ObjectiveTo investigate grey (GM) and white matter (WM) abnormalities and their effects on cognitive and behavioral deficits in a large, phenotypically and genotypically well-characterized cohort of classic adult (aDM1, age at onset ≥20 years) or juvenile (jDM1, age at onset <20 years) patients with myotonic dystrophy type 1 (DM1).MethodsA case-control study including 51 DM1 patients (17 jDM1 and 34 aDM1) and 34 controls was conducted at an academic medical center. Clinical, cognitive and structural MRI evaluations were obtained. Quantitative assessments of regional GM volumes, WM hyperintensities (WMHs), and microstructural WM tract damage were performed. The association between structural brain damage and clinical and cognitive findings was assessed.ResultsDM1 patients showed a high prevalence of WMHs, severe regional GM atrophy including the key nodes of the sensorimotor and main cognitive brain networks, and WM microstructural damage of the interhemispheric, corticospinal, limbic and associative pathways. WM tract damage extends well beyond the focal WMHs. While aDM1 patients had severe patterns of GM atrophy and WM tract damage, in jDM1 patients WM abnormalities exceeded GM involvement. In DM1, WMHs and microstructural damage, but not GM atrophy, correlated with cognitive deficits.ConclusionsWM damage, through a disconnection between GM structures, is likely to be the major contributor to cognitive impairment in DM1. Our MRI findings in aDM1 and jDM1 patients support the hypothesis of a degenerative (premature aging) origin of the GM abnormalities and of developmental changes as the principal substrates of microstructural WM alterations in DM1.

Myotonic dystrophy type 1 (DM1) is caused by a highly unstable expansion of CTG repeats in the DMPK gene. Its huge phenotypic variability cannot be explained solely by the repeat number. Recently, variant repeats within the DMPK expansions have emerged as potential disease modifiers. The frequency of variant expanded alleles was estimated in 242 DM1 patients from 174 Serbian families using repeat-primed PCR (RP-PCR). The patterns of variant repeats were determined by direct sequencing of RP-PCR or PCR products. PCR-based southern blot was performed to get insight into the intergenerational mutational dynamics of variant expanded alleles. All patients carrying variant repeats were clinically re-examined. Variant repeats were observed in eight patients from five families (2.9%). They were detected only at the 3' end of DMPK expansions. CCG variant repeats were present in seven patients, either as a part of regular runs of CCGCTG hexamer, individual repeats, or CCG blocks. Analyses of three intergenerational transmissions revealed a considerable stability or likely a contraction of variant expanded alleles. Intriguingly, a decrease in age at onset accompanied these transmissions. Overall, patients were characterized by a milder phenotype and/or some atypical symptoms that could be rather clinically suggestive of myotonic dystrophy type 2. In addition, the first case of de novo CTC variant repeat was observed. Variant repeats might explain a part of the phenotypic variability in a small percent of DM1 patients and likely display a stabilizing effect on the meiotic instability of DMPK expanded alleles.

The aim of this study was to investigate autonomic cardiac control in patients with amyotrophic lateral sclerosis (ALS). Fifty-five patients with sporadic ALS (28 female and 27 male; average age 56.00 +/- 10.34 years) were compared to 30 healthy controls (17 female and 13 male; average age 42.87 +/- 11.91 years). Patients with previous history of cardiac disease, diabetes mellitus, and impaired respiratory function were excluded from the study. Cardiovascular autonomic tests according to Ewing, power spectrum analysis of RR variability (low- and high-frequency bands - LF and HF, LF/HF index), real-time beat-to-beat ECG signal monitoring with heart rate variability analysis and baroreflex function analysis were carried out in all patients. Time-domain parameters of heart rate variability (mean RR interval, SDNN, SDANN, SDNN index, rMSSD and pNN50%) were obtained from 24-h ECG monitoring. ALS patients had a significantly higher score of sympathetic (p <0.01) and parasympathetic (p <0.001) dysfunction, as well as of the overall score of autonomic dysfunction (p <0.001). LF/HF index was significantly increased; baroreflex sensitivity and time-domain parameters of heart rate variability were highly significantly decreased in ALS patients (p <0.001). Our results demonstrated impaired cardiac autonomic control in ALS with marked parasympathetic dysfunction and sympathetic predominance.

The aim of this study was to assess factors that might influence the health-related quality of life (HRQoL) in patients with myasthenia gravis (MG). A cross-sectional study was performed including 230 consecutive patients with MG. Severity of the disease was estimated according to the MGFA classification and QMG score. HRQoL was assessed by the SF-36 questionnaire. Depressive and anxiety symptoms were assessed using the Hamilton rating scales for depression and anxiety, respectively. Social support was measured by the Multidimensional Scale of Perceived Social Support (MSPSS), and acceptance of the disease by the Acceptance of Illness Scale. The significant demographic predictors of worse HRQoL in MG patients were older age (p = 0.025) and lower education (p = 0.012). Among clinical features, significant independent contributing factors of worse HRQoL were more severe form of the disease according to MGFA (p = 0.001) and higher QMG score (p = 0.001). Finally, psychosocial predictors of worse quality of life were lower MSPSS score (p = 0.001), poor acceptance of the disease (p = 0.001), as well as higher levels of anxiety and depression (p = 0.001). Our study revealed that the HRQoL in patients with MG is similarly reduced in its psychological and physical aspects. These results may have a practical implication pointing out that different aspects of psychosocial support should be added to the regular therapeutic protocols.

CTG expansions in DMPK gene, causing myotonic dystrophy type 1 (DM1), are characterized by pronounced somatic instability. A large proportion of variability of somatic instability is explained by expansion size and patient’s age at sampling, while individual-specific differences are attributed to additional factors. The age at onset is extremely variable in DM1, and inversely correlates with the expansion size and individual-specific differences in somatic instability. Three to five percent of DM1 patients carry repeat interruptions and some appear with later age at onset than expected for corresponding expansion size. Herein, we characterized somatic instability of interrupted DMPK expansions and the effect on age at onset in our previously described patients. Repeat-primed PCR showed stable structures of different types and patterns of repeat interruptions in blood cells over time and buccal cells. Single-molecule small-pool PCR quantification of somatic instability and mathematical modeling showed that interrupted expansions were characterized by lower level of somatic instability accompanied by slower progression over time. Mathematical modeling demonstrated that individual-specific differences in somatic instability had greater influence on age at onset in patients with interrupted expansions. Therefore, repeat interruptions have clinical importance for disease course in DM1 patients due to stabilizing effect on DMPK expansions in somatic cells.