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.

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

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: 0-7), SMA II: 9 (R: 2-20), SMA III: 18 (R: 8-180). 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: 0-11), in SMA II: 10 (R: 3-46), in SMA III: 31.5 (R: 4-288). 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.

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 (346) 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.

Theragnosis for Duchenne Muscular Dystrophy.

Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA's metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.

The Latin American experience with a next generation sequencing genetic panel for recessive limb-girdle muscular weakness and Pompe disease.

BACKGROUND: Limb-girdle muscular dystrophy (LGMD) is a group of neuromuscular disorders of heterogeneous genetic etiology with more than 30 directly related genes. LGMD is characterized by progressive muscle weakness involving the shoulder and pelvic girdles. An important differential diagnosis among patients presenting with proximal muscle weakness (PMW) is late-onset Pompe disease (LOPD), a rare neuromuscular glycogen storage disorder, which often presents with early respiratory insufficiency in addition to PMW. Patients with PMW, with or without respiratory symptoms, were included in this study of Latin American patients to evaluate the profile of variants for the included genes related to LGMD recessive (R) and LOPD and the frequency of variants in each gene among this patient population. RESULTS: Over 20 institutions across Latin America (Brazil, Argentina, Peru, Ecuador, Mexico, and Chile) enrolled 2103 individuals during 2016 and 2017. Nine autosomal recessive LGMDs and Pompe disease were investigated in a 10-gene panel (ANO5, CAPN3, DYSF, FKRP, GAA, SGCA, SGCB, SGCD, SGCG, TCAP) based on reported disease frequency in Latin America. Sequencing was performed with Illumina's NextSeq500 and variants were classified according to ACMG guidelines; pathogenic and likely pathogenic were treated as one category (P) and variants of unknown significance (VUS) are described. Genetic variants were identified in 55.8% of patients, with 16% receiving a definitive molecular diagnosis; 39.8% had VUS. Nine patients were identified with Pompe disease. CONCLUSIONS: The results demonstrate the effectiveness of this targeted genetic panel and the importance of including Pompe disease in the differential diagnosis for patients presenting with PMW.

HNRNPDL-related muscular dystrophy: expanding the clinical, morphological and MRI phenotypes.

Autosomal dominant limb girdle muscular dystrophy D3 HNRNPDL-related is a rare dominant myopathy caused by mutations in HNRNPDL. Only three unrelated families have been described worldwide, a Brazilian and a Chinese carrying the mutation c.1132G>A p.(Asp378Asn), and one Uruguayan with the mutation c.1132G>C p. (Asp378His), both mutations occurring in the same codon. The present study enlarges the clinical, morphological and muscle MRI spectrum of AD-HNRNPDL-related myopathies demonstrating the significant particularities of the disease. We describe two new unrelated Argentinean families, carrying the previously reported c.1132G>C p.(Asp378His) HNRNPDL mutation. There was a wide phenotypic spectrum including oligo-symptomatic cases, pure limb girdle muscle involvement or distal lower limb muscle weakness. Scapular winging was the most common finding, observed in all patients. Muscle MRIs of the thigh, at different stages of the disease, showed particular involvement of adductor magnus and vastus besides a constant preservation of the rectus femoris and the adductor longus muscles, defining a novel MRI pattern. Muscle biopsy findings were characterized by the presence of numerous rimmed vacuoles, cytoplasmic bodies, and abundant autophagic material at the histochemistry and ultrastructural levels. HNRNPDL-related LGMD D3 results in a wide range of clinical phenotypes from the classic proximal form of LGMD to a more distal phenotype. Thigh MRI suggests a specific pattern. Codon 378 of HNRNPDL gene can be considered a mutation hotspot for HNRNPDL-related myopathy. Pathologically, the disease can be classified among the autophagic rimmed vacuolar myopathies as with the other multisystem proteinopathies.

