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.

Diagnóstico tardío de atrofia muscular espinal en paciente con síndrome de Down / Late diagnosis of spinal muscular atrophy in a patient with Down syndrome

El síndrome de Down (SD) es la anomalía cromosómica más frecuente entre los recién nacidos vivos. La atrofia muscular espinal (AME), por su parte, es una enfermedad neuromuscular caracterizada por la degeneración progresiva de las motoneuronas del asta anterior de la médula espinal que produce atrofia muscular, debilidad y parálisis. Presentamos el caso de una niña de 6 años con síndrome de Down derivada a nuestro centro para estudio por cuadro de debilidad muscular generalizada de evolución crónica con falta de adquisición de la marcha. Realizamos una revisión bibliográfica enfocándonos en el compromiso neurológico esperable en el síndrome de Down, la evolución de los hitos del desarrollo motor grueso estipulado para este grupo de pacientes y en los hallazgos que deben sugerir la presencia de una enfermedad neuromuscular.

A case of a 6-year-old girl with Down's syndrome is presented. She was referred to our center due to a history of generalized muscle weakness of chronic evolution, associated to her inability to walk. Her mother claimed that the girl's muscle weakness always called her attention as well as the difficulties to the development of motor skills shown by her daughter compared to other children, whether they were healthy or with Down's syndrome. There was information in her medical record and physical exam that strongly suggested the possibility of suffering a neuromuscular disorder. We asked for a molecular study that confirmed the spinal muscular atrophy diagnosis. We carried out a bibliographical revision focusing on the expected neurological impairment in Down's syndrome, the retardation of the gross motor skills development determined for this kind of patients and on the findings that must suggest a neuromuscular disorder.

Cribado neonatal en atrofia muscular espinal: un desafío para cambiar la historia natural / Neonatal screening in spinal muscular atrophy: a challenge to change the natural history

Introducción: la atrofia muscular espinal (AME) es la primera causa de origen genético de muerte en la infancia. En los últimos 20 años han sido excepcionales los avances en el conocimiento de su base genética, de su historia natural y se han desarrollado estándares de cuidado y nuevas terapias. Este veloz aumento del conocimiento ha llevado al desarrollo de terapias eficaces para esta devastadora enfermedad, pero el tiempo son neuronas, y esa frase nos lleva a pensar la importancia del diagnóstico precoz y, por qué no, del diagnóstico presintomático mediante pesquisa neonatal. Métodos: revisión de la bibliografía disponible, a través de búsqueda en PubMed y Google para trabajos no indexados o publicaciones de organismos de Salud. Resultados: varios estudios clínicos han mostrado la mayor eficacia del tratamiento en pacientes presintomáticos, por lo que lograrlo en estos pacientes llevaría a cambiar radicalmente la historia de esta enfermedad. Conclusión: es importante analizar y promover el desarrollo de pilotos para pesquisa neonatal en vistas a lograr experiencia para, a partir de ello, pensar en la posibilidad de incorporarlo a programas nacionales. (AU)

Introduction: spinal muscular atrophy (SMA) is the first cause of genetic origin of death in childhood. Throughout the last 20 years, we have witnessed exceptional advances in the knowledge of its genetic base, the history of its nature and several standards of care and new therapies have been developed. This rapid increase in knowledge has led to the development of effective therapies for this devastating disease. However, time is neurons, and that phrase reminds us of the importance of early diagnosis, and, why not, of pre-symptomatic diagnosis by means of neonatal screening. Methods: review of scientific papers searching in Pubmed or Google for non-indexed articles or publications of Health organisms. Results: several clinical studies have shown the greatest effectiveness of treatment in pre-symptomatic patients, so achieving the same in these patients would result in radically changing the history of this disease. Discussion: it is important to analyze and promote the development of pilots for neonatal screening in order to gain experience, so from there on to be able to think about the possibility of incorporating it into national programs. (AU)

Allele-specific PCR for a cost-effective & time-efficient diagnostic screening of spinal muscular atrophy.

