McLeod myopathy revisited: more neurogenic and less benign

The X-linked McLeod neuroacanthocytosis syndrome (MLS) has originally been denoted as ‘benign' McLeod myopathy. We assessed the clinical findings and the muscle pathology in the eponymous index patient, Hugh McLeod, and in nine additional MLS patients. Only one patient had manifested with neuromuscular symptoms. During a mean follow-up of 15 years, however, eight patients including the initial index patient showed elevated skeletal muscle creatine kinase levels ranging from 300 to 3000 U/L, and had developed muscle weakness and atrophy. Two patients had disabling leg weakness. Muscle histology was abnormal in all 10 patients. Clear but unspecific myopathic changes were found in only four patients. All patients, however, had neurogenic changes of variable degree. Post-mortem motor and sensory nerve examinations support the view that muscle atrophy and weakness are predominantly due to an axonal motor neuropathy rather than to a primary myopathy. Multisystem manifestations developed in eight patients at a mean age of 39 years. Three patients manifested with psychiatric features comprising schizophrenia-like psychosis and personality disorder, two presented with generalized seizures and one with chorea. During follow-up, seven patients developed chorea, six had psychiatric disorders, five had cognitive decline and three had generalized seizures. Five patients died because of MLS-related complications including sudden cardiac death, chronic heart failure and pneumonia between 55 and 69 years. In conclusion, our findings confirm that MLS is not a benign condition but rather a progressive multisystem disorder sharing many features with Huntington's diseas

Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5

Myotonic dystrophies type 1 (DM1) and type 2 (DM2) are neuromuscular diseases, caused by accumulation of CUG and CCUG RNAs in toxic aggregates. Here we report that the increased stability of the mutant RNAs in both types of DMis caused by deficiency of RNA helicase p68. We have identified p68 by studying CCUG-binding proteins associated with degradation of the mutant CCUG repeats. Protein levels of p68 are reduced in DM1 and DM2 biopsied skeletal muscle. Delivery of p68 in DM1/2 cells causes degradation of the mutant RNAs, whereas delivery of p68 in skeletal muscle of DM1 mouse model reduces skeletal muscle myopathy and atrophy. Our study shows that correction of p68 may reduce toxicity of the mutant RNAs in DM1 and in DM2

Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort

To evaluate the role of genetic variation at the locus on symptomatic diversity in 250 adult, ambulant patients with myotonic dystrophy type 1 (DM1) recruited to the Observational Prolonged Trial in Myotonic Dystrophy Type 1 to Improve Quality of Life-Standards, a Target Identification Collaboration (OPTIMISTIC) clinical trial.We used small pool PCR to correct age at sampling biases and estimate the progenitor allele CTG repeat length and somatic mutational dynamics, and AciI digests and repeat primed PCR to test for the presence of variant repeats.We confirmed disease severity is driven by progenitor allele length, is further modified by age, and, in some cases, sex, and that patients in whom the CTG repeat expands more rapidly in the soma develop symptoms earlier than predicted. We revealed a key role for variant repeats in reducing disease severity and quantified their role in delaying age at onset by approximately 13.2 years (95% confidence interval 5.7-20.7, 2-tailed test = -3.7, = 0.0019).Careful characterization of the CTG repeat to define progenitor allele length and presence of variant repeats has increased utility in understanding clinical variability in a trial cohort and provides a genetic route for defining disease-specific outcome measures, and the basis of treatment response and stratification in DM1 trials

Associations Between Variant Repeat Interruptions and Clinical Outcomes in Myotonic Dystrophy Type 1

Objective: To assess the association between variant repeat (VR) interruptions in patients with myotonic dystrophy type 1 (DM1) and clinical symptoms and outcome measures after cognitive behavioral therapy (CBT) intervention. Methods: Adult patients with DM1 were recruited within the OPTIMISTIC trial (NCT02118779). Disease-related history, current clinical symptoms and comorbidities, functional assessments, and disease- and health-related questionnaires were obtained at baseline and after 5 and 10 months. After genetic analysis, we assessed the association between the presence of VR interruptions and clinical symptoms' long-term outcomes and compared the effects of CBT in patients with and without VR interruptions. Core trial outcome measures analyzed were: 6-minute walking test, DM1-Activ-C, Checklist Individual Strength Fatigue Score, Myotonic Dystrophy Health Index, McGill-Pain questionnaire, and Beck Depression inventory—fast screen. Blood samples for DNA testing were obtained at the baseline visit for determining CTG length and detection of VR interruptions. Results: VR interruptions were detectable in 21/250 patients (8.4%)—12 were assigned to the standard-of-care group (control group) and 9 to the CBT group. Patients with VR interruptions were significantly older when the first medical problem occurred and had a significantly shorter disease duration at baseline. We found a tendency toward a milder disease severity in patients with VR interruptions, especially in ventilation status, mobility, and cardiac symptoms. Changes in clinical outcome measures after CBT were not associated with the presence of VR interruptions. Conclusions: The presence of VR interruptions is associated with a later onset of the disease and a milder phenotype. However, based on the OPTIMISTIC trial data, the presence of VR interruptions was not associated with significant changes on outcome measures after CBT intervention. Trial Registration: Information ClinicalTrials.gov NCT02118779

