RESUMEN

BACKGROUND: We recently reported that upregulation of Musashi 2 (MSI2) protein in the rare neuromuscular disease myotonic dystrophy type 1 contributes to the hyperactivation of the muscle catabolic processes autophagy and UPS through a reduction in miR-7 levels. Because oleic acid (OA) is a known allosteric regulator of MSI2 activity in the biogenesis of miR-7, here we sought to evaluate endogenous levels of this fatty acid and its therapeutic potential in rescuing cell differentiation phenotypes in vitro. In this work, four muscle cell lines derived from DM1 patients were treated with OA for 24 h, and autophagy and muscle differentiation parameters were analyzed. RESULTS: We demonstrate a reduction of OA levels in different cell models of the disease. OA supplementation rescued disease-related phenotypes such as fusion index, myotube diameter, and repressed autophagy. This involved inhibiting MSI2 regulation of direct molecular target miR-7 since OA isoschizomer, elaidic acid (EA) could not cause the same rescues. Reduction of OA levels seems to stem from impaired biogenesis since levels of the enzyme stearoyl-CoA desaturase 1 (SCD1), responsible for converting stearic acid to oleic acid, are decreased in DM1 and correlate with OA amounts. CONCLUSIONS: For the first time in DM1, we describe a fatty acid metabolism impairment that originated, at least in part, from a decrease in SCD1. Because OA allosterically inhibits MSI2 binding to molecular targets, reduced OA levels synergize with the overexpression of MSI2 and contribute to the MSI2 > miR-7 > autophagy axis that we proposed to explain the muscle atrophy phenotype.

Asunto(s)

RESUMEN

Myotonic dystrophy type 1 is a complex disease caused by a genetically unstable CTG repeat expansion in the 3'-untranslated region of the DMPK gene. Age-dependent, tissue-specific somatic instability has confounded genotype-phenotype associations, but growing evidence suggests that it also contributes directly toward disease progression. Using a well-characterized clinical cohort of DM1 patients from Costa Rica, we quantified somatic instability in blood, buccal cells, skin and skeletal muscle. Whilst skeletal muscle showed the largest expansions, modal allele lengths in skin were also very large and frequently exceeded 2000 CTG repeats. Similarly, the degree of somatic expansion in blood, muscle and skin were associated with each other. Notably, we found that the degree of somatic expansion in skin was highly predictive of that in skeletal muscle. More importantly, we established that individuals whose repeat expanded more rapidly than expected in one tissue (after correction for progenitor allele length and age) also expanded more rapidly than expected in other tissues. We also provide evidence suggesting that individuals in whom the repeat expanded more rapidly than expected in skeletal muscle have an earlier age at onset than expected (after correction for the progenitor allele length). Pyrosequencing analyses of the genomic DNA flanking the CTG repeat revealed that the degree of methylation in muscle was well predicted by the muscle modal allele length and age, but that neither methylation of the flanking DNA nor levels of DMPK sense and anti-sense transcripts could obviously explain individual- or tissue-specific patterns of somatic instability.

Asunto(s)

RESUMEN

INTRODUCTION: Myotonic dystrophy type 1 is a rare genetic disorder that mainly affects the musculoskeletal system; However, it may cause several complications in other body systems representing challenges for health care providers. PATIENT CONCERNS: We present the case of a patient with a history of previously diagnosed type 1 myotonic dystrophy who presented to the emergency department with cough dyspnea, and thoracic pain. DIAGNOSIS: Differential diagnoses included pulmonary embolism with a moderate probability according to the Wells score, acute coronary syndrome, acute heart failure, and pneumonia. Diagnostic workup involved chest radiography, EKG, and a CTPA which revealed pneumonia, posteriorly the patient presented de novo atrial fibrillation. INTERVENTIONS: The patient was successfully treated with empiric antibiotic therapy and amiodarone, respiratory and physical therapy. OUTCOMES: The patient was discharged on day 34, however oxygen weaning was not possible. CONCLUSION: Treatment of MD1 patients is challenging due to the various mechanisms of the disease; patients with new-onset deterioration should be screened for the most common complications such as cardio-respiratory events.The authors suggest pneumonia as a risk factor for basal respiratory function deterioration and a contributing factor for triggering cardiac events for further research in prospective studies.