Background & objectives: Genetic diagnosis of spinal muscular atrophy (SMA) is complicated by the presence of SMN2 gene as majority of SMA patients show absence or deletion of SMN1 gene. PCR may amplify both the genes non selectively in presence of high amount of DNA. We evaluated whether allelespecific PCR for diagnostic screening of SMA is reliable in the presence of high amount of genomic DNA, which is commonly used when performing diagnostic screening using restriction enzymes. Methods: A total of 126 blood DNA samples were tested in amounts ranging 80-200 ng, referred for the genetic diagnosis of SMA using both conventional PCR-RFLP and allele-specific PCR. Results: The results from both methods showed agreement. Further, allele-specific PCR was found to be a time-efficient and cost-effective method. Interpretation & conclusions: Our study demonstrated the accuracy of our allele-specific PCR and the results were comparable compatible with that of PCR-RFLP, indicating its practical application in SMA diagnostic screening.

Atrofia muscular espinal: Caracterización clínica, electrofisiológica y molecular de 26 pacientes / Clinical, electrophysiological and molecular study of 26 chilean patients with spinal muscular atrophy

Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder affecting the anterior horn cells of the spinal cord resulting in muscle weakness and atrophy, linked to the homozygous disruption of the survival motor neuron 1 (SMN1) gene. It is the leading genetic cause of infant death. It has been classified into three types based on the severity of symptoms. Type I SMA is the most severe form with death within the first 2 years of life. Type II and III SMA patients show intermediate and mild forms of the disorder. Aim: To describe the clinical and electrophysiological findings of 26 Chilean patients with SMA with molecular confirmation. Patients and Methods: Retrospective multicenter analysis of patients with SMA assessed between 2003 and 2010. The diagnosis was suspected on clinical and electrophysiological criteria. Since 2006 molecular genetics confirmation was implemented in one of our centers. Results: Twenty-six patients between 2 months and 18 years of age at presentation were analyzed; 15 (58 percent) were males. SMA I, II and III clinical criteria were observed in 4 (15.4 percent), 11 (42.3 percent) and 11 (42.3 percent)patients, respectively. All had proximal muscle weakness and atrophy. Electromyography showed features of acute denervation or re-innervation with normal motor and sensory nerve conduction. Nine patients required a muscle biopsy. The genetic confirmation of the disease by PCR technique followed by restriction fragment length polymorphism method disclosed the SMN1 gene deletion in all 26 cases. All patients died secondary to respiratory failure, between eight and 14 months of life. Conclusions: An adequate clinical and molecular diagnosis of spinal muscular atrophy will help for a better management of these patients.

Clinico-epidemiologic characteristics of spinal muscular atrophy among Egyptians

Spinal muscular atrophy [SMA] is characterized by progressive hypotonia and muscular weakness because of progressive degeneration of alpha motor neuron from anterior horn cells in the spinal cord. It is inherited by an autosomal recessive pattern. The precise frequency of SMA in Egypt has not been determined. We tried to estimate the frequency, clinical and molecular characteristics of SMAin Egypt. The study included all patients withSMAattended the Pediatric Hospital, Ain-Shams University during the period [year 1966-2009]. The study included 117 patients with SMA out of 660,280 patients attending the Pediatric Hospital. Patients selection was based on clinical examination, CPK, EMG, nerve conduction velocity, histopathology and molecular diagnosis. Frequency of SMA was 17.7/100,000, which is considered high. Type I was the commonest type [60.6%], followed by type II [26.79%], and type III [8.8%]. Consanguinity was reported in 45.5 and family history in 47.8% of patients. Molecular study was done and 54.5% of patients [types I and II] have homozygous deletion of exon 7, 36.3% of whom had also homozygous deletion of exon 8 of SMN1gene which is considered lower than that reported in other countries. SMA is more prevalent in Egypt than in many other countries. Forty-five percent of patients were chromosome 5-unlinked. We should continue to search for other mutation in Egypt to facilitate detection of carriers and prenatal diagnosis

