Physical and Mental Aspects of Quality of Life in Patients With Charcot-Marie-Tooth Disease Type 1A.

Introduction: Charcot-Marie-Tooth type 1A (CMT1A) comprises ~50% of all CMT cases. CMT1A is a slowly progressive motor and sensory neuropathy that leads to significant disability. We aimed to investigate the quality of life (QoL) in Serbian patients with CMT1A and to assess sociodemographic and clinical features associated with their QoL. Material and Methods: Forty-five genetically confirmed patients with CMT1A were included -60% women [age 50.4 ± 12.6 years, disease duration 22 (12.5-31.5) years]. SF-36, Medical Research Council (MRC) Sum Score, CMT Examination Score (CMTES), Overall Neuropathy Limitation Scale (ONLS), Beck Depression Inventory (BDI), and Krupp's Fatigue Severity Scale (FSS) were used in the study. Results: Regarding SF-36, Mental Health and Social Functioning were the scales with the best achievements, whereas Role Physical was the worst domain. Worse QoL in patients with CMT1A was associated with elder age (rho = -0.34, p < 0.05), longer disease duration (rho = -0.31, p < 0.05), more pronounced muscle weakness measured by MRC-SS (rho = 0.43, p < 0.01), presence of tremor (p < 0.05), worse CMTES (rho = -0.68, p < 0.01), more severe disability in upper (rho = -0.70, p < 0.01) and lower limbs (rho = -0.61, p < 0.01) measured by ONLS scores, use of walking aids (p < 0.01), and with depression (p < 0.01) and fatigue (p < 0.01). Worse scores on CMTES (beta = -0.43, p < 0.01), BDI (beta = -0.39, p < 0.01), and FSS (beta = -0.36, p < 0.01) were significant independent predictors of worse QoL in patients with CMT1A (adjusted R 2 = 0.77, p < 0.001). Conclusion: Besides impairment made directly by CMT1A itself, QoL in these patients was also strongly affected by the presence of depression and fatigue. Since CMT1A is still not a curable disease, it is of interest to identify factors associated with QoL that are amenable to treatment.

Fatigue in myotonic dystrophy type 1: a seven-year prospective study.

OBJECTIVES: Cross-sectional studies reported fatigue in 50-90% of patients with myotonic dystrophy type 1 (DM1). The aim of this research was to assess frequency of fatigue in DM1 patients during a seven-year period. MATERIALS AND METHODS: Study included 64 DM1 patients at baseline (50% males, age 42 ± 12 years), and 38 after seven years. Following scales were used: Muscular Impairment Rating Scale (MIRS), Fatigue Severity Scale (FSS, score equal to or greater than 36 indicates significant fatigue), and Daytime Sleepiness Scale (DSS, score of more than six is considered significant). RESULTS: At baseline, 54% of DM1 patients had fatigue and 46% had excessive daytime sleepiness (EDS). Ten (32%) patients with fatigue had no EDS. At the baseline, patients with fatigue were older, were more likely to had adult-onset DM1, worse MIRS and DSS compared to the patients without fatigue. After seven years, FSS score increased (34 ± 15 vs 48 14, p < 0.01), fatigue was found in 82% of patients, and EDS in 60%. Still eight (26%) patients with fatigue had no EDS. Fatigue progression did not parallel MIRS increase. CONCLUSIONS: Fatigue is a common symptom of DM1 and its progression during time did not correlate with the progression of muscle weakness.

Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness.

BACKGROUND: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by a primary deficiency of α-glucosidase and the associated accumulation of glycogen in lysosomal vacuoles. The deficiency of α-glucosidase can often be detected using an inexpensive and readily accessible dried blood spot test when Pompe disease is suspected. Like several neuromuscular disorders, Pompe disease typically presents with progressive weakness of limb-girdle muscles and respiratory insufficiency. Due to the phenotypic heterogeneity of these disorders, however, it is often difficult for clinicians to reach a diagnosis for patients with Pompe disease. Six hundred and six patients from a European population were recruited onto our study. Inclusion criteria stipulated that index cases must present with limb-girdle weakness or elevated serum creatine kinase activity. Whole exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. A panel of 169 candidate genes for limb-girdle weakness was analysed for disease-causing variants. RESULTS: A total of 35 variants within GAA were detected. Ten distinct variants in eight unrelated index cases (and four siblings not sequenced in our study) were considered disease-causing, with the patients presenting with heterogeneous phenotypes. The eight unrelated individuals were compound heterozygotes for two variants. Six patients carried the intronic splice site c.-13 T > G transversion and two of the six patients also carried the exonic p.Glu176ArgfsTer45 frameshift. Four of the ten variants were novel in their association with Pompe disease. CONCLUSIONS: Here, we highlight the advantage of using whole exome sequencing as a tool for detecting, diagnosing and treating patients with rare, clinically variable genetic disorders.

A novel recessive TTN founder variant is a common cause of distal myopathy in the Serbian population.