Asunto(s)

RESUMEN

AIM: To identify the standardized assessment scales for people with muscular dystrophy and investigate the quality/level of evidence of their measurement properties. METHOD: A systematic review of patient-reported outcome measures was conducted on the MEDLINE, Embase, AMED, DiTA, and PsycINFO databases in August 2020. We included psychometric studies that investigated the validity, reliability, and responsiveness of instruments assessing activity and participation for muscular dystrophy of any type (Duchenne, Becker, limb-girdle, facioscapulohumeral, congenital, and myotonic) or age. Two independent reviewers selected the studies, extracted data, and evaluated the instruments' quality and level of evidence following the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) checklist. The study followed the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) 2020 guidelines. RESULTS: The searches identified 6675 references; a total of 46 studies with 28 condition-specific or general instruments were included. The measurement properties of most instruments had sufficient (68.8%) or indeterminate (25.7%) results according to COSMIN. The quality of evidence of the measurement properties was moderate (23.8%) or low (22.6%) according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). INTERPRETATION: There is a lack of high-quality instruments whose psychometric properties are adequately measured. The highest quality instrument is the Muscular Dystrophy Functional Rating Scale. The Motor Function Measure (general instrument), Duchenne Muscular Dystrophy Upper-limb Patient-reported Outcome Measure, North Star Ambulatory Assessment, and Myotonic Dystrophy Type 1 Activity and Participation Scale for Clinical Use (specific) are also recommended. WHAT THIS PAPER ADDS: There are 28 available instruments for activity and participation of people with muscular dystrophy. The evidence quality is moderate or low because of imprecision and indirectness. The Muscular Dystrophy Functional Rating Scale is the highest quality instrument. The Motor Function Measure is the second most recommended instrument. The Duchenne Muscular Dystrophy Upper-limb Patient-reported Outcome Measure, North Star Ambulatory Assessment, and Myotonic Dystrophy Type 1 Activity and Participation Scale for Clinical Use are also recommended.

Asunto(s)

RESUMEN

Introducción: La distrofia miotónica tipo 1 es la distrofia muscular más frecuente a nivel mundial. Progresa lentamente llevando al paciente a la pérdida de autonomía lo que implica la necesidad del cuidador, quien con frecuencia, también padece la enfermedad. El síndrome de sobrecarga, desgaste o burnout, término en inglés muy utilizado en la bibliografía médica, se ha descrito en los últimos años para los cuidadores y es el desgaste emocional una de sus particularidades. Objetivo: Evaluar la autonomía para la realización de actividades diarias de los pacientes con distrofia miotónica tipo 1 en referencia al tiempo de evolución de la enfermedad y determinar la magnitud de desgaste en los cuidadores. Metodología: Se aplicó la escala de autonomía de Barthel a 29 pacientes y el cuestionario de Maslach a sus cuidadores. Resultados: Se demostró que las mujeres cuidadoras resultaron más afectadas en el intercambio con el enfermo para el cuidado, en la subescala despersonalización del instrumento Maslach (U de Mann-Whitney p = 0,05). Conclusiones: Se sugiere que los cuidadores femeninos son el grupo de mayor riesgo de padecer el síndrome de sobrecarga(AU)