Atrofia muscular distal bilateral dos membros superiores (Síndrome de O'Sullivan-McLeod): relato de caso / Bilateral distal muscular atrophy of upper limbs(O’Sullivan-McLeod syndrome): Case report

As amiotrofias espinhais progressivas (AEP) são um grupo de desordens geneticamente determinadas marcadas pela depleção dos neurônios da ponta anterior da medula espinhal e, frequentemente, núcleos de nervos cranianos (bulbares). A forma mais comum de AEP usualmente compromete os músculos proximais dos membros. Entretanto, existe uma forma incomum, usualmente esporádica, que envolve somente a região distal braquial. A proposta do presente relato é apresentar os achados clínicos e eletrofisiológicos de um paciente com AEP crônica e com comprometimento dos músculos do terço distal dos membros superiores. A eletroneumiografia revelou anormalidades neurogênicas e potenciais de desnervação com velocidade de condução sensitiva e motora normais. Descrevemos algumas teorias acerca da fisiopatologia. O reconhecimento dessa forma infrequente é muito importante para uma ótima abordagem terapêutica nesses pacientes.

The spinal muscular atrophies (SMA) are a group of genetically determined disorders in which the primary defect is a loss of the anterior horn neurons of the spinal cord and, commonly, of nuclei of cranial nerves (medulla). A more common chronic form of SMA usually affects proximal limb muscles. However, there is an uncommon form, frequently sporadic, involving only the distal part of upper limbs. The purpose of the present report is to describe the clinical and electrophysiological features of a patient with chronic SMA affecting the muscles of the distal third of the upper limbs. Electroneuromyography revealed neurogenic anomalies and denervation potentials with normal motor and sensory nerve conduction velocities. We describe some theories concerning its pathophysiology. The recognition of this infrequent form is very important for an optimized therapeutical approach of this kind of patients.

Atrofia muscular espinhal: diagnóstico, tratamento e perspectivas futuras / Spinal muscular atrophy: diagnosis, treatment and future prospects

OBJETIVO: Relatar as recentes descobertas genéticas e moleculares, juntamente com as perspectivas futuras, para o tratamento da atrofia muscular espinhal, auxiliando, dessa forma, os profissionais da área da saúde a fazerem um rápido diagnóstico e proporcionarem um suporte terapêutico correto e precoce. FONTES DOS DADOS: As informações foram coletadas a partir de artigos científicos publicados nas duas últimas décadas, pesquisados nas bases de dados SciELO, PubMed e MEDLINE. SÍNTESE DOS DADOS: A atrofia muscular espinhal é uma doença neurodegenerativa com herança genética autossômica recessiva. É causada por uma deleção homozigótica do gene de sobrevivência do motoneurônio. Essa alteração genética resulta na redução dos níveis da proteína de sobrevivência do motoneurônio, levando à degeneração de motoneurônios alfa da medula espinhal, o que resulta em fraqueza e paralisia muscular proximal progressiva simétrica. Sabe-se que alguns cuidados básicos referentes à nutrição, respiração e fisioterapia podem ser importantes para retardar o progresso da doença e prolongar a vida dos pacientes. Vários medicamentos estão sendo testados, alguns novos, outros já conhecidos, como o ácido valproico, sendo que a paralisia pode ser estacionada, mas não revertida. CONCLUSÕES: A atrofia muscular espinhal é uma desordem de difícil diagnóstico, por ser pouco conhecida, e de tratamento ainda incerto. Os tratamentos farmacológicos e as terapias de suporte existentes ainda não são capazes de recuperar os motoneurônios ou as células musculares que já foram perdidos, mas têm o objetivo de retardar o progresso da doença e melhorar a função muscular residual dos pacientes, bem como oferecer uma melhor qualidade e expectativa de vida.

