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Background and Purpose: This study was undertaken to examine vestibulo-ocular reflex (VOR) characteristics in myotonic dystrophy type 1 (DM1) and type 2 (DM2) using video head impulse testing (vHIT)., Methods: VOR gain, refixation saccade prevalence, first saccade amplitude, onset latency, peak velocity, and duration were compared in DM1, DM2, age-matched normal controls, and patients with peripheral and central vestibulopathies., Results: Fifty percent of DM1 and 37.5% of DM2 patients demonstrated reduced VOR gain. Refixation saccade prevalence for horizontal canal (HC) and posterior canal (PC) was significantly higher in DM1 (101 ± 42%, 82 ± 47%) and DM2 (70 ± 45%, 61 ± 38%) compared to controls (40 ± 28% and 43 ± 33%, p < 0.05). The first saccade amplitudes and peak velocities were higher in HC and PC planes in DM1 and DM2 compared to controls (p < 0.05). HC slow phase eye velocity profiles in DM1 showed delayed peaks. The asymmetry ratio, which represents the percentage difference between the first and second halves of the slow phase eye velocity response, was therefore negative (-22.5 ± 17%, -2.3 ± 16%, and - 4.7 ± 8% in DM1, DM2, and controls). HC VOR gains were lower and gain asymmetry ratio was larger and negative in patients with DM1 with moderate to severe ptosis and a history of imbalance and falls compared to the remaining DM1 patients (p < 0.05). In peripheral vestibulopathies, saccade amplitude was larger, peak velocity was higher, and onset latency was shorter (p < 0.05) than in DM1. In central vestibulopathy (posterior circulation strokes), saccade peak velocity was higher, but amplitude and onset latency were not significantly different from DM1., Conclusions: VOR impairment is common in DM1 and DM2. In DM1, refixation saccade characteristics are closer to central than peripheral vestibulopathies. Delayed peaks in the vHIT eye velocity profile observed in patients with DM1 may reflect extraocular muscle weakness. VOR impairment and VOR asymmetry in DM1 are associated with imbalance and falls., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: Myotonic dystrophy type 1 (DM1) is the most prevalent muscular dystrophy in adults. People with DM1 might represent a high-risk population for respiratory infections, including COVID-19. Our aim was to evaluate the characteristics of COVID-19 infection and vaccination rate in DM1 patients., Methods: This cross-sectional cohort study included 89 patients from the Serbian registry for myotonic dystrophies. Mean age at testing was 48.4 ± 10.4 years with 41 (46.1%) male patients. Mean duration of the disease was 24.0 ± 10.3 years., Results: COVID-19 infection was reported by 36 (40.4%) DM1 patients. Around 14% of patients had a more severe form of COVID-19 requiring hospitalization. The severity of COVID-19 was in accordance with the duration of DM1. A severe form of COVID-19 was reported in 20.8% of patients who were not vaccinated against SARS-CoV-2 and in none of the vaccinated ones. The majority of 89 tested patients (66.3%) were vaccinated against SARS-CoV-2. About half of them (54.2%) received three doses and 35.6% two doses of vaccine. Mild adverse events after vaccination were recorded in 20.3% of patients., Conclusions: The percentage of DM1 patients who suffered from COVID-19 was like in general population, but with more severe forms in DM1, especially in patients with longer DM1 duration. The study indicated an overall favorable safety profile of COVID-19 vaccines among individuals with DM1 and its ability to protect them from severe COVID-19., (© 2023. The Author(s).)

Introduction: Myotonic dystrophy type 2 (DM2) is a rare, multisystemic, autosomal dominant disease with highly variable clinical presentation. DM2 is considered to be highly underdiagnosed., Objective: The aim of this study was to determine which symptoms, signs, and diagnostic findings in patients referred to neurological outpatient units are the most indicative to arouse suspicion of DM2. We tried to make a useful and easy-to-administer clinical scoring system for early diagnosis of DM2-DM2 early diagnosis score (DM2-EDS)., Patients and Methods: Two hundred ninety-one patients with a clinical suspicion of DM2 were included: 69 were genetically confirmed to have DM2, and 222 patients were DM2 negative. Relevant history, neurological, and paraclinical data were obtained from the electronic medical records., Results: The following parameters appeared as significant predictors of DM2 diagnosis: cataracts (beta = 0.410, p < 0.001), myotonia on needle EMG (beta = 0.298, p < 0.001), hand tremor (beta = 0.211, p = 0.001), positive family history (beta = 0.171, p = 0.012), and calf hypertrophy (beta = 0.120, p = 0.043). In the final DM2-EDS, based on the beta values, symptoms were associated with the following values: cataracts (present 3.4, absent 0), myotonia (present 2.5, absent 0), tremor (present 1.7, absent 0), family history (positive 1.4, negative 0), and calf hypertrophy (present 1.0, absent 0). A cut-off value on DM2-EDS of 3.25 of maximum 10 points had a sensitivity of 84% and specificity of 81% to diagnose DM2., Conclusion: Significant predictors of DM2 diagnosis in the neurology outpatient unit were identified. We made an easy-to-administer DM2-EDS score for early diagnosis of DM2., (© 2022. The Author(s).)