Introduction: Myotonic dystrophy type 1 is the most common muscular dystrophy worldwide. It progresses slowly, depriving patients of their autonomy, which implies the need for a caregiver, who would often suffer from the disease as well. The overload or burnout syndrome, an English term very often found in medical bibliography, has been described for caregivers in recent years, and emotional wear is one of its features. Objective: Evaluate the autonomy to perform activities of daily living of patients with myotonic dystrophy type 1 with reference to the time of evolution of the disease, and determine the extent of wear in caregivers. Methods: A study of a clinical case series was conducted for two years at the Institute of Neurology and Neurosurgery in Havana. Patients were evaluated with the Barthel autonomy scale and caregivers with the Maslach burnout syndrome inventory. Inclusion criteria admitted patients of both sexes clinically and neurophysiologically characterized for this diagnosis. It was also required to obtain the informed consent of patients and caregivers responding to the overload measuring tool. Exclusion criteria left out patients with a dystrophic condition other than Steinert type 1, inconclusive clinical and electromyographic evaluations, or not willing to participate in the study. Results: According to the depersonalization subscale in the Maslach tool (Mann-Whitney U p = 0.05), female caregivers are more often affected by the interaction with the person cared for. Conclusions: Results suggest that female caregivers are under a greater risk of overload syndrome(AU)

Asunto(s)

RESUMEN

Myotonic dystrophy type 1 (DM1) is a complex disease with a wide spectrum of symptoms. The exact relationship between mutant CTG repeat expansion size and clinical outcome remains unclear. DM1 congenital patients (CDM) inherit the largest expanded alleles, which are associated with abnormal and increased DNA methylation flanking the CTG repeat. However, DNA methylation at the DMPK locus remains understudied. Its relationship to DM1 clinical subtypes, expansion size and age-at-onset is not yet completely understood. Using pyrosequencing-based methylation analysis on 225 blood DNA samples from Costa Rican DM1 patients, we determined that the size of the estimated progenitor allele length (ePAL) is not only a good discriminator between CDM and non-CDM cases (with an estimated threshold at 653 CTG repeats), but also for all DM1 clinical subtypes. Secondly, increased methylation at both CTCF sites upstream and downstream of the expansion was almost exclusively present in CDM cases. Thirdly, levels of abnormal methylation were associated with clinical subtype, age and ePAL, with strong correlations between these variables. Fourthly, both ePAL and the intergenerational expansion size were significantly associated with methylation status. Finally, methylation status was associated with ePAL and maternal inheritance, with almost exclusively maternal transmission of CDM. In conclusion, increased DNA methylation at the CTCF sites flanking the DM1 expansion could be linked to ePAL, and both increased methylation and the ePAL could be considered biomarkers for the CDM phenotype.

Asunto(s)

RESUMEN

CASE: We report a right-handed 37-year-old woman, with myotonic dystrophy type 1 (MD1), presenting with a posterior interosseus nerve injury because of a penetrating trauma in the right forearm. The tendon transfer technique was chosen based on tendon response and functionality of the arms during the surgery. The patient has been able return to her daily life activities with proper fine and gross motor control. CONCLUSION: Despite tendon transfer surgery being a common technique for radial nerve palsy reconstruction, its use has not been extensively described in the literature in patients with muscular dystrophies such as MD1.

Asunto(s)

RESUMEN

BACKGROUND: Myotonic dystrophy type 2 (DM2) is caused by a CCTG repeat expansion in intron 1 of the CCHC-Type Zinc Finger Nucleic Acid Binding Protein (CNBP) gene. Previous studies indicated that this repeat expansion originates from separate founders. OBJECTIVE: This study was set out to determine whether or not patients with DM2 originating from European and non-European countries carry the previously described European founder haplotypes. METHODS: Haplotype analysis was performed in 59 DM2 patients from 29 unrelated families. Twenty-three families were from European descent and 6 families originated from non-European countries (India, Suriname and Morocco). Seven short tandem repeats (CL3N122, CL3N99, CL3N59, CL3N117, CL3N119, CL3N19 and CL3N23) and 4 single nucleotide polymorphisms (SNP) (rs1871922, rs1384313, rs4303883 and CGAP_886192) in and around the CNBP gene were used to construct patients' haplotypes. These haplotypes were compared to the known DM2 haplotypes to determine the ancestral origin of the CNBP repeat expansion. RESULTS: Of 41 patients, the haplotype could be assigned to the previously described Caucasian haplotypes. Three patients from Morocco and Portugal had a haplotype identical to the earlier reported Moroccan haplotype. Twelve patients from India and Suriname, however, carried a haplotype that seems distinct from the previously reported haplotypes. Three individuals could not be assigned to a specific haplotype. CONCLUSION: The ancestral origin of DM2 in India might be distinct from the Caucasian families and the solely described Japanese patient. However, we were unable to establish this firmly due to the limited genetic variation in the region surrounding the CNBP gene.

