory therapy protocol application using cough machine and noninvasive ventilation (NIV). Discussion: despite the difficulties and complications observed, there was persistence of the proposed assistance, reaching goal of withdrawal of IMV and transfer to home care with noninvasive ventilation devices. The IMV for tracheostomy is considered treatment of choice in Brazil. Notwithstanding, families need to be clarified of the irreversibility of the disease and strategic possibilities of therapeutic strategies (IMV, NIV and palliation) for the management of the child with severe SMA 1...

O impacto do cuidado domiciliar na evolução da síndrome de Werdnig-Hoffmann: relato de caso / Impact of home care in the evolution of Werdnig-Hoffmann syndrome: case report

A atrofia muscular espinhal (AME) tipo I ou síndrome de Werdnig-Hoffmann é doença neuromuscular grave que se manifesta precocemente e apresenta elevada morbimortalidade. O objetivo deste trabalho é destacar a importância do serviço de assistência domiciliar na abordagem das doenças graves em que o cuidado é o principal fator promovedor da qualidade de vida.

Type 1 spinal muscular atrophy (SMA) or Werdnig-Hoffmann syndrome is a severe neuromuscular disease that has an early manifestation and presents high morbimortality. The aim of this paper was to highlight the importance of home care service when approaching severe diseases, in which care is the main factor that promotes quality of life.

Síndrome de Werdnig-Hoffman (atrofia muscular espinal de la infancia). Presentación de un caso y revisión de literatura / Werdnig-Hoffmann syndrome (spinal muscular atrophy of childhood). Case report and literature review

El síndrome de Werdnig-Hoffmann o atrofia muscular espinal (AME) de la infancia es una enfermedad de patrón autosómico recesivo de origen neuromuscular y degenerativo, poco prevalente en la población general, y que se caracteriza por la destrucción de las neuronas motoras del asta anterior de la médula espinal debido a alteraciones cromosómicas. La enfermedad no tiene tratamiento, es de mal pronóstico y, por lo general, culmina con la muerte del menor en los primeros años de vida por dificultad respiratoria, infecciones respiratorias o ambas. En el presente artículo se describe un caso de la enfermedad que se pone en evidencia con el árbol genealógico en el que se encuentra el patrón de herencia de la enfermedad, además de los síntomas y signos que la caracterizan. [Martínez SC, Lancheros EA, Rodríguez JC. Síndrome de Werdnig-Hoffmann (atrofia muscular espinal de la infancia). Presentación de un caso y revisión en la literatura. MedUNAB 2010; 13:116-122].

Werdnig-Hoffmann Syndrome or Spinal Muscular Atrophy (SMA) of childhood is a disease of autosomal recessive neuromuscular and degenerative origin, some prevalent in the general population, characterized by motor neurons destruction in anterior spinal cord due to chromosomal abnormalities. The disease has no treatment, had poor prognosis, and usually ends in child death in her/his first years of life caused by respiratory distress, respiratory infection, or both. This paper describes a case of SMA with and evident pedigree with a tipical inheritance pattern, and symptoms and signs that characterize this entity. [Martínez SC, Lancheros EA, Rodríguez JC. Werdnig-Hoffmann Syndrome (Spinal Muscular Atrophy). Case report and review. MedUNAB 2010; 13:116-122].

Atrofia muscular espinal en el niño / Spinal muscular atrophy present in children

Las atrofias musculares espinales en la infancia (AME) son trastornos genéticos autosómicos recesivos, caracterizados por degeneración de las motoneuronas espinales y bulbares. El presente estudio tuvo el objetivo principal de describir las principales características clínicas en una serie de niños con AME. MÉTODOS. Se realizó un estudio retrospectivo de los pacientes con AME atendidos en el Instituto de Neurología y Neurocirugía de Cuba, entre enero de 1997 y diciembre de 2001. Se recopilaron los datos de 35 pacientes, 4 de ellos, fetos con confirmación prenatal de AME. Se precisaron las principales características clínicas, electromiográficas, de la biopsia muscular y de los estudios genéticos moleculares realizados en cada caso. RESULTADOS. La AME de tipo II resultó la forma clínica mas frecuente (58 por ciento), seguida por la AME de tipo I (42 por ciento). Las principales manifestaciones clínicas resultaron la debilidad muscular generalizada con predominio proximal en extremidades, asociada a hipotonía y arreflexia osteotendinosa. La deleción de los exones 7 y 8 del gen SMN1 se detectó en 20 de 23 casos estudiados (87 por ciento).

Spinal muscular atrophies (SMA) in childhood are autosomal recessive genetic disorders, characterized by spinal and bulbar motoneurons degenerations. Aim of present paper was to describe the main clinical features in a series of children presenting SMA. METHODS: A retrospective study of patients with SMA seen in the Neurology and Neurosurgery Institute of Cuba from January, 2997 and December, 2001 was made. Data from 35 patients were available; four of them were fetus with prenatal confirmation of SMA. Main clinical, electromyography, muscular biopsy, and of molecular genetic studies performed in each case were determined. RESULTS: Type II SMA was the more frequent clinical presentation (58 percent), followed by type I SMA (42, percent). Main clinical manifestations were a systemic muscular weakness with predominance of the proximal type in limbs, associated to hypoxia and osteotendinous areflexia. Seven and eight exons deletion SMN1 gen was detected in 20 from 23 study cases (87 percent).