Myotonic dystrophy type 2 (DM2) is an autosomal dominant multisystemic disorder. Previous studies conducted on small cohorts of DM2 patients indicated presence of a cognitive dysfunction. We aimed to assess cognitive functions in a larger cohort of Serbian DM2 patients using an extensive battery of neuropsychological tests. The study included 76 patients with a genetically confirmed DM2, 68 of whom had all tests for different cognitive domains performed. Patients underwent clinical and neuropsychological testing, including cognitive screening and assessment of general intellectual level, attention, executive and visuospatial abilities, memory, and language functions. Only 6% of patients achieved a below-average score on the general intellectual level test. Cognitive screening tests indicated presence of cognitive deficits in 5.5% of patients according to the Mini Mental State Examination test and 25.8% according to the Addenbrooke's Cognitive Examination Revised test. Twenty-four (35.3%) patients had a cognitive impairment (being two standard deviations out of norm in at least two cognitive domains). Around one quarter of DM2 patients had a significant cognitive impairment that interfered with their everyday functioning. Patients with significant cognitive impairment were older at testing and at disease onset, less educated, and had more severe muscle weakness., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Myotonic dystrophy type 1 (DM1) is one of the most variable monogenic diseases at phenotypic, genetic, and epigenetic level. The disease is multi-systemic with the age at onset ranging from birth to late age. The underlying mutation is an unstable expansion of CTG repeats in the DMPK gene, varying in size from 50 to >1000 repeats. Generally, large expansions are associated with an earlier age at onset. Additionally, the most severe, congenital DM1 form is typically associated with local DNA methylation. Genetic variability of DM1 mutation is further increased by its structural variations due to presence of other repeats (e.g., CCG, CTC, CAG). These variant repeats or repeat interruptions seem to confer an additional level of epigenetic variability since local DNA methylation is frequently associated with variant CCG repeats independently of the expansion size. The effect of repeat interruptions on DM1 molecular pathogenesis is not investigated enough. Studies on patients indicate their stabilizing effect on DMPK expansions because no congenital cases were described in patients with repeat interruptions, and the age at onset is frequently later than expected. Here, we review the clinical relevance of repeat interruptions in DM1 and genetic and epigenetic characteristics of interrupted DMPK expansions based on patient studies.

Myotonic dystrophy type 2 (DM2) is an autosomal dominant multisystemic disorder caused by CCTG repeats expansion in the first intron of the CNBP gene. In this review we focus on the brain involvement in DM2, including its pathogenic mechanisms, microstructural, macrostructural and functional brain changes, as well as the effects of all these impairments on patients' everyday life. We also try to understand how brain abnormalities in DM2 should be adequately measured and potentially treated. The most important pathogenetic mechanisms in DM2 are RNA gain-of-function and repeat-associated non-ATG (RAN) translation. One of the main neuroimaging findings in DM2 is the presence of diffuse periventricular white matter hyperintensity lesions (WMHLs). Brain atrophy has been described in DM2 patients, but it is not clear if it is mostly caused by a decrease of the white or gray matter volume. The most commonly reported specific cognitive symptoms in DM2 are dysexecutive syndrome, visuospatial and memory impairments. Fatigue, sleep-related disorders and pain are also frequent in DM2. The majority of key symptoms and signs in DM2 has a great influence on patients' daily lives, their psychological status, economic situation and quality of life., Competing Interests: Declaration of Competing Interest All authors report no conflict of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: To date, there are only several reports on body composition in myotonic dystrophy type 1 (DM1) and there are no data for myotonic dystrophy type 2 (DM2). The aim was to analyze body composition of patients with DM1 and DM2, and its association with socio-demographic and clinical features of the diseases., Methods: There were no statistical differences in sociodemographic features between 20 DM1 patients and 12 DM2 patients. Body composition was assessed by DEXA (dual-energy x-ray absorptiometry). A three-compartment model was used: bone mineral content (BMC), fat mass (FM), and lean tissue mass (LTM)., Results: Patients with DM1 and DM2 had similar total body mass (TBM), BMC, FM, and LTM. Patients with DM1 had higher trunk-limb fat index (TLFI) in comparison to DM2 patients which indicates visceral fat deposition in DM1 (1.16 ± 0.32 for DM1 vs. 0.87 ± 0.23 for DM2, p < 0.05). Right ribs bone mineral density was lower in DM2 group (0.68 ± 0.07 g/cm 2 vs. 0.61 ± 0.09 g/cm 2 , p < 0.05). Higher percentage of FM in legs showed correlation with lower strength of the upper leg muscles in DM1 (ρ = - 0.47, p < 0.05). Higher muscle strength in DM2 patients was in correlation with higher bone mineral density (ρ = + 0.62, p < 0.05 for upper arm muscles, ρ = + 0.87, p < 0.01 for lower arm muscles, ρ = + 0.72, p < 0.05 for lower leg muscles)., Conclusion: DM1 patients had visceral obesity, and percentage of FM correlated with a degree of muscle weakness in upper legs. In DM2 patients, degree of muscle weakness was in correlation with higher FM index and lower bone mineral density.

Myotonic dystrophy type 2 (DM2) is a slowly progressive, autosomal-dominant disease. This is a multisystemic disorder that affects the heart, which is one of the main causes of morbidity and mortality in DM2. The aim of the study was to define cardiac impairments in patients with DM2 and its association with sociodemographic and clinical features of patients. This retrospective study comprised 62 adult patients with DM2 hospitalized at the Neurology Clinic, Clinical Center of Serbia from 2013 until 2018, who underwent electrocardiography (ECG) and echocardiography examinations. Hypertension was observed in 42% of DM2 patients. One-fifth of DM2 patients had bradycardia, while other conduction and rhythm impairments were rare. Only one patient had a pacemaker implanted because of the first degree AV block associated with incomplete left bundle branch block. Echocardiography showed diastolic dysfunction of the left ventricle in 44% of patients, while systolic dysfunction was found in only 4%. Cardiomyopathy was observed in 18% of patients, of whom three-fourth had dilated type. Cardiac conduction and rhythm defects are relatively rare in DM2, while diastolic dysfunction is common. This suggests that regular ECG and echocardiography screening is needed in DM2. Adequate therapy should be introduced in patients with DM2 on time to reduce the frequency of heart complications and to prevent premature death.