Asunto(s)

RESUMEN

Myotonic dystrophy type 1 (DM1), the most frequent inherited muscular dystrophy in adults, is caused by the CTG repeat expansion in the 3'UTR of the DMPK gene. Mutant DMPK RNA accumulates in nuclear foci altering diverse cellular functions including alternative splicing regulation. DM1 is a multisystemic condition, with debilitating central nervous system alterations. Although a defective neuroglia communication has been described as a contributor of the brain pathology in DM1, the specific cellular and molecular events potentially affected in glia cells have not been totally recognized. Thus, to study the effects of DM1 mutation on glial physiology, in this work, we have established an inducible DM1 model derived from the MIO-M1 cell line expressing 648 CUG repeats. This new model recreated the molecular hallmarks of DM1 elicited by a toxic RNA gain-of-function mechanism: accumulation of RNA foci colocalized with MBNL proteins and dysregulation of alternative splicing. By applying a microarray whole-transcriptome approach, we identified several gene changes associated with DM1 mutation in MIO-M1 cells, including the immune mediators CXCL10, CCL5, CXCL8, TNFAIP3, and TNFRSF9, as well as the microRNAs miR-222, miR-448, among others, as potential regulators. A gene ontology enrichment analyses revealed that inflammation and immune response emerged as major cellular deregulated processes in the MIO-M1 DM1 cells. Our findings indicate the involvement of an altered immune response in glia cells, opening new windows for the study of glia as potential contributor of the CNS symptoms in DM1.

Asunto(s)

RESUMEN

Abstract Myotonic dystrophy type-1 (Steinert disease) is an autosomal dominant, progressive multisystem disease in which myotonic crisis can be triggered by several factors including pain, emotional stress, hypothermia, shivering, and mechanical or electrical stimulation. In this report, dexmedetomidine-based general anesthesia, in combination with a thoracic epidural for laparoscopic cholecystectomy in a patient with Steinert disease, is presented. An Aintree intubation catheter with the guidance of a fiberoptic bronchoscope was used for intubation to avoid laryngoscopy. Prolonged anesthetic effects of propofol were reversed, and recovery from anesthesia was accelerated using an intravenous infusion of theophylline.

Resumo A Distrofia Miotônica (DM) tipo-1 (Doença de Steinert) é uma doença multissistêmica progressiva autossômica dominante em que a crise miotônica pode ser desencadeada por vários fatores, incluindo dor, estresse emocional, hipotermia, tremores e estímulo mecânico ou elétrico. O presente relato descreve anestesia geral realizada com dexmedetomidina em combinação com peridural torácica para colecistectomia laparoscópica em paciente com Doença de Steinert. Para evitar laringoscopia, a intubação traqueal foi realizada utilizando cateter de intubação Aintree guiado por broncofibroscopia óptica. Os efeitos anestésicos prolongados do propofol foram revertidos e a recuperação anestésica foi acelerada pelo uso de infusão intravenosa de teofilina.

Asunto(s)

RESUMEN

Resumen: Se presentan tres casos clínicos de pacientes con en Enfermedad de Steinert y Taquicardia ventricular recurrente asociada. En los 3 casos el diagnóstico involucró un exhaustivo estudio electrofisiológico que demostró que se trataban de TV rama a rama. Se describen los mecanismos y las maniobras electrofisiológicas para establecer el diagnóstico, como también el tratamiento. Incluye una extensa revisión bibliográfica.