[Argentine consensus on late-onset Pompe's disease]. / Consenso argentino sobre enfermedad de Pompe de inicio tardío.

Pompe's disease (PD) is an infrequent metabolic autosomic recessive disorder produced by the lack or deficiency of the acid alpha-glucosidase lysosomal enzyme in tissues of involved individuals. Delayed-onset PD is considered whenever symptoms onset start after one year of age. We present an update of the recommendations for the management of delayed-onset PD, taking as reference the guidelines from the Argentine Consensus for diagnosis, treatment and follow-up of PD published in 2013. The present consensus gathered several experts in PD in the areas of internal medicine, laboratory diagnosis, neuropathology, pulmonology, nutrition, neurology, metabolic and neuromuscular disorders as well as rehabilitation to perform an update of the literature of delayed-onset PD, with special attention on relevant information published within the last 4 years. The entire working group approved the final version of the consensus. Each participant provided a declaration of conflict of interest. As a result, it is an update of the previous Argentine PD Consensus with focus on the delayed-onset presentation of the disease. Being such infrequent disorder, available data were rather limited and thus, the recommendations represent expert opinions.

Consenso argentino sobre enfermedad de Pompe de inicio tardío / Argentine consensus on late-onset Pompe's disease

La enfermedad de Pompe (EP) es un desorden metabólico autosómico recesivo infrecuente, producido por la ausencia o deficiencia de la enzima lisosomal alfa-glucosidasa ácida en los tejidos de los individuos afectados. Se considera enfermedad de Pompe de inicio tardío (EPIT) en aquellos individuos de más de un año de edad al comienzo de los síntomas. El objetivo del presente consenso es el de actualizar las pautas y recomendaciones para un correcto tratamiento de los pacientes con EPIT, tomando como referencia los lineamientos del Consenso Argentino para el diagnóstico, seguimiento y tratamiento de la enfermedad de Pompe publicado en el año 2013. Se organizó un consenso que reunió profesionales con experiencia en la EP en las áreas de clínica médica, diagnóstico de laboratorio, neuropatología, neumonología, nutrición, neurología, enfermedades metabólicas, enfermedades neuromusculares y rehabilitación. Se realizó una actualización de la bibliografía sobre EPIT, con especial atención en las publicaciones relevantes de los últimos cuatro años. Los términos finales del documento fueron consensuados por todo el grupo de trabajo. Cada participante proporcionó su declaración de conflicto de intereses. El resultado es una actualización del último Consenso Argentino para la EP, con particular enfoque en su forma de comienzo tardío. Tratándose de una afección infrecuente, en la que los datos disponibles son limitados, las presentes recomendaciones deben ser consideradas como opinión de expertos.

Pompe's disease (PD) is an infrequent metabolic autosomic recessive disorder produced by the lack or deficiency of the acid alpha-glucosidase lysosomal enzyme in tissues of involved individuals. Delayed-onset PD is considered whenever symptoms onset start after one year of age. We present an update of the recommendations for the management of delayed-onset PD, taking as reference the guidelines from the Argentine Consensus for diagnosis, treatment and follow-up of PD published in 2013. The present consensus gathered several experts in PD in the areas of internal medicine, laboratory diagnosis, neuropathology, pulmonology, nutrition, neurology, metabolic and neuromuscular disorders as well as rehabilitation to perform an update of the literature of delayed-onset PD, with special attention on relevant information published within the last 4 years. The entire working group approved the final version of the consensus. Each participant provided a declaration of conflict of interest. As a result, it is an update of the previous Argentine PD Consensus with focus on the delayed-onset presentation of the disease. Being such infrequent disorder, available data were rather limited and thus, the recommendations represent expert opinions.

Intraneural perineuriomas: diagnostic value of magnetic resonance neurography.

