Dysferlinopathy misdiagnosed with juvenile polymyositis in the pre-symptomatic stage of hyperCKemia: a case report and literature review.

BACKGROUND: Dysferlinopathy encompasses a group of rare muscular dystrophies caused by recessive mutations in the DYSF gene. The phenotype ranges from asymptomatic elevated serum creatine kinase (hyperCKemia) to selective and progressive involvement of the proximal and/or distal muscles of the limbs. Bohan and Peter criteria are the most widely used for the diagnosis of polymyositis, but they have limitations and can misclassify muscular dystrophies with inflammation as polymyositis. Most dysferlinopathy patients have muscle biopsies with inflammation and thus are vulnerable to misdiagnosis with polymyositis and inappropriate treatment with steroids and immunosuppressors. CASE PRESENTATION: We describe a 14 years-old male patient who was referred for assessment of asymptomatic hyperCKemia (26,372 IU/L). An X-linked dystrophinopathy initially was ruled out by direct genetic testing. Juvenile polymyositis was considered based on muscle biopsy, creatine kinase levels, and electromyography changes. Corticosteroid treatment triggered proximal lower limb muscular weakness, and no full muscular strength recovery was observed after corticosteroid withdrawal. Based on these observations, a limb-girdle muscular dystrophy (LGMD) was suspected, and LGMDR2 was confirmed by whole exome sequencing. CONCLUSION: We report a dysferlinopathy patient who was misdiagnosed with juvenile polymyositis and explore in a literature review how common such misdiagnoses are. With diagnosis based only on routine clinicopathological examinations, distinguishing an inflammatory myopathy from dysferlinopathy is quite difficult. We suggest that before establishing a diagnosis of "definite" or "probable" juvenile polymyositis, according to Bohan and Peter or current ACR/EULAR criteria, a muscular dystrophy must first be ruled out.

Diagnostic yield of multi-gene panel for muscular dystrophies and other hereditary myopathies.

Genetic testing is being considered the first-step in the investigation of hereditary myopathies. However, the performance of the different testing approaches is little known. The aims of the present study were to evaluate the diagnostic yield of a next-generation sequencing panel comprising 39 genes as the first-tier test for genetic myopathies diagnosis and to characterize clinical and molecular findings of families from southern Brazil. Fifty-one consecutive index cases with clinical suspicion of genetic myopathies were recruited from October 2014 to March 2018 in a cross-sectional study. The overall diagnostic yield of the next-generation sequencing panel was 52.9%, increasing to 60.8% when including cases with candidate variants. Multi-gene panel solved the diagnosis of 12/25 (48%) probands with limb-girdle muscular dystrophies, of 7/14 (50%) with congenital muscular diseases, and of 7/10 (70%) with muscular dystrophy with prominent joint contractures. The most frequent diagnosis for limb-girdle muscular dystrophies were LGMD2A/LGMD-R1-calpain3-related and LGMD2B/LGMD-R2-dysferlin-related; for congenital muscular diseases, RYR1-related-disorders; and for muscular dystrophy with prominent joint contractures, Emery-Dreifuss-muscular-dystrophy-type-1 and COL6A1-related-disorders. In summary, the customized next-generation sequencing panel when applied in the initial investigation of genetic myopathies results in high diagnostic yield, likely reducing patient's diagnostic odyssey and providing important information for genetic counseling and participation in disease-specific clinical trials.

Genetic analysis of muscular dystrophies: our experience in Mexico.

Muscular dystrophies are a group of well-defined genetic disorders characterized by the variable distribution of muscle wasting and progressive weakness. The diagnosis and treatment of these diseases remain challenging due to genetic heterogeneity and clinical overlapping. Herein, we describe our 10 years' experience with the diagnosis and management of muscular dystrophy patients. In total, 169 patients were screened for pathogenic variants in eleven genes linked to frequent muscular dystrophies using MLPA and NGS sequencing panels. Most frequent muscular dystrophies found in the Mexican population were dystrophinopathies, dysferlinopathies and calpainopathies. Novel variants were found in genes: DMD, CAPN3, DYSF, and FKRP. For Duchenne muscular dystrophy, improvements in early diagnosis and prolonged ambulation were achieved, on the contrary, for limb-girdle muscular dystrophies and congenital muscular dystrophies, uncomplimentary follow-up and lack of detection strategies were observed. For most common muscular dystrophies, improvements in diagnosis and management have been achieved in the last 10 years, due to a collaborative effort done nationwide.