Abstract This is a report of three patients with Steinert´s disease who presented with ventricular tachycardia requiring electrical cardioversion. Extensive electrophysiologic study demonstrated an underlying bundle branch ventricular tachycardia. The mechanisms and the electrophysiological approach to diagnosis are described in detail and the treatment selected is discussed. An extensive review of the literature is included.

Asunto(s)

RESUMEN

Myotonic dystrophy type-1 (Steinert disease) is an autosomal dominant, progressive multisystem disease in which myotonic crisis can be triggered by several factors including pain, emotional stress, hypothermia, shivering, and mechanical or electrical stimulation. In this report, dexmedetomidine-based general anesthesia, in combination with a thoracic epidural for laparoscopic cholecystectomy in a patient with Steinert disease, is presented. An Aintree intubation catheter with the guidance of a fiberoptic bronchoscope was used for intubation to avoid laryngoscopy. Prolonged anesthetic effects of propofol were reversed, and recovery from anesthesia was accelerated using an intravenous infusion of theophylline.

Asunto(s)

RESUMEN

Introducción: La distrofia miotónica congénita es la forma clínica que produce la expresión fenotípica más grave, con alta morbilidad y mortalidad en los primeros meses de vida, dadas fundamentalmente por las complicaciones respiratorias. Objetivo: Describir una serie de casos con expresión clínica de distrofia miotónica congénita. Presentación de casos: La serie estaba conformada por cuatro pacientes con diagnóstico de la enfermedad en la provincia de Pinar del Río, Cuba. El estudio se realizó entre: enero de 2015-diciembre de 2019. Se revisaron las características clínicas, epidemiológicas y genéticas de la entidad. Se analizaron los antecedentes prenatales-perinatales de cada caso, las manifestaciones fenotípicas, los antecedentes familiares y el cálculo de la prevalencia. En el 100 por ciento de los casos se presentó parto pretérmino con depresión neonatal severa e hipotonía. Entre los antecedentes prenatales se describió la disminución de los movimientos fetales y el polihidramnios en el 75 y 50 por ciento de los casos, respectivamente. La totalidad de los pacientes eran descendientes de madres afectadas. Las principales complicaciones que condujeron a morbilidad y mortalidad en el 100 por ciento de los casos fueron las relacionadas con el sistema respiratorio, trastornos hidroelectrolíticos y las infecciones asociadas. Conclusiones: En el período neonatal son importantes los antecedentes prenatales-perinatales de los pacientes con distrofia miotónica. Estos antecedentes, constituyen acontecimientos que forman parte de la secuencia de hipoquinesia fetal dada por la afectación neuromuscular intraútero. Los antecedentes familiares y sobre todo cuando la madre está afectada conducen a expresiones severas en la descendencia(AU)

Introduction: Congenital myotonic dystrophy is a clinical form that produces the most severe phenotypic expression, with high morbility and mortality in the first months of life mainly due to respiratory complications. Objective: To describe a serie of cases with clinical expression of congenital myotonic dystrophy. Cases presentation: The serie was formed by 4 patients with diagnosis of the disease in Pinar del Río province, Cuba. The study was made from January, 2015 to December, 2019. There were reviewed the clinical, epidemiological and genetic characteristics of this entity. There were analyzed prenatal and perinatal backgrounds of each case, phenotypic manifestations, the family records and the prevalence calculations. In 100 percent of the cases it was presented preterm birth with severe neonatal depression and hypotonia. Among the prenatal backgrounds, it was described the decrease of the fetal movements and polyhydramnios in the 75 and 50 percent of the cases, respectively. All the patients were descendants of affected mothers. The main complications that led to morbility and mortality in 100 percent of the cases were the ones related with the respiratory system, hydrolectrolitic disorders and associated infections. Conclusions: In the neonatal period are important the prenatal-perinatal records of patients with myotonic dystrophy. This background shows events that are part of the fetal hypokinesia´s sequence caused by intrauterine neuromuscular affectation. Family background and especially when the mother is affected lead to severe expressions in the descendants(AU)