Intraneural perineurioma (IP) is an under-recognized hypertrophic peripheral nerve tumor. It affects young patients involving frequently the sciatic nerve and its branches and presents with a progressive, painless and predominantly motor deficit. Magnetic resonance neurography (MRN) is a useful tool to localize the lesion, evaluate its extension, and discriminate between different etiologies. We reviewed the clinical records of 11 patients with pathologically confirm IP. Eight patients were males with mean age 19 years. Initial complains were unilateral steppage (seven patients), bilateral steppage (one patient), unilateral gastrocnemius wasting (one patient), unilateral thigh atrophy (one patient), and unilateral hand weakness (one patient). Nine patients had mild painless sensory loss. Examinations revealed involvement of sciatic nerve extending into the peroneal nerve (eight patients), posterior tibial nerve (one patient), radial nerve (one patient), and femoral nerve (one patient). MRN revealed enlargement of the affected nerve isointense on T1-weighted, hyperintense on T2 fat-saturated images, and with avid enhancement on post-contrast imaging. In all patients, a nerve biopsy confirmed the diagnosis. MRN allows early and non-invasive identification of this tumor and is a key tool providing localization and differential diagnosis in patients with slowly progressive focal neuropathies.

A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy.

This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90% to actual 53%. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300-400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects.

A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy.

OBJECTIVE: To conduct a randomized trial to test the primary hypothesis that once-daily tadalafil, administered orally for 48 weeks, lessens the decline in ambulatory ability in boys with Duchenne muscular dystrophy (DMD). METHODS: Three hundred thirty-one participants with DMD 7 to 14 years of age taking glucocorticoids were randomized to tadalafil 0.3 mg·kg-1·d-1, tadalafil 0.6 mg·kg-1·d-1, or placebo. The primary efficacy measure was 6-minute walk distance (6MWD) after 48 weeks. Secondary efficacy measures included North Star Ambulatory Assessment and timed function tests. Performance of Upper Limb (PUL) was a prespecified exploratory outcome. RESULTS: Tadalafil had no effect on the primary outcome: 48-week declines in 6MWD were 51.0 ± 9.3 m with placebo, 64.7 ± 9.8 m with low-dose tadalafil (p = 0.307 vs placebo), and 59.1 ± 9.4 m with high-dose tadalafil (p = 0.538 vs placebo). Tadalafil also had no effect on secondary outcomes. In boys >10 years of age, total PUL score and shoulder subscore declined less with low-dose tadalafil than placebo. Adverse events were consistent with the known safety profile of tadalafil and the DMD disease state. CONCLUSIONS: Tadalafil did not lessen the decline in ambulatory ability in boys with DMD. Further studies should be considered to confirm the hypothesis-generating upper limb data and to determine whether ambulatory decline can be slowed by initiation of tadalafil before 7 years of age. CLINICALTRIALSGOV IDENTIFIER: NCT01865084. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that tadalafil does not slow ambulatory decline in 7- to 14-year-old boys with Duchenne muscular dystrophy.

[Thoracic Outlet Syndrome: is it always a surgical condition? Analysis of a series of 31 cases operated by the supraclavicular route]. / Síndrome del Outlet Torácico: ¿Una Patología Siempre Quirúrgica? Análisis de una Serie de 31 Cirugías Realizadas por Vía Supraclavicular Serie clínica.