Miopatía distal de tipo Miyoshi / Miyoshi Type´s distal myopathy

Introducción: La distrofia muscular a tipo Miyoshi es una enfermedad genética, neuromuscular que afecta a las cinturas escapular y pélvica, causando alto grado de discapacidad, su diagnóstico se realiza a través de exámenes enzimáticos y biopsia muscular. Caso clínico: Paciente de 48 años de edad con una evolución de su diagnóstico de hace 16 años, con gran limitación funcional para la marcha desde hace un año y medio, debilidad muscular y atrofia de la musculatura posterior de ambos miembros inferiores. Se le realizó tratamiento rehabilitador integral con objetivos específicos. Conclusiones: Luego de 30 sesiones de tratamiento, se cumplieron los objetivos trazados con evolución satisfactoria, siendo el tratamiento rehabilitador integral un pilar importante en la mejoría clínica del paciente(AU)

Introduction: Muscular dystrophy of Miyoshi type is a genetic and neuromuscular disease that affects the pelvic and shoulder girdle and causes high degree of disability. Its diagnosis is through enzyme testing and muscle biopsy. Clinical case: 48- years- male patient with evolution of his diagnosis made 16 years ago. The patient had great functional limitation for walking from a year and a half before, muscle weakness and atrophy of the posterior muscles of both lower limbs. It was applied comprehensive rehabilitation treatment with specific objectives. Conclusions: After 30 treatment sessions, the objectives were achieved with a satisfactory evolution. The comprehensive rehabilitative treatment proved to be an important pillar in the patient´s clinical improvement(AU)

Papel de las poliaminas en la transducción de señales intracelulares: posibles proyec­ciones de uso clínico en el manejo de las distrofias musculares por medio de su inhibi­ción con difluorometilornitina / Polyamines role in intracellular signals transduction: possible projections for clinical use in muscular dy strophies ' management through its inhibition with difluoromethylornithine

Las distrofias musculares de origen genético son muy diversas y, tanto su diagnóstico preciso como su manejo, suponen un reto importante. En cuanto a este último aspecto, no obstante el desarrollo en proceso de nuevas estrategias a nivel molecular para su tratamiento, las herramientas con que se cuenta para este propósito son limitadas, y pocas veces pueden influir de manera efectiva para evitar el deterioro progresivo que muchos de estos pacientes experimentan. Además, las terapias de última generación no abarcan la gran diversidad de estas patologías y no se espera que estén disponibles a corto plazo para la mayoría de los pacientes. El propósito del artículo es mostrar el papel de las poliaminas, actores ubicuos en el metabolismo in­ tracelular tal vez poco conocidos; cómo están involucrados en los procesos fisiológicos y patológicos, y cómo también pudiesen estar involucrados en la fisiopatología de las distrofias musculares. Su inhi­bición controlada, mediante Difluorometilornitina (DFMO), pudiese constituir un mecanismo para en­ lentecer o eliminar el deterioro muscular de estos pacientes, al utilizarse como una herramienta dentro del arsenal de las ya existentes

Muscular dystrophies of genetic origin are very diverse and, both their precise diagnosis and their management represent an important challenge. Regarding this last aspect, despite the development in process of new strategies at the molecular level for its treatment, the tools available for this pur­ pose are limited, and can rarely influence effectively to avoid the progressive deterioration that many of these patients experience. In addition, the lates t­generation therapies do not cover the great diversity of these pathologies and are not expected to be available in the short term for most patients. The purpose of the article is to show the role of polyamines, ubiquitous actors in intracellular meta­ bolism, perhaps little known; how they are involved in physiological and pathological processes, and how they could also be involved in the physiopathology of muscular dystrophies. Its controlled inhi­ bition, by difluoromethylilitin (DFMO), could be a mechanism to slow or eliminate the muscle deterio­ ration of these patients, by being used as a tool within the arsenal of those already existing.

[Collagen VI related myopathies. When to suspect, how to identify. The contribution of muscle magnetic resonance]. / Miopatías relacionadas a colágeno VI. Cuando sospecharlas, cómo identificarlas. Aporte de la resonancia magnética muscular.