Variants in the TTN gene have been associated with distal myopathies and other distinctive phenotypes involving skeletal and cardiac muscle. Through whole-exome sequencing we identified a novel stop-gain variant (c.107635C>T, p.(Gln35879Ter)) in the TTN gene, coding a part of the M-line of titin, in 14 patients with autosomal recessive distal myopathy and Serbian ancestry. All patients share a common 1 Mb core haplotype associated with c.107635C>T, suggesting a founder variant. In compound heterozygotes, nine other TTN variants were identified: four stop-gain, three frameshift, one missense and one splice donor variant. Patients homozygous for the common variant did not show significant clinical differences to the compound heterozygous patients. The clinical presentation of all patients was an adult onset distal myopathy with predominant lower limb involvement. In addition, most patients had normal to mildly elevated serum creatine kinase levels, myopathic electromyograms, normal cardiologic and respiratory tests and muscle pathology consistent with a dystrophic process. In this study, we describe a distinct phenotype for patients with distal myopathy associated with novel recessive TTN variants including a Serbian founder variant. Our results expand the phenotypic and genetic spectrum of titinopathies and will facilitate the diagnosis of this condition in patients of Serbian origin.

Evaluation of the adequacy of requests for electrodiagnostic examination in a tertiary referral center.

OBJECTIVE: Diagnostic procedures are often overused in the attempt to substitute for the good clinical examination. The aim of this study was to evaluate the type and the accuracy of the referral diagnosis to our EMG lab, as well as the impact of electrodiagnostic (EDX) examination on the diagnosis of our patients. METHODS: In this prospective study all patients examined in the six months period in a single tertiary referral EMG lab were analyzed. All patients were tested in a uniform fashion and by the same neurologist, according to the referral diagnosis. RESULTS: EDX examination was performed in 570 patients. Most of the patients (43.9%) were referred with the diagnosis of polyneuropathy, lumbosacral (23.7%) or cervical (11.2%) radiculopathy and myasthenia gravis (11.6%). The outcome after EDX examination was: diagnosis confirmation in 49.6% of patients, new clinically relevant diagnosis in 16%, incidental diagnosis in 4% and normal EDX examination in 36.1% of patients. EDX examination confirmed referral diagnosis more often in patients referred by neuromuscular neurologists, while normal EDX finding was reported more often in patients referred by other neurologists. CONCLUSION: This study has confirmed the inappropriateness of a large number of referrals to EDX testing, especially made by the non-neuromuscular neurologists.

Myopathic changes detected by quantitative electromyography in patients with MuSK and AChR positive myasthenia gravis.

Myopathic changes are frequent a electrophysiological finding in patients with muscle specific tyrosine kinase (MuSK) positive myasthenia gravis (MG). The aim of this study was to explore the importance of quantitative electromyography (EMG) in the detection of myopathic changes in MuSK MG patients. Classical and quantitative EMG were performed in 31 MuSK and 28 acetylcholine receptor (AChR) positive MG patients, matched by sex, age, disease duration and severity. Classical EMG revealed the presence of myopathic changes more frequently in MuSK MG compared to AChR MG patients, especially in the facial muscles. Quantitative EMG registered myopathic lesions more frequently than classical EMG, but the frequency was similar between MuSK and AChR MG patients. Quantitative EMG revealed myopathic changes in the majority of both MuSK and AChR positive MG patients. This examination is sensitive, but it cannot be used to differentiate between MG patients belonging to the different disease groups. It should not be used in isolation. Rather, it should complement classical EMG in the detection of myopathic changes.

The presence of dysautonomia in different subgroups of myasthenia gravis patients.

To analyze the presence of autonomic dysfunction in different subgroups of myasthenia gravis (MG) patients. Standard cardiovascular reflex tests according to Ewing, spectral and time domain analysis of heart rate variability (HRV) at rest were assessed in 27 patients with thymoma-associated acetylcholine receptor (AChR)-positive MG, 25 AChR-positive MG patients without thymoma and 23 patients with muscle-specific tyrosine kinase (MuSK) MG. All patients were compared to the healthy controls, matched for sex and age. In the group of AChR-positive MG patients with thymoma, hand grip (p < 0.05), orthostasis (p < 0.05), breathing test (p < 0.05) and Valsalva maneuver (p < 0.01) were more often pathological than in the controls. Analysis of the spectral domain of HRV showed increased low-frequency (p < 0.05) and decreased high-frequency component (p < 0.05). Time domain parameters of HRV and baroreflex sensitivity (BRS) at rest were significantly reduced (p < 0.01). In the patients with AChR MG without thymoma, Valsalva maneuver test was more often pathological (p < 0.05) and higher rate of supraventricular extrasystoles (p < 0.01) was registered than in the healthy controls. In the patients with MuSK-positive MG, hand grip and Valsalva maneuver tests were more often pathological than in the controls (p < 0.05). Low-frequency component of the spectral domain of HRV (p < 0.05) and the frequency of cardiac arrhythmia were increased. BRS at rest was significantly lower in patients compared to the controls (p < 0.01). We determined the presence of autonomic failure in all subgroups of MG patients. Since autonomic dysfunction can lead to cardiac arrhythmias and even sudden death, it is of major importance to be aware of this association and to properly diagnose and treat these patients.