BACKGROUND: Thoracic Outlet Syndrome is a compression of the brachial plexus that remains highly controversial. Classification in True or Neurogenic Outlet (TTO) and Disputed or Non-neurogenic Outlet (DTO) is becoming very popular. The former is characterized by a muscular atrophy of the intrinsic muscles of the hand, while the latter has only sensitive symptoms. The purpose of this article is to analyze the results obtained in a series of 31 patients. METHODS: All patients with diagnosis of Thoracic Outlet operated between January 2003 and December 2012 with a minimum follow-up of six months where included. Age, sex, symptoms, classification, preoperative studies results, complications and recurrences were analyzed. RESULTS: 31 surgeries performed in 30 patients, 9 with TTO (8 women, mean age 24.3 years) and 21 with DTO (18 women, mean age 37.4 years, 1 recurrence) were included. Ninety percent of patients presented neurophysiological and 66.6% imagenological preoperative disturbances. All TTO and only 36.7% of DTO showed clear pathological findings during surgical exploration. A high percentage (87,5% sensitive and 77.7% motor) of TTO ameliorated after surgical decompression. Only 45.5% of DTO showed permanent positive changes, 13.6% temporary, 36.6% no changes, and 4.5%(one case) showed deterioration after decompresive surgery. Complications after surgery were more frequent ­but temporary- in TTO cases (33.3%), than in DTO (13.6%). CONCLUSIONS: TTO showed a favorable outcome after surgery. DTO showed a worst ­but still positive- postoperative result if patients are selected properly. These data are in concordance with other recent reports.

Generating color-coded anatomic muscle maps for correlation of quantitative magnetic resonance imaging analysis with clinical examination in neuromuscular disorders.

INTRODUCTION: Fatty infiltration of muscles may be seen in many neuromuscular disorders, including glycogen storage disease (GSD), muscular dystrophy, and amyotrophic lateral sclerosis. Recording pathologic involvement of musculature in these patients is cumbersome, given marked disease heterogeneity within each individual. We describe a novel method for simplifying this process and present its application in a patient with GSD type IIIa. METHODS: A color-coded visual mapping tool was developed based on a commonly used spreadsheet platform. RESULTS: This tool depicts individual muscle groups as shapes linked to data cells corresponding to quantitative MRI-based measures of fatty infiltration and weakness assessed by physical examination. It allows for rapid evaluation and chronological comparison of all mapped muscle groups on a single graphical sheet, as well as assessment of response to therapy. CONCLUSION: This approach can be applied in any neuromuscular disorder where muscle function is assessed by clinical or imaging scores.

Pompe disease, the must-not-miss diagnosis: A report of 3 patients.

INTRODUCTION: Pompe disease is a progressive and debilitating neuromuscular disorder that presents with a heterogeneous array of signs and symptoms including proximal muscle weakness, respiratory insufficiency, and/or elevated creatine kinase levels. It mimics other neuromuscular disorders, making its diagnosis challenging and often significantly delayed, thereby increasing morbidity and early mortality of the disease. METHODS: Three Pompe disease patients are discussed to highlight the challenging path to diagnosis and the common cluster of symptoms that could lead to timely and accurate diagnosis. RESULTS: After significant delays in diagnosis, Pompe disease was diagnosed on the basis of the pattern of proximal weakness. CONCLUSIONS: Suspicion and recognition of the characteristic symptoms of Pompe disease may improve both the timing and accuracy of the diagnosis, which will improve clinical outcomes and minimize disease progression.

Motor-language coupling: direct evidence from early Parkinson's disease and intracranial cortical recordings.

Language and action systems are functionally coupled in the brain as demonstrated by converging evidence using Functional magnetic resonance imaging (fMRI), electroencephalography (EEG), transcranial magnetic stimulation (TMS), and lesion studies. In particular, this coupling has been demonstrated using the action-sentence compatibility effect (ACE) in which motor activity and language interact. The ACE task requires participants to listen to sentences that described actions typically performed with an open hand (e.g., clapping), a closed hand (e.g., hammering), or without any hand action (neutral); and to press a large button with either an open hand position or closed hand position immediately upon comprehending each sentence. The ACE is defined as a longer reaction time (RT) in the action-sentence incompatible conditions than in the compatible conditions. Here we investigated direct motor-language coupling in two novel and uniquely informative ways. First, we measured the behavioural ACE in patients with motor impairment (early Parkinson's disease - EPD), and second, in epileptic patients with direct electrocorticography (ECoG) recordings. In experiment 1, EPD participants with preserved general cognitive repertoire, showed a much diminished ACE relative to non-EPD volunteers. Moreover, a correlation between ACE performance and action-verb processing (kissing and dancing test - KDT) was observed. Direct cortical recordings (ECoG) in motor and language areas (experiment 2) demonstrated simultaneous bidirectional effects: motor preparation affected language processing (N400 at left inferior frontal gyrus and middle/superior temporal gyrus), and language processing affected activity in movement-related areas (motor potential at premotor and M1). Our findings show that the ACE paradigm requires ongoing integration of preserved motor and language coupling (abolished in EPD) and engages motor-temporal cortices in a bidirectional way. In addition, both experiments suggest the presence of a motor-language network which is not restricted to somatotopically defined brain areas. These results open new pathways in the fields of motor diseases, theoretical approaches to language understanding, and models of action-perception coupling.

