ABSTRACT
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 (â¼40%). 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.
ABSTRACT
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.
Subject(s)
Glycogen Storage Disease Type II/diagnosis , Glycogen Storage Disease Type II/therapy , Age of Onset , Argentina , Expert Testimony , Glycogen Storage Disease Type II/complications , HumansABSTRACT
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.
Subject(s)
Humans , Glycogen Storage Disease Type II/diagnosis , Glycogen Storage Disease Type II/therapy , Argentina , Glycogen Storage Disease Type II/complications , Age of Onset , Expert TestimonyABSTRACT
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.
Subject(s)
Magnetic Resonance Imaging , Muscles/pathology , Neuromuscular Diseases/pathology , Adult , Female , Humans , Image Processing, Computer-Assisted , Severity of Illness IndexABSTRACT
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.
Subject(s)
Glycogen Storage Disease Type II/diagnosis , Neuromuscular Diseases/diagnosis , Adult , Aged , Delayed Diagnosis/prevention & control , Diagnosis, Differential , Enzyme Replacement Therapy , Female , Glycogen Storage Disease Type II/complications , Glycogen Storage Disease Type II/drug therapy , Humans , Male , Middle Aged , Muscle Weakness/diagnosis , Muscle Weakness/drug therapy , Muscle Weakness/etiology , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/drug therapy , Respiratory Insufficiency/etiology , alpha-Glucosidases/therapeutic useABSTRACT
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.