Objectives: metabolic syndrome (MetS) increases risk of cardiovascular diseases and diabetes mellitus type 2. Aim of this study was to investigate frequency and features of MetS in a large cohort of patients with DM2., Materials & Methods: this cross-sectional study included 47 DM2 patients. Patients were matched with 94 healthy controls (HCs) for gender and age. MetS was diagnosed according to the new worldwide consensus criteria from 2009., Results: mean age of DM2 patients was 52 ± 11 years, 15 (32%) were males, and mean disease duration was 15 ± 14 years. MetS was present in 53% of DM2 patients and 46% of HCs (p > 0.05). All components of the MetS appeared with the similar frequency in DM2 and HCs, respectively: hypertension 64 vs 52%, central obesity 62 vs 74%, hypertriglyceridemia 49 vs 39%, hyperglycemia 42 vs 33% and low HDL cholesterol 30 vs 42% (p > 0.05). DM2 patients were more commonly on lipid lowering therapy compared to HCs (12 vs 3%, p = 0.05). Fifteen (32%) patients with DM2 and only one (1%) subject from control group had diabetes mellitus (p < 0.01). Insulin resistance was found in thirty (65%) patients with DM2. Presence of MetS was not associated with patient's gender, age, severity nor duration of the disease (p > 0.05)., Conclusions: more than half of DM2 subjects met the criteria for the MetS. We suppose that treatment of metabolic disturbances may reduce cardiovascular complications and improve quality of life in patients with DM2, which is progressive and still incurable disorder.

Background: Myotonic Dystrophy is the most common form of muscular dystrophy in adults, affecting an estimated 10 per 100,000 people. It is a multisystemic disorder affecting multiple generations with increasing severity. There are currently no licenced therapies to reverse, slow down or cure its symptoms. In 2009 TREAT-NMD (a global alliance with the mission of improving trial readiness for neuromuscular diseases) and the Marigold Foundation held a workshop of key opinion leaders to agree a minimal dataset for patient registries in myotonic dystrophy. Eight years after this workshop, we surveyed 22 registries collecting information on myotonic dystrophy patients to assess the proliferation and utility the dataset agreed in 2009. These registries represent over 10,000 myotonic dystrophy patients worldwide (Europe, North America, Asia and Oceania)., Results: The registries use a variety of data collection methods (e.g. online patient surveys or clinician led) and have a variety of budgets (from being run by volunteers to annual budgets over €200,000). All registries collect at least some of the originally agreed data items, and a number of additional items have been suggested in particular items on cognitive impact., Conclusions: The community should consider how to maximise this collective resource in future therapeutic programmes.

Background: Myotonic dystrophy type 2 (DM2) is a multisystem disorder, mostly presented with mild but heterogeneous spectrum of symptoms., Objective: The aim of this research was to provide detailed sociodemographic, clinical and laboratory data of a large DM2 cohort from the Serbian registry., Methods: In 2008, we started to prospectively enter data of all DM patients. We also retrospectively collected data of patients hospitalized from 1990 until 2008., Results: At the end of 2017, registry comprised 87 (68%) of 128 genetically confirmed DM2 patients in Serbia, i.e. 1.2 registered cases per 100,000 inhabitants. Female subjects were more prevalent (63%). The diagnostic delay was 11.8±11.3 years. The most common first symptoms in our patients were lower limb weakness, handgrip myotonia and limb pain, although some percentage of patients presented with cataracts or extrapyramidal symptoms and signs. Lens opacities were present in 75% of patients. Severe ECG abnormalities were noted in 8% and pacemaker was implanted in 5% of DM2 subjects. Pulmonary restriction was observed in 10% of DM2 patients. Insulin resistance and diabetes mellitus were frequent in our cohort (21% and 17%, respectively). Male subjects more frequently had snoring, baldness, sterility, polyneuropathy, lower HDL and higher glycaemia, while waddling gait and increased muscle reflexes were more common in females., Conclusions: This registry offers a spectrum of different features presented in Serbian DM2 population, which could be at service of earlier diagnosis and better treatment.

Introduction: Generic patient reported outcome measures have had varied success in tracking QoL in myotonic dystrophy type 1 (DM1)., Aim: To analyze changes of Individualized Neuromuscular Quality of Life questionnaire (INQoL) scores in clinic patients with DM1 over a 6-year period., Method: Patients completed the INQoL at baseline and after a 6-year period through their attendance in a neurology outpatient clinic. Severity of muscular involvement in DM1 was analyzed using the Muscular Impairment Rating Scale (MIRS)., Results: Ninety-nine DM1 patients completed a baseline visit. Sixty-seven of these patients were retested at an interval time. The overall INQoL score improved in our sample of patients (P<.05) as did the following subscales: myotonia (P<.05), pain (P<.05), activities (P<.01), social relationships (P<.01), and body image (P<.05). No changes were observed for the independence and emotions scales. There were no differences in mean change of INQoL scores between patients with worsened MIRS and those with no change in MIRS scale after follow-up (P>.05)., Conclusion: Individualized Neuromuscular Quality of Life questionnaire scores improved in our cohort of DM1 patients during a 6-year period. INQoL score did not correlate with progression of muscle weakness. This must be better understood before the selection of the instrument for use in trials to measure therapeutic benefit in DM1 patients., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Magnetic resonance imaging (MRI) of muscles has recently become a significant diagnostic procedure in neuromuscular disorders. There is a lack of muscle MRI studies in patients with myotonic dystrophy type 1 (DM1), especially type 2 (DM2). To analyze fatty infiltration of leg muscles, using 3.0 T MRI in patients with genetically confirmed DM1 and DM2 with different disease durations. The study comprised 21 DM1 and 10 DM2 adult patients. Muscle MRI was performed in axial plane of the lower limbs using T1-weighted (T1w) sequence. Six-point scale by Mercuri et al. was used. Fatty infiltration registered in at least one muscle of lower extremities was found in 71% of DM1 and 40% of DM2 patients. In DM1 patients, early involvement of the medial head of gastrocnemius and tibialis anterior muscles was observed with later involvement of other lower leg muscles and of anterior and posterior thigh compartments with relative sparing of the rectus femoris. In DM2, majority of patients had normal MRI findings. Early involvement of lower legs and posterior thighs was found in some patients. Less severe involvement of the medial head of the gastrocnemius compared to other lower leg muscles was also observed, while involvement of proximal muscles was rather diffuse than selective. It seems that both in DM1 and DM2 some muscles may be affected before weakness is clinically noted and vice versa. We described characteristic pattern and way of progression of muscle involvement in DM1 and DM2.