Síndrome del outlet torácico: una patología siempre quirúrgica? / Thoracic outlet syndrome: an always surgical entity?

Objetivo: el objetivo de este trabajo es analizar los resultados obtenidos en una serie de cirugías realizadas en esta patología. Material y métodos: se analizaron todos los casos de cirugías de nervios efectuados en el período 2003-2012, separando los casos con diagnóstico de outlet torácico operados con un período de seguimiento postoperatorio mínimo de 6 meses. Se buscaron los siguientes datos: edad, sexo, presencia de síntomas sensitivos y/o motores, tipo de outlet (verdadero o disputado), resultado de los estudios neurofisiológicos y de imágenes, resultado de la cirugía, complicaciones postoperatorias y recidivas. Resultados: se incluyeron 31 cirugías realizadas en 30 pacientes, 9 con diagnóstico de OTV (8 mujeres) con un promedio de edad fue de 24.3 años, y 21 con OTD (18 mujeres) de 37.4 años en promedio. Un 90% de todos los casos de outlet presentaron alteraciones neurofisiológicas preoperatorios, y los estadios imagenológicos fueron anormales en 66.6%. Una vez realizada la exploración, el 100% de los OTV presentó una alteración anatómica claramente relacionada con la sintomatología, hecho observado sólo en el 36.7% de los OTD operados. El 87.5% de los OTV mejoraron sus síntomas sensitivos luego de la cirugía, mientras que 77.7% mejoraron desde el punto de vista motor. Por el contrario, 45.4% de los OTD mejoraron permanentemente, 36.3% no tuvieron cambios, 13.6% mejoraron transitoriamente y 405% (un caso) empeoró. Las complicaciones postoperatorias fueron más frecuentes aunque transitorias en el grupo de OTV (3 casos sobre 9 operados, 33.3%) que en los OTD (3 casos sobre 22, un 13.6%). Conclusión: el OTV es una patología infrecuente cuyo tratamiento quirúrgico suele evolucionar favorablemente. En cambio, el OTD constituye un diagnóstico de exclusión y su tratamiento quirúrgico da un resultado bueno aunque inferior al del OTV.

Síndrome del outlet torácico: una patología siempre quirúrgica? / Thoracic outlet syndrome: an always surgical entity?