Asunto(s)

RESUMEN

In myotonic dystrophy type 1 (DM1), somatic mosaicism of the (CTG)n repeat expansion is age-dependent, tissue-specific and expansion-biased. These features contribute toward variation in disease severity and confound genotype-to-phenotype analyses. To investigate how the (CTG)n repeat expansion changes over time, we collected three longitudinal blood DNA samples separated by 8-15 years and used small pool and single-molecule PCR in 43 DM1 patients. We used the lower boundary of the allele length distribution as the best estimate for the inherited progenitor allele length (ePAL), which is itself the best predictor of disease severity. Although in most patients the lower boundary of the allele length distribution was conserved over time, in many this estimate also increased with age, suggesting samples for research studies and clinical trials should be obtained as early as possible. As expected, the modal allele length increased over time, driven primarily by ePAL, age-at-sampling and the time interval. As expected, small expansions <100 repeats did not expand as rapidly as larger alleles. However, the rate of expansion of very large alleles was not obviously proportionally higher. This may, at least in part, be a result of the allele length-dependent increase in large contractions that we also observed. We also determined that individual-specific variation in the increase of modal allele length over time not accounted for by ePAL, age-at-sampling and time was inversely associated with individual-specific variation in age-at-onset not accounted for by ePAL, further highlighting somatic expansion as a therapeutic target in DM1.

Asunto(s)

RESUMEN

OBJECTIVE: To present a case of bilateral gynecomastia in a prepubertal boy with autism spectrum disorder, diagnosed with myotonic dystrophy type 1. CASE DESCRIPTION: A 12-year-old boy with autism spectrum disorder presented at a follow-up visit with bilateral breast growth. There was a family history of gynecomastia, cataracts at a young age, puberty delay, and myotonic dystrophy type 1. The physical examination showed that he had bilateral gynecomastia with external genitalia Tanner stage 1. Neurologic examination was regular, without demonstrable myotonia. The analytical study revealed increased estradiol levels and estradiol/testosterone ratio. After excluding endocrine diseases, the molecular study of the dystrophia myotonica protein kinase gene confirmed the diagnosis of myotonic dystrophy type 1. COMMENTS: A diagnosis of prepubertal gynecomastia should include an investigation for possible underlying diseases. This case report highlights the importance of considering the diagnosis of myotonic dystrophy type 1 in the presence of endocrine and neurodevelopmental manifestations.

Asunto(s)

RESUMEN

ABSTRACT Objective: To present a case of bilateral gynecomastia in a prepubertal boy with autism spectrum disorder, diagnosed with myotonic dystrophy type 1. Case description: A 12-year-old boy with autism spectrum disorder presented at a follow-up visit with bilateral breast growth. There was a family history of gynecomastia, cataracts at a young age, puberty delay, and myotonic dystrophy type 1. The physical examination showed that he had bilateral gynecomastia with external genitalia Tanner stage 1. Neurologic examination was regular, without demonstrable myotonia. The analytical study revealed increased estradiol levels and estradiol/testosterone ratio. After excluding endocrine diseases, the molecular study of the dystrophia myotonica protein kinase gene confirmed the diagnosis of myotonic dystrophy type 1. Comments: A diagnosis of prepubertal gynecomastia should include an investigation for possible underlying diseases. This case report highlights the importance of considering the diagnosis of myotonic dystrophy type 1 in the presence of endocrine and neurodevelopmental manifestations.