Electrophysiological profile of the patients with MuSK positive myasthenia gravis.

OBJECTIVES: To determine the electrophysiological profile of our cohort of patients with muscle-specific tyrosine kinase (MuSK) positive myasthenia gravis (MG). METHODS: Repetitive nerve stimulation test (RNS) and jitter analysis using concentric needle electrode were performed in 31 MuSK and in 28 acetylcholine receptor (AChR) positive MG patients. RESULTS: Pathological RNS was verified in 16 (51.6%) MuSK and 26 (92.9%) AChR MG patients (P < 0.01). Pathological jitter analysis was registered in 28 (90.3%) MuSK and 26 (92.9%) AChR MG patients (P > 0.05). Increased jitter was present in extensor digitorum communis (EDC) in 23 (74.2%) MuSK and in 25 (89.3%) AChR MG patients (P > 0.05) as well as in orbicularis oculi (OO) muscle in 24 (85.7%) MuSK and 22 (81.5%) AChR MG patients (P > 0.05). Lower mean value of mean consecutive difference (MCD) and fewer potential pairs with increased jitter were registered in MuSK MG compared to AChR MG patients only in EDC muscle (P < 0.05). In MuSK MG patients, increased jitter was observed to be more frequent in patients with longer disease duration (P < 0.05) and also in those patients exhibiting more severe disease forms (P < 0.01) only in EDC muscle. DISCUSSION: Repetitive nerve stimulation test has low sensitivity in MuSK MG patients, while jitter analysis shows high sensitivity, especially in facial muscles. The EDC muscle in MuSK MG patients usually shows increased jitter in more severe disease forms and later in the course of the disease.

Peripheral neuropathy in patients with myotonic dystrophy type 1.

OBJECTIVES: To assess the frequency and type of peripheral neuropathy (PNP) in patients with myotonic dystrophy type 1 (DM1), as well as to identify factors that may be associated with this abnormality. METHODS: This study comprised 111 adult patients with DM1. Nerve conduction study was performed on sural, peroneal and median nerves of both limbs. RESULTS: PNP was somewhat more frequent in DM1 patients with glucose intolerance and diabetes mellitus (66.7 vs. 33.7%, P = 0.05). In DM1 patients with no glucose intolerance, diabetes mellitus and thyroid dysfunction, the most frequent type of PNP was demyelinating (70.0%) and motor (83.3%). PNP was more frequent in males (45.7 vs. 20.9%, P<0.05). Patients with PNP were older (43.7±7.3 vs. 39.6±9.6 years, P<0.05) and had a longer duration of DM1 compared to those without PNP (18.6±9.9 vs 12.7±8.3 years, P<0.01). DM1 patients with PNP had a higher body mass index) (24.9±5.5 vs. 22.4±4.2 kg/cm2, P<0.05), higher triglycerides (3.1±3.3 vs. 1.8±0.8 mmol/l, P<0.01), total cholesterol (6.2±1.4 vs. 5.4±1.1 mmol/l) and LDL cholesterol (4.3±1.2 vs. 3.4±1.0, P<0.05). Achilles reflexes were absent in 76.9% patients with PNP and in 51.9% patients without PNP (P<0.05). Patellar reflexes and muscle strength were similar in both groups (P>0.05). CONCLUSIONS: PNP was present in one-third of DM1 patients. The most common type was motor and demyelinating PNP. Our results suggest the association between the presence of peripheral nerve impairment in DM1 and male gender, age, duration of disease and certain metabolic parameters.

Is hyperlipidemia correlated with longer survival in patients with amyotrophic lateral sclerosis?

Amyotrophic lateral sclerosis (ALS) is the most serious form of degenerative motor neuron disease in adults, whose relentless course leads to death within 2-5 years, generally due to respiratory failure. Apart from the age and site of onset, no other factors have consistently demonstrated to be related to the ALS outcome. The aim of the study was to investigate the influence of fasting serum lipid levels (cholesterol and triglycerides) and the body mass index (BMI) at the time of diagnosis on survival in ALS patients. The study included 82 patients with ALS residing in the Belgrade area who were diagnosed with ALS over a time period of 4 years (2006-2009). Survival was assessed by the Kaplan-Meier method. In this retrospective study, 39 (47.56%) patients had normal values of lipids and 43 (52.43%) patients had hyperlipidemia. The mean survival time from the onset of symptoms for patients with normal lipidemia was 4.21 ± 0.5 years, while the mean survival time from the onset of symptoms for patients with hyperlipidemia was 5.0 ± 0.67 years (P = 0.36). We also did not register a significant difference in survival in relation to gender, the site or age of onset, even though we noticed a longer survival in patients with hyperlipidemia in all of the examined groups, especially in the group of younger patients, with the onset of the disease before the age of 45 years. If we take into account the fact that BMI is pathophysiologically associated with cholesterol and triglyceride serum levels, the results in our study complement each other showing that patients with a higher BMI, registered in 28.8% of the cases, do not live longer. Our findings show that hyperlipidemia, which we found in 52.43% of our ALS patients, at the time of diagnosis, is not related to significantly longer survival.