Aim: To determine regions of reduced brain metabolism in patients with myotonic dystrophy type 1 (DM1) and type 2 (DM2) using 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), and to analyse their potential association with cognitive deficit., Method: Study included 29 patients (16 DM1 and 13 DM2). FDG-PET and detailed neuropsychological testing were performed in both groups., Results: The most common cognitive findings were executive, visuospatial, and naming dysfunction in DM1, and executive and naming dysfunction in DM2. FDG-PET showed the most prominent glucose hypometabolism in prefrontal, temporal, and pericentral regions in both DM1 and DM2 patients, with additional affection of insula and subcortical grey matter in DM2. In DM1 patients, we found association between right frontotemporal hypometabolism and executive dysfunction (p<0.05). In DM2 patients attention deficit was in association with prefrontal, insular, and striatal hypometabolism, as well as right frontotemporal hypometabolism (p<0.05). Executive dysfunction in DM2 was more common in patients with prefrontal and insular hypometabolism, right parietotemporal and frontotemporal hypometabolism, as well as left striatal hypometabolism (p<0.05). Patients with parietotemporal defect on FDG-PET were more likely to have naming dysfunction (p<0.01)., Conclusion: FDG-PET findings corresponded well with the results of neuropsychological testing. FDG-PET may be a good biomarker of central nervous system involvement in DM1 and DM2, but this hypothesis will have to be more strongly supported by larger studies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Myotonic dystrophy type 1 (DM1) is an autosomal-dominant disease. One third of DM1 patients die suddenly, most of them due to the heart conduction abnormalities and arrhythmias. The aim of this study was to analyze echocardiographic findings in a large cohort of DM1 patients., Methods: This retrospective study comprised 111 patients and 71 healthy controls (HCs) matched for gender and age., Results: Mitral valve (MV) prolapse was observed in 23% of our DM1 patients vs. 8.5% of HCs (p < 0.05). Left ventricle (LV) systolic dysfunction was observed in 6% of patients and none of the HCs (p < 0.05). Frequency of diastolic dysfunction showed no significant difference between DM1 patients and HCs (8.1% vs. 15.5%, p > 0.05). Systolic dysfunction was more common in patients with severe electrocardiographic (ECG) abnormality (18.8% vs. 2.7%, p < 0.01)., Conclusion: One fourth of DM1 patients have MV prolapse. Approximately 15% of DM1 patients have systolic or diastolic LV dysfunction. These patients should have benefit from medical therapy. Furthermore, it seems that treatment of conduction defects might prevent development of the heart failure (HF)., (Copyright © 2017. Published by Elsevier Taiwan LLC.)

Neuropsychological examinations in myotonic dystrophy (DM) patients show a great variability of results from a condition of intellectual disability to the subtle cognitive impairments. It is unclear if different clusters of neuropsychological deficits appear in different phenotypes of DM, or if there are patients with no cognitive deficit at all. The aim of this study is to assess cognitive impairments among patients with different phenotypes of DM type 1 (DM1) and type 2 (DM2), and to potentially define cognitive clusters in these disorders. Study comprised 101 DM1 and 46 DM2 adult patients who were genetically confirmed. Patients underwent analysis of five cognitive domains (visuospatial, executive, attention, memory and language). Virtually all DM1 patients had cognitive defect with approximately 2-3 cognitive domains affected. On the other hand, one-third of DM2 patients had completely normal neuropsychological findings, and in other two-thirds approximately 1-2 domains were affected. Cluster analysis showed that in both diseases visuospatial and executive dysfunctions seemed to be the main cognitive defects, while memory and language impairments appeared in more severe phenotypes. Our results showed that a single form of DM1 or DM2 may consist of several cognitive clusters. Understanding of cognitive impairments in DM is very important to follow positive and side effects in ongoing and future clinical trials.

Myotonic dystrophy type 2 (DM2) is a multisystem disorder that affects many organs and systems, including the brain. The objective is to analyze personality patterns in myotonic dystrophy type 2 (DM2) compared to DM1 control group. The study comprised 27 consecutive genetically confirmed DM2 patients and control group of 44 DM1 patients. Personality traits were assessed with the Millon Multiaxial Clinical Inventory III (MMCI III). In DM2 group there were no scale with pathological scores, although compulsive and paranoid traits were the most prominent. DM2 patients had lower scores compared to DM1 patients in almost all scales. Pathological scores on clinical symptom scales were not observed, although anxiety scale almost approached this value. Patients with higher compulsive score had higher level of education (rho = +0.53, p < 0.01). On the other hand, higher paranoid score correlated with younger age at onset (rho = -0.34, p < 0.01) and lower educational level (rho = -0.26, p < 0.05). Our results did not show significant personality impairments in patients with DM2. However, following personality traits were predominant: compulsive (in patients with higher education) and paranoid (in patients with lower education and earlier age at onset). The most common clinical symptoms were anxiety and somatization.

Introduction: The aim of this study was to present a family co-segregating myotonic dystrophy type 1 (DM1) and 2 (DM2), and one member affected with neuromyelitis optica (NMO)., Case Report: Index case underwent cataract surgery at age 39. Although she had no muscle symptoms, genetic testing revealed a DM2 mutation and a DM1 protomutation. The patient noticed difficulties in climbing stairs at age 47. Clinical examination showed mild muscle weakness, calf hypertrophy, mild myotonia and several multisystem signs. Patient's mother had DM1 protomutation and clinically exhibited only cataract. Two proband's sisters, one with DM2 mutation and another with DM2 mutation and DM1 protomutation, had a clinical presentation similar to the index case. In addition, the latter also developed NMO., Conclusion: Our findings suggest that screening for both DM1 and DM2 should be done and a positive result in either gene should not be an indication to stop screening, but to move to the other gene.