OBJECTIVE: To report on recent genetic and molecular discoveries and on future prospects for the treatment of spinal muscular atrophy (SMA), thereby helping healthcare professionals to make a quick diagnosis and provide appropriate and timely therapeutic support. SOURCES: Information was collected from scientific articles published in the last 2 decades, retrieved from the databases SciELO, PubMed, and MEDLINE. SUMMARY OF THE FINDINGS: SMA is a neurodegenerative disorder with autosomal recessive genetic heredity. It is caused by a homozygous deletion of the survival motor neuron (SMN1) gene. This genetic alteration results in reduced levels of the SMN protein, leading to degeneration of alpha motor neurons of the spinal cord and resulting in muscle weakness and progressive symmetrical proximal paralysis. It is known that basic nutritional and respiratory care and physiotherapy can be important to delaying disease progression and prolonging patients' lives. Several drugs are being tested, some new, others, such as valproic acid, already known; paralysis can be halted, but not reversed. CONCLUSIONS: SMA is a difficult to diagnose disorder, because it is little known, and treatment is uncertain. Pharmacological treatments and supportive therapies are not yet able to recover motor neurons or muscle cells that have already been lost, but are aimed at delaying disease progression and improving patients' residual muscle function, as well as offering better quality of life and life expectancy.

Spinal muscular atrophy from northern Iran: a clinical and genetic spectrum of ten patients

Autosomal recessive spinal muscular atrophy [SMA] is, after cystic fibrosis, the second most common fatal monogenic disorder and the second most common hereditary neuromuscular disease after duchenne dystrophy. The disease is characterized by degeneration of anterior horn cells leading to progressive paralysis with muscular atrophy. Depending on the clinical type [Werdnig-Hoffmann = type I, intermediate form = type II, Kugelberg-Welander = type III], some workers also have delineated an adult form of SMA [SMA type 4]. SMA causes early death or increasing disability in childhood. The aim of this investigation was to describe the clinical findings of patients with spinal muscular atrophy [SMA] with survival motor neuron [SMN] gene deletion. This is a descriptive study conducted on 10 patients of SMA, confirmed by deletion of the SMN gene. All 10 patients had symmetrical muscle weakness, which was diffuse in those with onset of symptoms up to 1 months of age, and either proximal or predominant in lower limbs. Frequency determination of positive clinical and laboratory data was done according to revised diagnostic criteria. It was found that all patients with SMA had homozygous deletions of exons 7 and 8 of the survival motor neuron 1 [SMNl] gene, which is one of the candidate genes identified within 5q13. Fasciculations, atrophy and decreased DTR were frequent findings. Laboratory metabolic tests and all brain CT scans were normal. EMC and NCV findings, all showed normal motor and Sensory NCV and denervation of muscles of upper and lower extremities were compatible with a diagnosis of spinal muscular atrophy. Our results confirm that SMN1 copy number analysis is an important parameter for identification of couples at risk of having a child affected with SMA and reduces unwarranted prenatal diagnosis for SMA

Kennedy's disease phenotype with positive genetic study for Kugelberg-Welander's disease: case report

Descrevemos um paciente com achados clínicos de doença de Kennedy e estudo genético positivo para doença de Kugelberg-Welander. Homem, 24 anos e história familiar negativa, iniciou aos 14 anos com atrofia muscular espinhal de caráter progressivo com ginecomastia. Obteve diagnóstico clínico de doença de Kennedy, entretanto o estudo genético foi negativo para esta doença e positivo para doença de Kugelberg-Welander, com deleções dos exons 7 e 8 e do gene do survival of motor neuron.

Dificuldades diagnósticas na atrofia muscular espinhal / Spinal muscular atrophy diagnostic difficulties

OBJETIVO: Descrever o perfil clínico e laboratorial de pacientes com atrofia muscular espinhal (AME) com deleção no gene da proteína sobrevivência do neurônio motor (SMN). MÉTODO: Estudo descritivo de uma série de casos confirmados pela presença da deleção no gene SMN. Determinação da freqüência da positividade dos critérios clínicos e laboratoriais revisados. RESULTADOS: Foram incluídos no estudo 22 casos. Em todos havia paresia simétrica, sendo a localização difusa predominante nos casos de início antes de 6 meses (75 por cento), enquanto nos demais havia predominância de localização proximal e/ou em membros inferiores (67 por cento). Fasciculações e atrofia foram freqüentes (82 por cento). Os exames complementares tiveram resultados variáveis, sendo a positividade da eletroneuromiografia (ENMG) de 57 por cento e da biopsia muscular de 58 por cento. CONCLUSÃO: A presença de deleção no gene SMN pode ajudar a confirmar o diagnóstico de casos indefinidos .