Objetivo: el objetivo de este trabajo es analizar los resultados obtenidos en una serie de cirugías realizadas en esta patología. Material y métodos: se analizaron todos los casos de cirugías de nervios efectuados en el período 2003-2012, separando los casos con diagnóstico de outlet torácico operados con un período de seguimiento postoperatorio mínimo de 6 meses. Se buscaron los siguientes datos: edad, sexo, presencia de síntomas sensitivos y/o motores, tipo de outlet (verdadero o disputado), resultado de los estudios neurofisiológicos y de imágenes, resultado de la cirugía, complicaciones postoperatorias y recidivas. Resultados: se incluyeron 31 cirugías realizadas en 30 pacientes, 9 con diagnóstico de OTV (8 mujeres) con un promedio de edad fue de 24.3 años, y 21 con OTD (18 mujeres) de 37.4 años en promedio. Un 90% de todos los casos de outlet presentaron alteraciones neurofisiológicas preoperatorios, y los estadios imagenológicos fueron anormales en 66.6%. Una vez realizada la exploración, el 100% de los OTV presentó una alteración anatómica claramente relacionada con la sintomatología, hecho observado sólo en el 36.7% de los OTD operados. El 87.5% de los OTV mejoraron sus síntomas sensitivos luego de la cirugía, mientras que 77.7% mejoraron desde el punto de vista motor. Por el contrario, 45.4% de los OTD mejoraron permanentemente, 36.3% no tuvieron cambios, 13.6% mejoraron transitoriamente y 405% (un caso) empeoró. Las complicaciones postoperatorias fueron más frecuentes aunque transitorias en el grupo de OTV (3 casos sobre 9 operados, 33.3%) que en los OTD (3 casos sobre 22, un 13.6%). Conclusión: el OTV es una patología infrecuente cuyo tratamiento quirúrgico suele evolucionar favorablemente. En cambio, el OTD constituye un diagnóstico de exclusión y su tratamiento quirúrgico da un resultado bueno aunque inferior al del OTV. (AU)

Expanding the phenotype of late-onset Pompe disease: tongue weakness: a new clinical observation.

INTRODUCTION: Following the clinical observation of lingual weakness in 2 patients with late-onset Pompe disease (LOPD), tongue strength was assessed in 19 consecutive patients to determine the frequency and severity of this neurological sign. METHODS: Lingual strength was assessed using manual muscle testing; if weakness was present, severity was established as mild, moderate, or severe. RESULTS: All the patients exhibited lingual weakness, even 2 asymptomatic patients with a positive family history. Weakness was mild in 12 (63%), moderate in 6 (32%), and severe in 1 (5%). Dysarthria and/or dysphagia were observed or reported in 7 of 19 (37%) patients. CONCLUSIONS: Lingual weakness may be present as an axial sign of LOPD, even relatively early in the disease course, and may contribute to the differential diagnosis of this now treatable condition. Dysphagia and/or dysarthria may also occur. This finding further expands the phenotype of LOPD.

Utilidad del tratamiento de sustitución enzimática en la enfermedad de Fabry / Utility of enzyme replacement therapy in Fabry disease

Fundamento y objetivos: La enfermedad de Fabry (EF) es una enfermedad por depósito lisosomal de esfingolípidos secundaria al déficit de la enzima alfagalactosidasa A. El depósito a nivel endotelial de los vasa nervorum y de los axones de pequeño calibre resulta en la característica neuropatía dolorosa. Es nuestro objetivo presentar los resultados de la evaluación de la neuropatía antes y después de 18 meses de tratamiento de reemplazo enzimático con agalsidasa β. Materiales y método: Se trata de un estudio exploratorio realizado a 5 pacientes con EF. Se les realizó un estudio neurofisiológico con medición de velocidades de conducción y amplitudes motoras y sensitivas, y un test de cuantificación sensitiva así como medición del dolor por medio de escalas. Resultados: Previo al tratamiento no se encontraron anomalías en las velocidades de conducción ni en las amplitudes del potencial de acción muscular compuesto, el test de cuantificación sensitiva fue anormal en todos los pacientes. Luego del tratamiento se evidenció mejoría en las escalas de dolor y en el test de cuantificación sensitiva. Conclusiones: El tratamiento de reemplazo enzimático con agalsidasa-β demostró beneficio subjetivo y objetivo en relación con la neuropatía dolorosa de la EF (AU)