Myopathies secondary to collagen VI mutations (COLVI-M) are the most frequent in the northern hemisphere, affecting the adult and pediatric population. There are no data on its prevalence in Latin America. They are characterized by a great clinical variability, from severe phenotypes, such as Ullrich congenital muscular dystrophy (UCMD), to intermediate and mild ones such as Bethlem myopathy (BM). Its onset is also variable and extends from the neonatal period to adulthood. Given the presence of joint hypermobility, the differential diagnosis should be made with various connective tissue diseases. The classical diagnostic algorithm in many patients has been insufficient to guide the genetic study in an adequate way, and from this the muscular magnetic resonance imaging has emerged as a very useful tool for a better diagnostic approach of this and other muscular pathologies. This ob jective of this review is to study the forms of presentation, clinical characteristics, specific diagnostic study, differential diagnosis and management of one of the most frequent hereditary muscular patho logies, with emphasis on the contribution of muscle magnetic resonance imaging.

Miopatías relacionadas a colágeno VI: cuando sospecharlas, cómo identificarlas: aporte de la resonancia magnética muscular / Collagen VI related myopathies: when to suspect, how to identify: the contribution of muscle magnetic resonance

Resumen: Las miopatías secundarias a mutaciones en el colágeno VI (M-COLVI) son las más frecuentes en el hemisferio norte, afectando población adulta y pediátrica. No existen datos de su prevalencia en Latinoamérica. Se caracterizan por presentar una gran variabilidad clínica, desde fenotipos severos, como la distrofia muscular congénita de Ullrich (DMCU), a intermedios y leves como la Miopatía de Bethlem (MB). Su inicio también es variable y se extiende desde el período de recién nacido hasta la vida adulta. Dada la presencia de hiperlaxitud articular, el diagnóstico diferencial se debe realizar con diversas enfermedades del tejido conectivo. El algoritmo diagnóstico clásico en muchos pacientes ha sido insuficiente para orientar el estudio genético de forma adecuada, y a partir de esto la resonancia magnética muscular ha emergido como una herramienta de gran utilidad para una mejor aproxima ción diagnóstica de ésta y otras patologías musculares. Esta revisión tiene como objetivo examinar las formas de presentación, características clínicas, estudio diagnóstico específico, diagnóstico dife rencial y manejo de una de las patologías musculares herediatarias más frecuentes, con énfasis en el aporte de la resonancia magnética muscular.

Abstract: Myopathies secondary to collagen VI mutations (COLVI-M) are the most frequent in the northern hemisphere, affecting the adult and pediatric population. There are no data on its prevalence in Latin America. They are characterized by a great clinical variability, from severe phenotypes, such as Ullrich congenital muscular dystrophy (UCMD), to intermediate and mild ones such as Bethlem myopathy (BM). Its onset is also variable and extends from the neonatal period to adulthood. Given the presence of joint hypermobility, the differential diagnosis should be made with various connective tissue diseases. The classical diagnostic algorithm in many patients has been insufficient to guide the genetic study in an adequate way, and from this the muscular magnetic resonance imaging has emerged as a very useful tool for a better diagnostic approach of this and other muscular pathologies. This ob jective of this review is to study the forms of presentation, clinical characteristics, specific diagnostic study, differential diagnosis and management of one of the most frequent hereditary muscular patho logies, with emphasis on the contribution of muscle magnetic resonance imaging.

Hand Function in Muscular Dystrophies.

The aim of this study was to investigate the relationship between Performance of Upper Limb (PUL) and Jebsen-Taylor Test (JTT) to assess and monitor upper limb function progression in patients with muscular dystrophy. Thirty patients diagnosed with Duchenne muscular dystrophy, limb-girdle muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy Type 1, and fascioscapulohumeral dystrophy were submitted to the shoulder, elbow, and wrist domains of PUL, and to JTT subtests. Spearman tests investigated the relationships between PUL and JTT total scores and domains. Correlations were classified as strong ( r ≥ 0.70), moderate (0.40 ≤ r < 0.70), or weak ( r ≤ 0.40). There were strong correlations between the PUL and JTT total scores ( r = -0.706). Although JTT measures time and PUL provides kinesiologic scores, these measures were related. Therefore, muscle synergies, which control the compensatory movements and motor functions involving mainly shoulder, elbow, wrist, and finger movements, are related to timed performance in patients with muscular dystrophies.

Guía de práctica clínica para la detección temprana, atención integral, seguimiento y rehabilitación de pacientes con diagnóstico de distrofia muscular. Guía para padres y cuidadores / Clinical practice guide for early detection, comprehensive care, monitoring and rehabilitation of patients diagnosed with muscular dystrophy. Guide for parents and caregivers

La Guía desarrollará recomendaciones para la atención integral de pacientes con sospecha o diagnóstico de distrofia muscular de Duchenne, Becker, miotónica, facioescapulohumeral y de cinturas. No están incluidos los pacientes con distrofias musculares congénitas (enfermedad de Ullrich, síndrome de espina rígida, enfermedad multinúcleo, distrofia muscular congénita por déficit de Merosina), ni con la distrofia muscular Emery Dreifuss.

