George K. Papadimas

Effect of aerobic and resistance exercise training on late-onset Pompe disease patients receiving enzyme replacement therapy.

Pompe disease is a rare autosomal recessive disorder characterized by the deficiency of acid α-glycosidase resulting in lysosomal accumulation of glycogen. The late-onset disease form is characterized by progressive skeletal and respiratory muscle dysfunction. In addition to the recently introduced enzyme replacement therapy (ERT), treatments such as protein-enriched diet and exercise training have been proposed, although little is known about their effectiveness on the physical condition of such patients. Aim of the present study was to investigate the effect of exercise training on muscular strength and body composition in five patients with late-onset Pompe disease receiving ERT. All subjects followed a 20 week lasting program of supervised aerobic and progressive resistance exercise training. Before and after the training period, body composition was determined with dual X-ray absorptiometry and isometric muscular strength was measured with a specialized load transducer. Functional capacity was assessed using the 6-min shuttle walk test. A significant increase in muscular strength (15-50% at various body parts, p<0.05) and 6-minute walking distance (203.8 ± 177 m before vs. 248.2 ± 184 m after, p<0.01) was observed after training, whereas total and lower extremities lean body mass did not change significantly. These results suggest that exercise training has a positive effect on muscular strength and functional capacity in patients on ERT with late-onset Pompe disease.

Elevated Muscle-Specific miRNAs in Serum of Myotonic Dystrophy Patients Relate to Muscle Disease Progress

The discovery of reliable and sensitive blood biomarkers is useful for the diagnosis, monitoring and potential future therapy of diseases. Recently, microRNAs (miRNAs) have been identified in blood circulation and might have the potential to be used as biomarkers for several diseases and clinical conditions. Myotonic Dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy primarily characterized by muscle myotonia, weakness and atrophy. Previous studies have shown an association between miRNAs and DM1 in muscle tissue and, recently, in plasma. The aim of this study was to detect and assess muscle-specific miRNAs as potential biomarkers of DM1 muscle wasting, an important parameter in the disease’s natural history. Disease stable or progressive DM1 patients with muscle weakness and wasting were recruited and enrolled in the study. RNA isolated from participants’ serum was used to assess miRNA levels. Results suggest that the levels of muscle-specific miRNAs are correlated with the progression of muscle wasting and weakness observed in the DM1 patients. Specifically, miR-1, miR-133a, miR133b and miR-206 serum levels were found elevated in DM1 patients with progressive muscle wasting compared to disease stable DM1 patients. Based on these results, we propose that muscle-specific miRNAs might be useful molecular biomarkers for monitoring the progress of muscle atrophy in DM1 patients.

Bone density in patients with late onset Pompe disease.

Background Pompe disease is an inherited metabolic disorder characterized by α-glycosidase deficiency, which leads to lysosomal glycogen accumulation in many different tissues. The infantile form is the most severe with a rapidly fatal outcome, while the late onset form has a greater phenotypic variability, characterized by skeletal muscle dysfunction and early respiratory involvement. Bone mineral density (BMD) has been recently reported to be reduced in many patients with both forms of the disease. Enzyme replacement therapy (ERT) is now available with an undefined, impact on BMD in patients with late onset disease. Objectives The present study aimed to investigate BMD in patients with late onset form of Pompe disease before and after ERT initiation. Patients and Methods Dual x-ray absorptiometry (DEXA) was examined in four newly diagnosed patients with late onset Pompe disease and in four adults under ERT before and after ERT initiation with a treatment duration of 18 to 36 months. Results The initial DEXA showed normal total body BMD z-score in all the patients, while L2-L4 and femoral neck BMD was reduced in three and two patients, respectively. After ERT administration, two patients had an improvement in L2-L4 lumbar spine and one patient in femoral neck BMD z-score with values within normal range. Conclusions The results suggested that regional BMD may moderately reduce in some patients with the late onset form of Pompe disease, although profound osteopenia was not observed. The improvement of measurements in L2-L4 and femoral neck BMD z-score in some patients with low pre-treatment values after ERT administration needs to be confirmed in larger scale studies.