RESUMO Objetivo: Apresentar o caso de um adolescente pré-púbere com ginecomastia bilateral e transtorno do espectro autista, diagnosticado com distrofia miotônica tipo 1. Descrição do caso: Adolescente do sexo masculino de 12 anos, com transtorno do espectro autista, observado em consulta de seguimento por crescimento mamário bilateral. O paciente tinha antecedentes familiares de ginecomastia, catarata em idade jovem, atraso pubertário e distrofia miotônica tipo 1. À observação física, apresentava ginecomastia bilateral estádio 1 de Tanner. O exame neurológico era normal, sem miotonia aparente. O estudo analítico mostrou níveis elevados de estradiol e da relação estradiol/testosterona. Após exclusão de causas endócrinas, o estudo molecular do gene DMPK confirmou o diagnóstico de distrofia miotônica tipo 1. Comentários: Perante um quadro de ginecomastia pré-púbere, deve-se excluir doenças subjacentes. Este caso reforça a importância de considerar o diagnóstico de distrofia miotônica tipo 1 na presença de manifestações endócrinas e do neurodesenvolvimento.

Asunto(s)

RESUMEN

BACKGROUND: Stem cell transplantation represents a potential therapeutic option for muscular dystrophies (MD). However, to date, most reports have utilized mouse models for recessive types of MD. Here we performed studies to determine whether myotonic dystrophy 1 (DM1), an autosomal dominant type of MD, could benefit from cell transplantation. METHODS: We injected human pluripotent stem (PS) cell-derived myogenic progenitors into the muscles of a novel mouse model combining immunodeficiency and skeletal muscle pathology of DM1 and investigated transplanted mice for engraftment as well as for the presence of RNA foci and alternative splicing pattern. FINDINGS: Engraftment was clearly observed in recipient mice, but unexpectedly, we detected RNA foci in donor-derived engrafted myonuclei. These foci proved to be pathogenic as we observed MBNL1 sequestration and abnormal alternative splicing in donor-derived transcripts. INTERPRETATION: It has been assumed that toxic CUG repeat-containing RNA forms foci in situ in the nucleus in which it is expressed, but these data suggest that CUG repeat-containing RNA may also exit the nucleus and traffic to other nuclei in the syncytial myofiber, where it can exert pathological effects. FUND: This project was supported by funds from the LaBonte/Shawn family and NIH grants R01 AR055299 and AR071439 (R.C.R.P.). R.M-G. was funded by CONACyT-Mexico (#394378).

Asunto(s)

RESUMEN

Genotype-to-phenotype correlation studies in myotonic dystrophy type 1 (DM1) have been confounded by the age-dependent, tissue-specific and expansion-biased features of somatic mosaicism of the expanded CTG repeat. Previously, we showed that by controlling for the confounding effects of somatic instability to estimate the progenitor allele CTG length in blood DNA, age at onset correlations could be significantly improved. To determine the suitability of saliva DNA as a source for genotyping, we used small pool-PCR to perform a detailed quantitative study of the somatic mutational dynamics of the CTG repeat in saliva and blood DNA from 40 DM1 patients. Notably, the modal allele length in saliva was only moderately higher in saliva and not as large as previously observed in most other tissues. The lower boundary of the allele distribution was also slightly higher in saliva than it was in blood DNA. However, the progenitor allele length estimated in blood explained more of the variation in age at onset than that estimated from saliva. Interestingly, although the modal allele length was slightly higher in saliva, the overall degree of somatic variation was typically lower than in blood DNA, revealing new insights into the tissue-specific dynamics of somatic mosaicism. These data indicate that saliva constitutes an accessible, non-invasive and suitable DNA sample source for performing genetic studies in DM1.