Segmental uniparental isodisomy of chromosome 6 causing transient diabetes mellitus and merosin-deficient congenital muscular dystrophy.

Segmental uniparental isodisomy (iUPD) is a rare genetic event that may cause aberrant expression of imprinted genes, and reduction to homozygosity of a recessive mutation. Transient neonatal diabetes mellitus (TNDM) is typically caused by imprinting aberrations in chromosome 6q24 TNDM differentially-methylated region (DMR). Approximately, 15.12 Mb upstream in 6q22-q23 is located LAMA2, the gene responsible of merosin-deficient congenital muscular dystrophy type 1A (MDC1A). We investigated a patient diagnosed both with TNDM and MDC1A, born from a twin dichorionic discordant pregnancy. Parents are first-degree cousins. Methylation sensitive-PCR of the imprinted 6q24 TNDM CpG island showed only the non-methylated (paternal) allele. Microsatellite markers and SNP array profiling disclosed normal biparental inheritance at 6p and a segmental paternal iUPD, between 6q22.33 and 6q27. Sequencing of LAMA2 exons showed a homozygous frameshift mutation, c.7490_7493dupAAGA, which predicts p.Asp2498GlufsX4, in exon 54. Her father, but not her mother, was a carrier of the mutation. While segmental paternal iUPD6 causing TNDM was reported twice, there are no previous reports of MDC1A caused by this event. This is a child with two genetic disorders, yet neither is caused by the parental consanguinity, which reinforces the importance of considering different etiological mechanisms in the genetic clinic.

Molecular diagnosis of dystrophinopathies using a multi-technique analysis algorithm.

INTRODUCTION: Dystrophinopathies are X-linked recessive neuromuscular diseases caused by mutations in the dystrophin gene. In this study we aimed to detect mutations within the dystrophin gene in DMD patients, to determine the carrier status of women, and to perform a prenatal diagnosis. METHODS: We analyzed 17 individuals from 2 unrelated families with a history of DMD. We used multiplex PCR, multiplex ligation-dependent probe amplification (MLPA), and short tandem-repeat (STR) segregation analysis to accurately detect and characterize the mutations and to identify the at-risk haplotype. RESULTS: The selected methodology allowed for characterization of 2 single-exon out-of-frame deletions in affected patients. Nine of 13 women and a fetus were excluded from being carriers. Three recombination events were found and suggested that germline mosaicism had occurred in both families. CONCLUSIONS: This methodology proved to be efficient for characterizing the disease-causing mutation in affected individuals and for assessing the carrier status in healthy relatives. These findings helped inform precise genetic counseling and contributed to characterization of the disease in the Argentine population.

Guía de práctica clínica para la detección temprana, atención integral, seguimiento y rehabilitación de pacientes con diagnóstico de distrofia muscular. Guía para los profesionales de la salud / Clinical practice guide for early detection, comprehensive care, monitoring and rehabilitation of patients diagnosed with muscular dystrophy. Guide for health professionals

La Guía desarrollará recomendaciones para la atención integral de pacientes con sospecha o diagnóstico de distrofia muscular de Duchenne, Becker, miotónica, facioescapulohumeral y de cinturas. No están incluidos los pacientes con distrofias musculares congénitas (enfermedad de Ullrich, síndrome de espina rígida, enfermedad multinúcleo, distrofia muscular congénita por déficit de Merosina), ni con la distrofia muscular Emery Dreifuss.

Guía de práctica clínica para la detección temprana, atención integral, seguimiento y rehabilitación de pacientes con diagnóstico de distrofia muscular. Guía completa / Clinical practice guide for early detection, comprehensive care, monitoring and rehabilitation of patients diagnosed with muscular dystrophy. Complete guide

La Guía desarrollará recomendaciones para la atención integral de pacientes con sospecha o diagnóstico de distrofia muscular de Duchenne, Becker, miotónica, facioescapulohumeral y de cinturas. No están incluidos los pacientes con distrofias musculares congénitas (enfermedad de Ullrich, síndrome de espina rígida, enfermedad multinúcleo, distrofia muscular congénita por déficit de Merosina), ni con la distrofia muscular Emery Dreifuss.