X-linked spinal and bulbar muscular atrophy (Kennedy's disease) with long-term electrophysiological evaluation: case report

Atrofia muscular bulbo-espinal ligada ao cromossomo X (doença de Kennedy) é uma neuronopatia motora em adultos causada por expansões na repetição CAG no gene do receptor andrógeno. Neste relato, descreve-se o caso de homem de 66 anos, com diagnóstico prévio de doença do neurônio motor (DNM) que apresentou quadro agudo e reversível de paresia de prega vocal (disfonia) e de músculos faríngeos à esquerda; posteriormente seguiram-se surtos de fraqueza lentamente progressiva, atrofia e fasciculações em língua, masseter, face, faringe e membros superiores predominantemente proximal, associada a tremor bilateral de mãos e ginecomastia leve. Foram realizadas 5 eletroneuromiografias entre 1989 e 2003 que mostraram reinervação crônica, algumas fasciculações, raras fibrilações e redução progressiva de amplitude ou ausência dos potenciais de ação dos nervos sensitivos (PANS). Técnica de PCR para análise de DNA revelou expansão anormal de repetições CAG, sendo encontrado 44 (normal, 11-34). Este caso teve apresentação clínica aguda e assimétrica relacionada aos motoneurônios bulbares; PANS ausentes ou de baixa amplitude com leve assimetria; envolvimento subclínico ou leve de músculos proximais e distais tanto de membros superiores como inferiores; e, provável evolução com surtos agudos de desnervação aguda, seguida por reinervação eficiente.

Primary hyperparathyroidism simulating motor neuron disease: case report

Descrevemos o caso de homem de 26 anos que apresentou síndrome do neurônio motor inferior devido a hiperparatiroidismo. A eletromiografia mostrou aspecto neurogênico com estudos da condução normal. Hipercalcemia levou à descoberta de hiperparatiroidismo primário com hiperplasia da glândula. Após a cirurgia de ressecção da paratiróide, houve regressão dos sintomas neurológicos.

Muscle disorders in pediatric patients in King Chulalongkorn Memorial Hospital.

The authors retrospectively studied histopathologic findings and diagnoses of muscle specimens taken from 188 pediatric patients presenting with clinical neuromuscular disorders in King Chulalongkorn Memorial Hospital between August 1991 and December 2003. Eighty patients (67.8%) established the definite diagnosis by histopathological findings of muscle specimens. About 18.6, 17.7, 7.6, 5.9, 5.0, 3.4, 2.5 and 1.7 percent of the total number of patients were diagnosed as Duchenne muscular dystrophy, spinal muscular atrophy, congenital myopathies, mitochondrial disease, inflammatory myopathies, Becker muscular dystrophy, congenital muscular dystrophy and vacuolar myopathies respectively. Since the histopathological findings in muscle helped to establish the definite diagnosis in most pediatric patients in the present study, thus muscle biopsy is essential for establishing a definite diagnosis in any patient with a suspected neuromuscular disorder.

Distal spinal muscular atrophy.

Spinal muscular atrophies (SMA) are clinically heterogenous group of motor system disorders characterised by progressive pure lower motor neuron involvement. The distal form of SMA is an extremely rare disorder, which presents in the adults and has a relatively slow progression with almost no effect on the patients' life-span. Differential diagnosis of this syndrome include other forms of neuromuscular disorders with peroneal muscular atrophy like hereditary motor sensory neuropathy (HMSN) and distal myopathies, which need exclusion before confirming this rare entity. We present a young male with this disorder and briefly discuss the theoretical aspects.