Background - Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. There is a complete lack of studies that assessed quality of life (QoL) trajectory during time in DM1 cohorts. Aim - To analyze changes of QoL in patients with DM1 during a 5-year follow-up period and to assess responsiveness of the SF-36 questionnaire. Patients and Method - At the baseline, this study comprised 84 DM1 patients, of whom 62 were retested after the mean period of 64.2 ± 3.9 months. Severity of muscular weakness was assessed using the Muscular Impairment Rating Scale (MIRS). Patients completed Serbian version of the SF-36 questionnaire as a measure of health-related QoL. Results - After 5 years, MIRS score of our DM1 patients showed significant progression of 0.5 grade (P < 0.01). All mental subdomains, role physical, and total SF-36 scores significantly improved after 5 years (P < 0.01). Unexpectedly, worsening of muscular weakness from mild to severe was in association with improvement of QoL. Conclusion - QoL improved in our cohort of DM1 patients during a 5-year period despite the progression of the disease. SF-36 should be used with caution as a patient-reported outcome measure in DM1 clinical trials., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To analyze quality of life (QoL) in a large cohort of myotonic dystrophy type 2 (DM2) patients in comparison to DM1 control group using both generic and disease specific questionnaires. In addition, we intended to identify different factors that might affect QoL of DM2 subjects., Patients and Method: 49 DM2 patients were compared with 42 adult-onset DM1 patients. Patients completed SF-36 questionnaire and individualized neuromuscular quality of life questionnaire (INQoL). Following measures were also included: Medical Research Council 0-5 point scale for muscle strength, Addenbrooke's cognitive examination revised for cognitive status, Hamilton rating scale for depression, Krupp's fatigue severity scale and daytime sleepiness scale (DSS) RESULTS: SF-36 total score and physical composite score did not differ between DM1 and DM2 patients (p>0.05). However, role emotional and mental composite score were better in DM2 (p<0.05). INQoL total score was similar in both groups (p>0.05), although DM2 patients showed less impairment in independence (p<0.05) and body image domains (p<0.01). Regarding symptoms assessed by INQoL, DM2 patients showed less severe complaint of myotonia (p<0.01). Multiple linear regression analysis showed that significant predictors of worse QoL in DM2 patients were older age, worse muscle strength and higher level of fatigue., Conclusion: QoL reports of DM2 patients with the most severe form of the disease are comparable to those of DM1 patients. Special attention of clinicians should be paid to DM2 patients with older age, more severe muscle weakness and higher level of fatigue since they may be at higher risk to have worse QoL., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: The aim of this study was to analyze transcranial sonography (TCS) findings in genetically confirmed myotonic dystrophy type 2 (DM2) patients., Methods: Forty DM2 patients and 38 gender- and age-matched healthy controls (HCs) underwent TCS through the pre-auricular acoustic bone window., Results: Substantia nigra hyperechogenicity was found in 20% of DM2 patients compared with 3% of HCs. Brainstem raphe (BR) hypoechogenicity was more common in DM2 patients compared with HCs (56% vs. 10%, P < 0.01), and it was more common in patients with fatigue and excessive daytime sleepiness (P < 0.05). Diameter of the third ventricle was increased in DM2 patients compared with HCs (5.8 ± 1.7 vs. 5.1 ± 1.0 mm, P < 0.05)., Conclusions: Finding BR hypoechogenicity might have clinical implication because of the potential response to serotonin-reuptake inhibitors. TCS revealed alterations in brain structures previously not seen in MRI studies., (© 2015 Wiley Periodicals, Inc.)

To analyze the frequency and intensity of pain and its association with different characteristics of patients with myotonic dystrophy type 1 (DM1) and type 2 (DM2), 52 adult genetically confirmed DM1 and 44 DM2 patients completed the Brief Pain Inventory questionnaire (BPI). Frequency and average intensity of pain on numerical rating scale (0-10) were similar in DM1 and DM2 (88% vs. 86% and 4.6 ± 2.3 vs. 4.2 ± 1.8, respectively, p > 0.05). In DM1, average pain intensity showed strong association with longer duration of disease and inverse relation with cognition. In DM2, average pain intensity showed association with female gender and emotions. Average pain intensity correlated with Individualized Neuromuscular Quality of Life (INQoL) total score in both DM1 (rho = +0.30, p < 0.05) and DM2 patients (rho = +0.61, p < 0.01). In conclusion, the majority of DM1 and DM2 patients have mild to moderate pain. Our results open new opportunities for behavioral and cognitive interventions.

Background: Myotonic dystrophy type 1 (DM1) is a rare disease. Creating registry for such a disease is of outstanding importance since it provides us with a full spectrum of the disorder., Aim: To assess variability of different multisystemic features in a large cohort of patients with DM1., Patients and Method: Data from the Serbian registry for myotonic dystrophies were used in the study. Final number of included DM1 subjects was 275., Results: Registry included 53.8% of male patients. Age at enrollment was 47.2 ± 9.9 years, mean disease duration 20.4 ± 9.9 years, and mean CTG repeats number 598.3 ± 269.8.Progression of muscle weakness was pretty slow, slower in proximal than distal muscles, and slower in arms than in legs. Severe ECG abnormality was found in 25.0% of patients and pacemaker was implanted in 9.5%. Lens opacities were observed in 83.5% of DM1 patients and 35.3% had ocular hypotony. Metabolic disturbances were very common, while 19.5% of patients had hypokalemia and 37.8% hypochloremia. Sterility was found in 20.5% of males and 4.1% of females. Cholelithiasis was found in 36.4% of patients and constipation in 29.9%., Conclusions: We defined the most common characteristics of our DM1 patients and observed some treatable symptoms that have been neglected previously. Certain findings deserve further investigations in terms of their causes and consequences. Besides this, presented data analysis directs us to make further improvements of the registry.

Introduction: The aim of this study was to assess the frequency and features of metabolic syndrome (MetS) in myotonic dystrophy type 1 (DM1)., Methods: We studied 66 DM1 patients (50% men, aged 41.9 ± 10.5 years, disease duration of 19.3 ± 8.6 years). New worldwide consensus criteria for MetS from 2009 were used., Results: Components of MetS were present at the following frequencies: hypertriglyceridemia 67%; low HDL cholesterol 35%; hypertension 18%; central obesity 14%; and hyperglycemia 9%. MetS was present in 11 (17%) patients. The presence of MetS was not associated with patients' gender, age, disease severity, disease duration, or CTG repeat length (P > 0.05). Patients with MetS had significantly lower total SF-36 scores as a measure of quality of life in comparison to patients without MetS (P < 0.05)., Conclusion: Although certain components of MetS were very frequent in patients with DM1, only 17% met the criteria for MetS., (© 2014 Wiley Periodicals, Inc.)