Weight-based nutritional diagnosis of Mexican children and adolescents with neuromotor disabilities.

BACKGROUND: Nutrition related problems are increasing worldwide but they have scarcely been evaluated in people with neuromotor disabilities, particularly in developing countries. In this study our aim was to describe the weight-based nutritional diagnoses of children and adolescents with neuromotor disabilities who attended a private rehabilitation center in Mexico City. METHODS: Data from the first visit's clinical records of 410 patients who attended the Nutrition department at the Teleton Center for Children Rehabilitation, between 1999 and 2008, were analyzed. Sex, age, weight and height, length or segmental length data were collected and used to obtain the nutritional diagnosis based on international growth charts, as well as disability-specific charts. Weight for height was considered the main indicator. RESULTS: Cerebral palsy was the most frequent diagnosis, followed by spina bifida, muscular dystrophy, and Down's syndrome. Children with cerebral palsy showed a higher risk of presenting low weight/undernutrition (LW/UN) than children with other disabilities, which was three times higher in females. In contrast, children with spina bifida, particularly males, were more likely to be overweight/obese (OW/OB), especially after the age of 6 and even more after 11. Patients with muscular dystrophy showed a significantly lower risk of LW/UN than patients with other disabilities. In patients with Down's syndrome neither LW/UN nor OW/OB were different between age and sex. CONCLUSIONS: This is the first study that provides evidence of the nutritional situation of children and adolescents with neuromotor disabilities in Mexico, based on their weight status. Low weight and obesity affect a large number of these patients due to their disability, age and sex. Early nutritional diagnosis must be considered an essential component in the treatment of these patients to prevent obesity and malnutrition, and improve their quality of life.

Immunodetection analysis of muscular dystrophies in Mexico.

INTRODUCTION: The muscular dystrophies (MDs) result from perturbations in the myofibers. These alterations are induced in part by mechanical stress due to membrane cell fragility, disturbances in mechanotransduction pathways, muscle cell physiology, and metabolism. METHODS: We analyzed 290 biopsies of patients with a clinical diagnosis of muscular dystrophy. Using immunofluorescence staining, we searched for primary and secondary deficiencies of 12 different proteins, including membrane, costamere, cytoskeletal, and nuclear proteins. In addition, we analyzed calpain-3 by immunoblot. RESULTS: We identified 212 patients with varying degrees of protein deficiencies, including dystrophin, sarcoglycans, dysferlin, caveolin-3, calpain-3, emerin, and merosin. Moreover, 78 biopsies showed normal expression of all investigated muscle proteins. The frequency rates of protein deficiencies were as follows: 52.36% dystrophinopathies; 18.40% dysferlinopathies; 14.15% sarcoglycanopathies; 11.32% calpainopathies; 1.89% merosinopathies; 1.42% caveolinopathies; and 0.47% emerinopathies. Deficiencies in lamin A/C and telethonin were not detected. CONCLUSION: We have described the frequency of common muscular dystrophies in Mexico.

Síndrome de Walker-Warburg / Walker-Warburg syndrome

A síndrome de Walker-Warburg (SWW) é uma doença autossômica recessiva rara, caracterizada por distrofia muscular congênita e associada a malformações cerebrais e oculares. Pode ser suspeitada ainda no pré-natal e o diagnóstico é firmado ao nascimento através de alterações clínicas e patológicas. O objetivo deste trabalho é relatar o caso de uma paciente com 3 meses de vida portadora de SWW. A SWW é uma síndrome severa e letal, diagnosticada através de quatro critérios: distrofia muscular congênita, anormalidades oculares, lissencefalia tipo II e malformação cerebelar. Seu tratamento visa apenas ao suporte e à prevenção de complicações. Pacientes com esta doença geralmente vão a óbito ainda no primeiro ano de vida

The Walker-Warburg syndrome (WWS) is a rare autosomal recessive disorder characterized by congenital muscular dystrophy and associated with cerebral and ocular malformations. It may be suspected even in the prenatal period and the diagnosis is made at birth through clinical and pathological characteristics. The aim of this study is to report the case of a 3-month-old with WWS. The WWS is a severe and lethal syndrome that is diagnosed by four criteria: congenital muscular dystrophy, ocular abnormalities, type II lissencephaly, and cerebellar malformation. Its treatment is only supportive and intended to prevent complications. Patients with this disease usually will die within the first year of life