Asunto(s)

RESUMEN

INTRODUCTION: Myotonic dystrophy type 1 (DM1) is a multisystemic disorder characterized mainly by skeletal muscle alterations. Although oropharyngeal dysphagia is a prominent clinical feature of DM1, it remains poorly studied in its early disease stages. METHODS: Dysphagia was investigated in 11 presymptomatic DM1 carriers, 14 patients with DM1 and 12 age-matched healthy controls, by using fiberoptic endoscopic evaluation of swallowing (FEES) and clinical scores. RESULTS: Scores for the FEES variables, delayed pharyngeal reflex, posterior pooling, and postswallow residue were significantly greater in patients with DM1 and in presymptomatic DM1 carriers than in healthy controls (P < 0.05); oropharyngeal dysfunction was more severe in patients than in presymptomatic carriers. Penetration/aspiration was found altered exclusively in patients with DM1 (P < 0.05). DISCUSSION: Swallowing dysfunction occurs in presymptomatic DM1 carriers. Timely diagnosis of dysphagia in preclinical stages of the disease will aid in the timely management of presymptomatic carriers, potentially preventing medical complications. Muscle Nerve, 2019.

Asunto(s)

RESUMEN

Abstract Background and objectives: Ultrasound-guided upper limb blocks may provide great benefits to patients with serious diseases. Patients with Steinert's disease have muscle weakness and risk of triggering myotony or malignant hyperthermia due to the use of anesthetic agents and surgical stress. The objective of this report was to demonstrate a viable alternative for clavicle fracture surgery with upper trunk and supraclavicular nerve block, thus reducing the spread of local anesthetic to the phrenic nerve in a patient with muscular dystrophy. Case report: A 53-year-old male patient with Steinert's disease, associated with dyspnea, hoarseness and dysphagia, referred to the surgical theater for osteosynthesis of clavicle fracture. Upper limb (1 mL 0.75% ropivacaine) and supraclavicular nerve block (1 mL 0.75% ropivacaine in each branch) were combined with venous anesthesia with propofol under laryngeal mask (infusion pump target of 4 mcg.mL-1). Upon awakening, the patient had no pain or respiratory complaints. He was transferred to the ICU for immediate postoperative follow-up with discharge from this unit after 24 h without complications. Conclusions: The superior trunk and cervical plexus block associated with venous anesthesia under laryngeal mask, without the use of opioids, proved to be adequate in the case of a patient with clavicle fracture and Steinert's disease. With the use of ultrasonography in regional anesthesia it is possible to perform increasingly selective blocks, thus allowing greater security for the anesthetic-surgical procedure and lower morbidity for the patient.

Resumo Justificativa e objetivos: Bloqueios seletivos dos membros superiores guiados por ultrassom podem trazer grandes benefícios em pacientes portadores de doenças graves. Pacientes portadores da doença de Steinert apresentam fraqueza muscular e riscos de desencadear miotonia ou hipertermia maligna devido ao uso de agentes anestésicos e ao estresse cirúrgico. O objetivo deste relato foi mostrar uma opção viável para a cirurgia de fratura de clavícula com bloqueio do tronco superior e nervo supraclavicular, diminui-se assim a dispersão do anestésico local para o nervo frênico em paciente com distrofia muscular. Relato de caso: Paciente do sexo masculino, 53 anos, portador de doença de Steinert, associada a dispneia, rouquidão e disfagia. Encaminhado ao bloco cirúrgico para osteossíntese de fratura de clavícula. Feito bloqueio de tronco superior (1 mL ropivacaína a 0,75%) e de nervo supraclavicular (1 mL de ropivacaína 0,75 em cada ramificação) associado à anestesia venosa com propofol sob máscara laríngea (alvo de 4 mcg.mL-1 em bomba de infusão). Ao despertar, o paciente apresentava-se sem dor ou queixas respiratórias. Admitido em CTI para acompanhamento do pós-operatório imediato com alta dessa unidade após 24 horas sem intercorrências. Conclusões: O bloqueio do tronco superior e do plexo cervical associado à anestesia venosa sob máscara laríngea, sem uso de opioides, mostrou-se adequado no caso de fratura da clavícula em paciente com doença de Steinert. Com o uso da ultrassonografia em anestesia regional é possível fazer bloqueios cada vez mais seletivos e possibilitar assim maior segurança para o procedimento anestésico-cirúrgico e menor morbidade para o paciente.

Asunto(s)