Scapuloperoneal syndrome type Kaeser and a wide phenotypic spectrum of adult-onset, dominant myopathies are associated with the desmin mutation R350P

In 1965, an adult-onset, autosomal dominant disorder with a peculiar scapuloperoneal distribution of weakness and atrophy was described in a large, multi-generation kindred and named ‘scapuloperoneal syndrome type Kaeser' (OMIM #181400). By genetic analysis of the original kindred, we discovered a heterozygous missense mutation of the desmin gene (R350P) cosegregating with the disorder. Moreover, we detected DES R350P in four unrelated German families allowing for genotype-phenotype correlations in a total of 15 patients carrying the same mutation. Large clinical variability was recognized, even within the same family, ranging from scapuloperoneal (n = 2, 12%), limb girdle (n = 10, 60%) and distal phenotypes (n = 3, 18%) with variable cardiac (n = 7, 41%) or respiratory involvement (n = 7, 41%). Facial weakness, dysphagia and gynaecomastia were frequent additional symptoms. Overall and within each family, affected men seemingly bear a higher risk of sudden, cardiac death as compared to affected women. Moreover, histological and immunohistochemical examination of muscle biopsy specimens revealed a wide spectrum of findings ranging from near normal or unspecific pathology to typical, myofibrillar changes with accumulation of desmin. This study reveals that the clinical and pathological variability generally observed in desminopathies may not be attributed to the nature of the DES mutation alone, but may be influenced by additional genetic and epigenetic factors such as gender. In addition, mutations of the desmin gene should be considered early in the diagnostic work-up of any adult-onset, dominant myopathy, even if specific myofibrillar pathology is absen

Towards development of a statistical framework to evaluate myotonic dystrophy type 1 mRNA biomarkers in the context of a clinical trial

Myotonic dystrophy type 1 (DM1) is a rare genetic disorder, characterised by muscular dystrophy, myotonia, and other symptoms. DM1 is caused by the expansion of a CTG repeat in the 3'-untranslated region of DMPK. Longer CTG expansions are associated with greater symptom severity and earlier age at onset. The primary mechanism of pathogenesis is thought to be mediated by a gain of function of the CUG-containing RNA, that leads to transdysregulation of RNA metabolism of many other genes. Specifically, the alternative splicing (AS) and alternative polyadenylation (APA) of many genes is known to be disrupted. In the context of clinical trials of emerging DM1 treatments, it is important to be able to objectively quantify treatment efficacy at the level of molecular biomarkers. We show how previously described candidate mRNA biomarkers can be used to model an effective reduction in CTG length, using modern high-dimensional statistics (machine learning), and a blood and muscle mRNA microarray dataset. We show how this model could be used to detect treatment effects in the context of a clinical trial

Large atom number dual-species magneto-optical trap for fermionic 6Li and 40K atoms

We present the design, implementation and characterization of a dual-species magneto-optical trap (MOT) for fermionic 6Li and 40K atoms with large atom numbers. The MOT simultaneously contains 5.2x10^9 6Li-atoms and 8.0x10^9 40K-atoms, which are continuously loaded by a Zeeman slower for 6Li and a 2D-MOT for 40K. The atom sources induce capture rates of 1.2x10^9 6Li-atoms/s and 1.4x10^9 40K-atoms/s. Trap losses due to light-induced interspecies collisions of ~65% were observed and could be minimized to ~10% by using low magnetic field gradients and low light powers in the repumping light of both atomic species. The described system represents the starting point for the production of a large-atom number quantum degenerate Fermi-Fermi mixture

104-week efficacy and safety of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease:a phase III open-label extension study (ATB200-07)