Identification of exosomal muscle-specific miRNAs in serum of myotonic dystrophy patients relating to muscle disease progress

Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy, which is characterised by progressive muscle wasting and the discovery of reliable blood-based biomarkers could be useful for the disease progress monitoring. There have been some reports showing that the presence of specific miRNAs in blood correlates with DM1. In one of these, our group identified four muscle-specific miRNAs, miR-1, miR-133a, miR-133b and miR-206, which correlated with the progression of muscle wasting observed in DM1 patients. The levels of the four muscle-specific miRNAs were elevated in the serum of DM1 patients compared to healthy participants and were also elevated in the serum of progressive muscle wasting DM1 patients compared to disease-stable DM1 patients. The aim of this work was to characterise the ontology of these four muscle-specific miRNAs in the blood circulation of DM1 patients. Here we show that the four muscle-specific miRNAs are encapsulated within exosomes isolated from DM1 patients. Our results show for the first time, the presence of miRNAs encapsulated within exosomes in blood circulation of DM1 patients. More interestingly, the levels of the four exosomal muscle-specific miRNAs are associated with the progression of muscle wasting in DM1 patients. We propose that exosomal muscle-specific miRNAs may be useful molecular biomarkers for monitoring the progress of muscle wasting in DM1 patients. There has been a growing interest regarding the clinical applications of exosomes and their role in prognosis and therapy of various diseases and the above results contribute towards this way.

Corpus callosum infarct associated with combined variants in circle of willis

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Caveolinopathies in Greece.

Introduction: Mutations in the CAV3 gene are usually inherited in an autosomal dominant manner and lead to distinct disorders including limb-girdle muscular dystrophy 1C, rippling muscle disease, and isolated creatine kinase elevation. Patients and Methods: The features of the first patients with caveolin-3 deficiency from Greece are presented. Patients’ phenotypes ranged from asymptomatic creatine kinase elevation to severe weakness of lower extremities. Clinical evaluation disclosed muscle hypertrophy in 2 patients, whereas percussion-induced muscle mounding was a consistent finding in all of them. Muscle histopathology was variable and unrelated with disease severity. The diagnosis was based on the immunohistochemical study of caveolin-3 expression and molecular analysis of the caveolin-3 gene. Conclusions: Clinical manifestations and histochemical findings in caveolinopathy patients may be mild or nonspecific or overlapping with features of other muscular dystrophies. Immunohistochemical study of caveolin-3 expression on muscle biopsy should be routinely performed when investigating isolated hyperCKemia or undetermined myopathy especially in the presence of percussion-induced muscle mounding.

Bent spine syndrome in facioscapulohumeral muscular dystrophy.

We read with great interest the article by Kottlors et al., who reported bent spine syndrome as the only manifestation of facioscapulohumeral muscular dystrophy (FSHD). Although FSHD has been suggested as a possible underlying disease in patients with bent spine syndrome, theirs is the first report of isolated involvement of paraspinal muscles in FSHD. They concluded that genetic analysis might be performed in selected cases with bent spine syndrome to rule out or confirm underlying FSHD. In accordance with the aforementioned case, we report the case of a female FSHD patient who developed severe camptocormia 10 years after diagnosis. The patient, who had a positive family history of FSHD (with no camptocormia in any of her affected relatives), presented at the age of 46 years with difficulty in climbing stairs. The physical examination disclosed lumbar lordosis and moderate weakness of neck extensor and proximal lower extremity muscles. Genetic testing revealed restriction fragments at 4q35 with repeat contraction of 31 kb with EcoI and of 28 kb with EcoI/Bln, confirming FSHD. In the absence of an alternative explanation after an extensive work-up, her bent spine syndrome was considered to be a rare phenotypic feature of FSHD. Axial weakness and bent spine syndrome have been reported in patients with the D4Z4 deletion on chromosome 4q35 as an early manifestation in the course of the disease and all patients had suffered from proximal limb and facial weakness. In our patient, camptocormia was a late feature that presented 10 years after the initial diagnosis. In contrast, in the case of Kottlors et al., camptocormia seemed to be the initial and sole manifestation of the disease. Because the patient’s mother had a similar posture, it would be of interest to know whether she had additional clinical features of FSHD, such as steppage gait, facial asymmetry, or scapular winging. Another question to be answered is whether their patient will eventually develop involvement of other muscle groups over time or will have a disease restricted to the paraspinal muscles, thus extending the spectrum of FSHD and the differential diagnosis of isolated bent spine syndrome. In conclusion, camptocormia may be variably manifested even among members of the same family, as evident from our patient with a positive FSHD family history but without bent spine syndrome in any of the many other affected family members. Moreover, it will be of great interest to determine the frequency of bent spine syndrome as an early manifestation accompanying the classical phenotype of the disease or, as in the case of our patient, as a symptom manifesting late in the course of FSHD. Finally, we agree that molecular analysis for FSHD should be considered in carefully selected cases of bent spine syndrome, especially in those patients with concomitant clinical manifestations suggestive of the disease or those with a positive family history.