Background and Objective: The lysosomal deposit of sphingolipids secondary to alpha-galactosidase-A deficiency causes Fabry disease. The deposit in the endothelial cells of the vasa nervorum and the small caliber axons, among other structures, results in the characteristic painful neuropathy. It is our objective to present the findings of the neuropathy evaluation before and after 18 months of agalsidase beta enzyme replacement therapy. Materials and method: A neurological exam, a neurophysiological study measuring sensory and motor conduction velocities and amplitudes and a quantitative sensory testing were performed on 5 patients with confirmed Fabry disease; quantification on pain measurement scales was also done. Results; Prior to treatment, no anomalies were found in the conduction velocities or the compound muscular action potential amplitudes; the quantitative sensory test was abnormal in all patients. After treatment, improvement was seen in the pain scales and the quantitative sensory test. Conclusions: Enzyme replacement therapy with agalsidase beta demonstrated subjective and objective benefits related to the painful neuropathy of Fabry disease (AU)

[Utility of enzyme replacement therapy in Fabry disease]. / Utilidad del tratamiento de sustitución enzimática en la enfermedad de Fabry.

BACKGROUND AND OBJECTIVE: The lysosomal deposit of sphingolipids secondary to alpha-galactosidase-A deficiency causes Fabry disease. The deposit in the endothelial cells of the vasa nervorum and the small caliber axons, among other structures, results in the characteristic painful neuropathy. It is our objective to present the findings of the neuropathy evaluation before and after 18 months of agalsidase beta enzyme replacement therapy. MATERIALS AND METHOD: A neurological exam, a neurophysiological study measuring sensory and motor conduction velocities and amplitudes and a quantitative sensory testing were performed on 5 patients with confirmed Fabry disease; quantification on pain measurement scales was also done. RESULTS: Prior to treatment, no anomalies were found in the conduction velocities or the compound muscular action potential amplitudes; the quantitative sensory test was abnormal in all patients. After treatment, improvement was seen in the pain scales and the quantitative sensory test. CONCLUSIONS: Enzyme replacement therapy with agalsidase beta demonstrated subjective and objective benefits related to the painful neuropathy of Fabry disease.

Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1.

We recently identified the X-chromosomal four and a half LIM domain gene FHL1 as the causative gene for reducing body myopathy, a disorder characterized by progressive weakness and intracytoplasmic aggregates in muscle that exert reducing activity on menadione nitro-blue-tetrazolium (NBT). The mutations detected in FHL1 affected highly conserved zinc coordinating residues within the second LIM domain and lead to the formation of aggregates when transfected into cells. Our aim was to define the clinical and morphological phenotype of this myopathy and to assess the mutational spectrum of FHL1 mutations in reducing body myopathy in a larger cohort of patients. Patients were ascertained via the detection of reducing bodies in muscle biopsy sections stained with menadione-NBT followed by clinical, histological, ultrastructural and molecular genetic analysis. A total of 11 patients from nine families were included in this study, including seven sporadic patients with early childhood onset disease and four familial cases with later onset. Weakness in all patients was progressive, sometimes rapidly so. Respiratory failure was common and scoliosis and spinal rigidity were significant in some of the patients. Analysis of muscle biopsies confirmed the presence of aggregates of FHL1 positive material in all biopsies. In two patients in whom sequential biopsies were available the aggregate load in muscle sections appeared to increase over time. Ultrastructural analysis revealed that cytoplasmic bodies were regularly seen in conjunction with the reducing bodies. The mutations detected were exclusive to the second LIM domain of FHL1 and were found in both sporadic as well as familial cases of reducing body myopathy. Six of the nine mutations affected the crucial zinc coordinating residue histidine 123. All mutations in this residue were de novo and were associated with a severe clinical course, in particular in one male patient (H123Q). Mutations in the zinc coordinating residue cysteine 153 were associated with a milder phenotype and were seen in the familial cases in which the boys were still more severely affected compared to their mothers. We expect the mild end of the spectrum to significantly expand in the future. On the severe end of the spectrum we define reducing body myopathy as a progressive disease with early, but not necessarily congenital onset, distinguishing this condition from the classic essentially non-progressive congenital myopathies.