The aim of this study was to assess cognitive status in a large group of patients with myotonic dystrophy type 2 (DM2) compared to type 1 (DM1) subjects matched for gender and age, using a comprehensive battery of neuropsychological tests. Thirty-four genetically confirmed adult DM2 patients were recruited and matched for gender and age with 34 adult-onset DM1 subjects. All patients underwent detailed classic pen and pencil neuropsychological investigation and also computerized automated battery-CANTAB. More than half of DM2 patients had abnormal results on executive tests [Intra/Extradimensional Set Shift (IED), Stockings of Cambridge (SOC)] and verbal episodic memory (Ray Auditory Verbal Learning Test). Regarding DM1, abnormal results in more than 50 % of subjects were achieved in even ten tests, including visuospatial, language, executive, cognitive screening and visual memory tests. Direct comparison between patient groups showed that lower percentage of DM2 patients had abnormal results on following tests: Addenbrooke's Cognitive Examination-Revised, Raven Standard Progressive Matrices, Block Design, copy and recall of Rey-Osterieth Complex Figure, number of categories and perseverative responses on Wisconsin Card Sorting Test and Boston Naming Test (p < 0.01), as well as Trail Making Test-B and Spatial Span (p < 0.05). Our results showed significant dysexecutive syndrome and certain impairment of episodic verbal memory in DM2 patients that are reflective of frontal (especially frontostriatal) and temporal lobe dysfunction. On the other hand, dysexecutive and visuospatial/visuoconstructional deficits predominate in DM1 which correspond to the frontal, parietal (and occipital) lobe dysfunction.

Objective: To assess an impact of cognitive and behavioral impairment on QoL in a larger cohort of patients with DM1., Methods: Sixty six genetically confirmed DM1 patients (22 with juvenile (jDM1) and 44 with adult form (aDM1) of the disease) were recruited. Following behavioral tests were used: Hamilton scales for depression and anxiety (HamD and HamA), Daytime Sleepiness Scale (DSS), and Krupp's Fatigue Severity Scale (FSS). Patients also underwent detailed classic neuropsychological investigation and Cambridge Neuropsychological Test Automated Battery (CANTAB). Individualized Neuromuscular Quality of Life questionnaire (INQoL) was used as a measure of QoL., Results: Patients with jDM1 scored lower than aDM1 patients regarding total INQoL score and all INQoL subdomains, except for myotonia. Significant predictors of total INQoL score in patients with jDM1 were severity of fatigue (β=+0.60, p<0.01) and percentage of correct responses on Spatial Recognition Memory test from CANTAB that measures visuospatial abilities (β=-0.38, p<0.05). The most important predictors of total INQoL score in patients with aDM1 were severity of fatigue (β=+0.36, p<0.05) and level of education (β=-0.29, p<0.05)., Conclusion: Our results showed clear influence of different central manifestations on QoL in patients with both aDM1 and jDM1., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Introduction: In this study we analyzed transcranial sonography (TCS) in patients with myotonic dystrophy type 1 (DM1)., Methods: This cross-sectional study included 66 DM1 patients and 55 matched healthy controls (HCs). Echogenicity of the brainstem raphe (BR) and substantia nigra (SN) and third ventricle width (DTV) were assessed by TCS., Results: BR hypoechogenicity was more common in DM1 patients than in HCs (37.7% vs. 7.8%, P < 0.01). Patients with depression or fatigue were more likely to have BR hypoechogenicity (80.0% vs. 29.4%, P < 0.01 and 51.9% vs. 24.2%, P < 0.05, respectively). Both hypoechogenicity and hyperechogenicity of SN were more frequent in DM1 patients than in controls (26.2% vs. 10.9% and 13.1% vs. 1.8%, respectively, P < 0.01). DTV was increased in DM1 patients compared with HCs (6.0 ± 1.4 vs. 4.9 ± 0.9 mm, P < 0.01)., Conclusion: TCS can offer new insight into structural changes of several cerebral areas in patients with DM1., (Copyright © 2014 Wiley Periodicals, Inc.)

Objectives: To analyze frequency and type of personality pattern in patients with myotonic dystrophy type 1 (DM1), to correlate these findings with clinical data, and to assess its possible influence on quality of life (QoL)., Materials and Methods: This cross-sectional study comprised 62 patients with DM1. Following measures were used: Muscular Impairment Rating Scale, Raven's Standard Progressive Matrices (RSPM), Millon Multiaxial Clinical Inventory I (MMCI), SF-36, and Individualized Neuromuscular Quality of Life (INQoL) questionnaires., Results: The presence of at least one pathological personality trait with score above 85 on MMCI was found in 47 (75.8%) patients. After clinical interview, 36 (58.1%) subjects had significant personality impairment. The most common personality trait in our cohort of patients was dependent found in 51.6% of patients, followed by paranoid (38.7%). Higher score on dependent personality scale correlated with lower education (rho = -0.251, P = 0.049). Dependent personality scores significantly differed between patients with physical and intellectual work (93.1 ± 8.9 vs 66.9 ± 31.7, P = 0.011). Paranoid score was higher in patients with lower education (rho = -0.293, P = 0.021), lower score on RSPM test (rho = -0.398, P = 0.004) and larger number of CTG repeats (rho = 0.254, P = 0.046). Presence of dependent personality was not in association with QoL scores (P > 0.05). On the other hand, patients with paranoid personality trait had worse QoL than those without it (P < 0.05)., Conclusion: Almost 60% of our patients with DM1 had clinically significant personality impairment, with dependent and paranoid personality patterns being the most common. Paranoid personality may decrease QoL in these patients, which gives us new opportunities for symptomatic therapy in DM1., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Purpose: The aim of the present study was to analyze cerebrospinal fluid (CSF) levels of total tau (T-tau), phosphorylated tau (P-tau) and the 42-amino-acid form of β-amyloid (Aβ42 ) in patients with myotonic dystrophy type 1 (DM1), and their possible correlations with cognitive and behavioral manifestations in these patients., Methods: Lumbar puncture was performed in 74 patients with DM1 [27 with the childhood/juvenile form (jDM1) and 47 with the adult form (aDM1) of the disease] and 26 control subjects who were subjected to orthopedic surgery. Sandwich ELISA was used for measuring the levels of T-tau, P-tau and Aβ42., Results: The CSF level of Aβ42 was at its lowest in patients with jDM1 and at its highest in controls (P < 0.05). A tendency of T-tau and P-tau to increase was greater in aDM1 patients than in jDM1 patients and controls (P > 0.05). In both jDM1 and aDM1 patients, significant correlations were found between Aβ42 and T-tau (rho = 0.81 and rho = 0.67, respectively, P < 0.01), as well as between Aβ42 and P-tau (rho = 0.87 and rho = 0.67, respectively, P < 0.01). The Aβ42/P-tau ratio decreased with age in aDM1 patients (rho = -0.30, P < 0.05). Only the level of Aβ42 in the CSF of jDM1 patients was correlated with the size of the CTG expansion (rho = -0.53, P < 0.05). Only a few correlations were observed between levels of biomarkers and neuropsychological testing., Conclusion: The CSF level of Aβ42 was decreased in patients with jDM1, whilst the Aβ42/P-tau ratio was decreased in aDM1 patients. Positive correlations between Aβ42 , T-tau and P-tau were observed in both forms of disease. Further studies with larger cohorts of DM1 patients are necessary., (© 2013 The Author(s) European Journal of Neurology © 2013 EFNS.)

Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. It affects many organs and systems besides muscle. Aim of this study was to assess frequency of erectile dysfunction (ED) and hypogonadism, the correlation between them and the impact of ED on quality of life (QoL) in patients with DM1. A series of 25 men (aged from 22 to 58 years) with a diagnosis of DM1 was analyzed. Muscular Impairment Rating Scale (MIRS) was used to assess severity of muscular involvement. Erectile function was assessed using the short form of the International Index of Erectile Function test (IIEF-5). Levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone were assessed. All patients completed the Serbian version of the SF-36 questionnaire as a measure of health-related QoL. ED was present in 18 (72%) of patients. Seven (28%) patients were euogonadic, 16 (64%) had compensated hypogonadism and 2 (8%) had primary hypogonadism. ED was somewhat more common in patients with hypogonadism (78% vs. 57%). Mental composite score of SF-36 was lower in patients with ED (p<0.05). Our results showed that 72% of men with DM1 had ED and hypogonadism. Studies with larger number of subjects are needed to resolve cascade of events that lays behind ED in DM1. Development of therapeutic strategies may have positive impact on QoL. Substitutive therapy with androgens may be benefitial.

The aim of this study was to analyze survival, causes of death and cardiologic predictors of sudden death in a large cohort of patients with myotonic dystrophy type 1 (DM1). The study was comprised of 171 adult DM1 patients hospitalized at the Neurology Clinic in a 20-year period. Severe electrocardiographic (ECG) abnormality included at least one of the following: rhythm other than sinus, PR interval of ≥240 ms, QRS complex duration of 120 ms or more, and second-degree or third-degree atrioventricular (AV) block. Survival data were analyzed by the Kaplan-Meier test, log-rank test and Cox regression analysis. During the mean follow-up period of 9.4±5.4 years, a pacemaker was implanted in 5.8% of DM1 patients and 14% of patients died. The mean age at death was 55.6±12.5 years. The most common causes of death in our cohort were sudden death (41.7%) and respiratory failure (29.2%). The presence of palpitations (hazard ratio [HR]=4.7, p<0.05) and increased systolic blood pressure (HR=9.8, p<0.05) were significant predictors of sudden death. Among ECG parameters, severe ECG abnormality (HR=4.7, p<0.05), right bundle branch block (RBBB; HR=3.9, p<0.05) and bifascicular block (HR=5.8, p<0.05) were significant predictors of sudden death., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Aim: To assess health-related quality of life (HRQoL) in patients with DM1, to identify muscular, multisystemic, central and social factors that may affect QoL and to define a DM1 patient in risk of poor QoL., Patients and Method: This cross-sectional study comprised 120 DM1 consecutive patients. The following scales were used: Multidimensional Scale of Perceived Social Support (MSPSS), Muscular Impairment Rating Scale (MIRS), battery of neuropsychological tests, acceptance of illness scale (AIS), Hamilton rating scale for depression (Ham-D), Krupp's Fatigue Severity Scale (FSS), Daytime Sleepiness Scale (DSS) and SF-36 questionnaire., Results: HRQoL was impaired in DM1 patients in both physical and mental domains (PCS was 41.8±23.5, MCS 47.0±24.3 and total SF-36 score 45.6±24.0). The most significant factors correlating with better SF-36 total score were younger age (β=-0.45, p<0.001), shorter duration of disease (β=-0.27, p=0.001), higher education (β=0.20, p=0.009), less severe muscular weakness (β=-0.52, p<0.001), normal swallowing (β=0.22, p=0.005), absence of fainting (β=0.31, p=0.002), absence of snoring (β=0.21, p=0.036), better acceptance of disease (β=-0.17, p=0.036), lower depressiveness (β=-0.46, p=0.001), lower fatigue (β=-0.32, p=0.001), absence of cataract (β=-0.21, p=0.034), absence of kyphosis (β=0.31, p=0.004) and absence of constipation (β=0.24, p=0.016). Second linear regression analysis revealed that depressed (β=-0.38, p<0.001) and elder patients (β=-0.27, p=0.007) and as well as those with poor acceptance of illness (β=-0.21, p=0.006) were in especially higher risk of having poor HRQoL (R(2)=0.68)., Conclusion: We identified different central, social, muscular, cardiorespiratory and other factors correlating with HRQoL. It is of great importance that most of these factors are amenable to treatment., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The aim was to assess factors that might influence health-related quality of life (HRQoL) in patients with two different neuromuscular disorders - myotonic dystrophy type 1 (DM1) and amyotrophic lateral sclerosis (ALS). A cross-sectional study was performed on 79 patients with DM1 and 74 with ALS. The HRQoL was evaluated by SF-36, Serbian version. Depressive and anxiety symptoms were assessed using the Hamilton rating scale for depression and the Hamilton rating scale for anxiety respectively. Severity of muscular involvement in DM1 was measured with MRC scale and severity of ALS with ALSFRSr score. The mean total score as well as all domain scores of SF-36 were similar in DM1 and ALS patients (p > 0.05), except that ALS patients experienced less bodily pain (p < 0.05). Depressiveness was found in 51% and marked anxiety in 38% of DM1 patients. Emotional status and severity of muscular involvement emerged as significant independent contributing factors to the total SF-36 in DMI patients (p < 0.05). Only 3% of ALS patients showed depressiveness and 4% anxiety symptoms. The factors found to contribute to HRQoL in ALS patients were severity of disease and educational level ofpatients (p < 0.05). We found significant percentage of potentially treatable emotional disturbances which together with severity of disease significantly contributed to HRQoL in DM1 patients. On the other hand, in ALS patients depressiveness and anxious symptoms were uncommon and the factors found to contribute to HRQoL were severity of disease and educational level.