The phase III double-blind PROPEL study compared the novel two-component therapy cipaglucosidase alfa + miglustat (cipa + mig) with alglucosidase alfa + placebo (alg + pbo) in adults with late-onset Pompe disease (LOPD). This ongoing open-label extension (OLE; NCT04138277) evaluates long-term safety and efficacy of cipa + mig. Outcomes include 6-min walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. Data are reported as change from PROPEL baseline to OLE week 52 (104 weeks post-PROPEL baseline). Of 118 patients treated in the OLE, 81 continued cipa + mig treatment from PROPEL (cipa + mig group; 61 enzyme replacement therapy [ERT] experienced prior to PROPEL; 20 ERT naïve) and 37 switched from alg + pbo to cipa + mig (switch group; 29 ERT experienced; 8 ERT naive). Mean (standard deviation [SD]) change in % predicted 6MWD from baseline to week 104 was + 3.1 (8.1) for cipa + mig and − 0.5 (7.8) for the ERT-experienced switch group, and + 8.6 (8.6) for cipa + mig and + 8.9 (11.7) for the ERT-naïve switch group. Mean (SD) change in % predicted FVC was − 0.6 (7.5) for cipa + mig and − 3.8 (6.2) for the ERT-experienced switch group, and − 4.8 (6.5) and − 3.1 (6.7), respectively, in ERT-naïve patients. CK and Hex4 levels improved in both treatment groups by week 104 with cipa + mig treatment. Three patients discontinued the OLE due to infusion-associated reactions. No new safety signals were identified. Cipa + mig treatment up to 104 weeks was associated with overall maintained improvements (6MWD, biomarkers) or stabilization (FVC) from baseline with continued durability, and was well tolerated, supporting long-term benefits for patients with LOPD. Trial registration number: NCT04138277; trial start date: December 18, 2019.</p

New insights into the protein aggregation pathology in myotilinopathy by combined proteomic and immunolocalization analyses

Introduction: Myofibrillar myopathies are characterized by progressive muscle weakness and impressive abnormal protein aggregation in muscle fibers. In about 10 % of patients, the disease is caused by mutations in the MYOT gene encoding myotilin. The aim of our study was to decipher the composition of protein deposits in myotilinopathy to get new information about aggregate pathology. Results: Skeletal muscle samples from 15 myotilinopathy patients were included in the study. Aggregate and control samples were collected from muscle sections by laser microdissection and subsequently analyzed by a highly sensitive proteomic approach that enables a relative protein quantification. In total 1002 different proteins were detected. Seventy-six proteins showed a significant over-representation in aggregate samples including 66 newly identified aggregate proteins. Z-disc-associated proteins were the most abundant aggregate components, followed by sarcolemmal and extracellular matrix proteins, proteins involved in protein quality control and degradation, and proteins with a function in actin dynamics or cytoskeletal transport. Forty over-represented proteins were evaluated by immunolocalization studies. These analyses validated our mass spectrometric data and revealed different regions of protein accumulation in abnormal muscle fibers. Comparison of data from our proteomic analysis in myotilinopathy with findings in other myofibrillar myopathy subtypes indicates a characteristic basic pattern of aggregate composition and resulted in identification of a highly sensitive and specific diagnostic marker for myotilinopathy. Conclusions: Our findings i) indicate that main protein components of aggregates belong to a network of interacting proteins, ii) provide new insights into the complex regulation of protein degradation in myotilinopathy that may be relevant for new treatment strategies, iii) imply a combination of a toxic gain-of-function leading to myotilin-positive protein aggregates and a loss-of-function caused by a shift in subcellular distribution with a deficiency of myotilin at Z-discs that impairs the integrity of myofibrils, and iv) demonstrate that proteomic analysis can be helpful in differential diagnosis of protein aggregate myopathies

New insights into the protein aggregation pathology in myotilinopathy by combined proteomic and immunolocalization analyses

Introduction: Myofibrillar myopathies are characterized by progressive muscle weakness and impressive abnormal protein aggregation in muscle fibers. In about 10 % of patients, the disease is caused by mutations in the MYOT gene encoding myotilin. The aim of our study was to decipher the composition of protein deposits in myotilinopathy to get new information about aggregate pathology. Results: Skeletal muscle samples from 15 myotilinopathy patients were included in the study. Aggregate and control samples were collected from muscle sections by laser microdissection and subsequently analyzed by a highly sensitive proteomic approach that enables a relative protein quantification. In total 1002 different proteins were detected. Seventy-six proteins showed a significant over-representation in aggregate samples including 66 newly identified aggregate proteins. Z-disc-associated proteins were the most abundant aggregate components, followed by sarcolemmal and extracellular matrix proteins, proteins involved in protein quality control and degradation, and proteins with a function in actin dynamics or cytoskeletal transport. Forty over-represented proteins were evaluated by immunolocalization studies. These analyses validated our mass spectrometric data and revealed different regions of protein accumulation in abnormal muscle fibers. Comparison of data from our proteomic analysis in myotilinopathy with findings in other myofibrillar myopathy subtypes indicates a characteristic basic pattern of aggregate composition and resulted in identification of a highly sensitive and specific diagnostic marker for myotilinopathy. Conclusions: Our findings i) indicate that main protein components of aggregates belong to a network of interacting proteins, ii) provide new insights into the complex regulation of protein degradation in myotilinopathy that may be relevant for new treatment strategies, iii) imply a combination of a toxic gain-of-function leading to myotilin-positive protein aggregates and a loss-of-function caused by a shift in subcellular distribution with a deficiency of myotilin at Z-discs that impairs the integrity of myofibrils, and iv) demonstrate that proteomic analysis can be helpful in differential diagnosis of protein aggregate myopathies