An Age-Related Morphometric Profile of Skeletal Muscle in Healthy Untrained Women

There is a paucity of data on muscle biopsies in females of mixed ages in terms of age-related changes. Cross sections of autopsy material including the quadriceps femoris and biceps brachii muscles were obtained from 23 healthy women, aged 24–82 years, who had suffered sudden death. We calculated the percentage of the number, and the mean diameter, of type I and type II muscle fibers within the fascicles as well as in their peripheral parts. The number of type II fibers were shown to reduce significantly with age (p < 0.005), especially in the fascicle periphery, but the percentage of type 1 fibers did not alter significantly. It was noted that type II fibers diminished in size with age, indicating a relationship between fiber size and age. This result became more apparent in the fascicle periphery (p < 0.05). In women, type II muscle fibers were seen to reduce in size and number with advancing age. We postulate that regular physical activity can increase the size of type II muscle fibers, thus helping to both prevent and treat age-related muscle loss.

A single amino acid loss in the dystrophin protein associated with a mild clinical phenotype.

Introduction: The dystrophinopathies include a spectrum of muscle diseases caused by mutations in the dystrophin (DMD) gene. The clinical phenotype ranges from severe Duchenne muscular dystrophy to a mild phenotype with elevated creatine kinase (CK). Methods: Clinical and molecular assessment of 7 patients carrying a single amino acid loss in the dystrophin protein (p.His1690del) caused by a c.5068_5070delCAC tri‐nucleotide deletion in exon 36 of the DMD gene. Results: All patients were asymptomatic or oligosymptomatic and had elevated CK levels. Febrile illness, but not exercise, induced muscle symptoms in some patients. None had evidence of cardiomyopathy. Analysis of the short tandem repeat (STR)45 locus and sequencing of exon 36 of the DMD gene indicates that c.5068_5070delCAC is a founder mutation. Conclusions: The c.5068_5070delCAC locus in the DMD gene is associated with a very mild phenotype. Further study is needed to evaluate disease progression in these patients. Muscle Nerve 55: 46–50, 2017

Phenotypic variability and molecular genetics in proximal myotonic myopathy.

Introduction: Myotonic dystrophy type 2 (DM2) is an autosomal dominant inherited disorder with (CCTG)n repeat expansion in intron 1 of the CNBP gene. Methods: We studied the first 16 Greek DM2 patients who had undergone thorough evaluation. Results: The age at diagnosis ranged from 38 to 69 years. The initial symptoms were proximal weakness, myalgias, and myotonia. Clinical myotonia was elicited in 10 patients, whereas electromyographic myotonic discharges were observed in almost all patients. Subcapsular cataract was frequently present, but cardiac arrhythmias were rare. Conclusions: In this study of Greek DM2 patients, proximal weakness was the most common initial symptom. Myalgias were also reported in a few patients, yet myotonia was not a major complaint. Although DM2 is considered relatively benign, there are patients who may be affected severely. Thus, a high index of suspicion must be maintained to make a timely diagnosis, especially in those of reproductive age. Muscle Nerve 51:686–691, 2015