Objectives: To evaluate serum leptin concentration and its relation to metabolic syndrome (MSy) in non-diabetic patients with myotonic dystrophy type 1 (DM1)., Materials and Methods: This study included 34 DM1 patients, and the same number of healthy subjects matched for age, sex and body mass index (BMI)., Results: DM1 patients had increased BMI and insulin resistance, and increased leptin and insulin concentrations, but the other features of MSy such as diabetes, glucose intolerance and hypertension were not detected in DM1 patients. Serum leptin levels were higher in patients with DM1 than in healthy controls (8.5 +/- 6.6 ng/ml vs 3.6 +/- 2.9 ng/ml in men, and 13.9 +/- 10.0 ng/ml vs 10.9 +/- 6.9 ng/ml in women, respectively). In DM1 patients, leptin levels correlated with BMI, fasting insulin and insulin resistance (HOMA) (P < 0.01)., Conclusions: The leptin overproduction correlated with insulin resistance in DM1 patients but the significance of this finding remains unclear.

The aim of this study was to estimate the incidence and prevalence of myotonic dystrophy type 1 (DM1) in Belgrade during the period 1983-2002. The patients who had DM1 were ascertained through hospital records from all neurological departments in Belgrade during 1983-2002. The molecular genetic analysis was performed in all patents included in the study. We identified 101 DM1 patients (52 males and 49 females). The average annual incidence rate of DM1 in Belgrade for the period observed was 2.0/1,000,000 (95% confidence interval (CI), 0.3-8.3), 2.1/1,000,000 (95% CI, 0.3-8.3) for males and 2.0/1,000,000 (95% CI, 0.3-8.3) for females. The highest age-specific DM1 incidence was registered in the age group 20-49: 3.4/1,000,000 (95% CI, 0.5-7.6), 4.0/1,000,000 (95% CI, 1.1-10.2) in males and 2.5/1,000,000 (95% CI, 0.5-7.6) in females. In the population of Belgrade, a cumulative probability of acquiring DM1 was 1 per 8621 for men and 1 per 9259 for women (1 per 8940 of the population for both sexes). The prevalence of DM1 in Belgrade on 31 December 2002 was 5.3/100,000 (95% CI, 4.2-6.6).

The purpose of this investigation was to determine survival and mortality in patients with myotonic dystrophy type 1 (DM1) in the Belgrade population within the period from 1983 to 2002. Data of a number of diagnosed DM1 patients with their demographic, clinical and genetic characteristics were gathered from hospital records in all neurologic institutions in Belgrade for the period 1983-2002. Death certificates were reviewed to determine the cause of death. Survival analysis by life table method and Cox proportional hazard model was performed. Within the observed period, in the population of Belgrade, 15 fatal outcomes among 101 patients with DM1 were registered. Average DM1 mortality rate was 0.5/1,000,000 (95% CI 0.3-0.8), and standardized mortality ratio (SMR) was 5.3. A significant inverse correlation was found between age at onset of DM1 and CTG repeats (P=0.023). The cumulative probability of 15-year survival for DM1 patients in Belgrade was 49+/-5% (48+/-2% for males and 50+/-7% for females). Younger age at onset was a significant unfavorable prognostic factor (hazard ratio=4.2; P=0.012).

Myotonic dystrophy type 1 (DM1) is associated with an expansion of CTG repeats in the 3'UTR of the DMPK gene. It is accepted, as in other trinucleotide diseases, that the number of the repeats is correlated with age at onset and severity of the disease. However, assessment of genotype-phenotype correlation in DM1 is complicated with the expansion-biased somatic instability of mutant alleles over time and difficulties in precise assessment of the number of repeats by standard Southern blot hybridization. In order to clarify this issue we defined DM1 expansion size in lymphocytes by three parameters: size of progenitor, average, and largest allele, using a more precise small-pool/long-range PCR technique. We found a negative linear correlation of age at onset and average expansion size in juvenile-adult DM1 patients (35 out of 46) whose progenitor allele is less than 245 repeats long. Our result favors the hypothesis of the existence of a threshold in the progenitor allele size beyond which number of CTG repeats does not influence age at onset. Potential clinical significance is that the average allele size could be a useful indicator for the age at onset in juvenile-adult DM1 patients with relatively short progenitor allele. To test whether somatic instability of mutant alleles influences the progression of DM1, patients were divided in three phenotypic classes according to the severity of neuromuscular symptoms. We showed that the largest expansion in each DM1 phenotypic class reflects somatic instability of mutant allele over time independently of progenitor allele size and patient's age at sampling. The mean of the largest expansion was significantly different between phenotypic classes, implying the possible association between expansion-biased somatic instability of mutant alleles over time and progression of neuromuscular symptoms., (Copyright 2002 Wiley-Liss, Inc.)