GNE-Myopathy in a Greek Romani Family with Unusual Calf Phenotype and Protein Aggregation Pathology.

BACKGROUND: GNE-myopathy is increasingly diagnosed in different ethnicities worldwide. No clear genotype-phenotype correlation has been established to date. CASE REPORTS: We describe two affected members of the same family from Balkan population carrying an already known homozygous pathogenic mutation in the kinase domain of the UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamime kinase (GNE) gene. The patients presented with severe distal weakness of lower legs combined with rimmed vacuoles in muscle biopsy. However, in contrast to the typical pattern of muscle involvement, one of them showed severe involvement of posterior calf muscles with spared anterior compartment of the lower leg muscles. CONCLUSIONS: These patients provide evidence for a larger variability and further extend the phenotypic spectrum of GNE-myopathy to include preferential calf involvement.

Electrodiagnosis and muscle biopsy in asymptomatic hyperckemia.

Purpose/aim of the study: An increased serum level of creatine kinase (CK) in asymptomatic individuals is a diagnostic challenge, as it may be associated with either physiological conditions, such as exercise or even signal an ominous neuromuscular disease at a presymptomatic stage. The electromyogram (EMG) and the muscle biopsy play a key role in the evaluation of asymptomatic hyperckemia. The objective of this study was to investigate asymptomatic individuals with increased CK levels. MATERIALS AND METHODS: We comparatively studied EMG, quantitative EMG and muscle biopsy in asymptomatic clinically normal individuals with repeatedly increased CK levels. RESULTS: Conventional EMG was abnormal in 76% of patients, while quantitative EMG showed abnormal results in 88.9%. Muscle biopsy was diagnostic in 28%, one patient had neurogenic findings, 40% showed non-specific changes and 28% had normal results. CONCLUSIONS: EMG and especially quantitative EMG are highly sensitive in detecting subclinical neuromuscular diseases, whereas muscle biopsy may better contribute in the final diagnosis. No strong correlations were found between histological abnormalities and electrophysiological data, but further research is needed.

Highlighting intrafamilial clinical heterogeneity in late-onset Pompe disease.

BACKGROUND/AIMS: Pompe disease is a rare metabolic disorder caused by deficiency of the lysosomal enzyme acid alpha-glycosidase (GAA). The late onset form of the disease is characterized by muscle weakness and respiratory involvement of variable severity. The aim of this short communication is to highlight the clinical variability of Pompe disease within siblings suffering from the disease. CASE REPORTS: We report three pairs of siblings with late-onset Pompe disease presenting with different clinical phenotypes within the spectrum of disease phenotypes. CONCLUSION: Clinical manifestations in Pompe disease within the same family can be very different. Clinicians should investigate patients' siblings for symptoms throughout the entire spectrum of the disease in order to avoid delays in the diagnosis and to pick-up mildly affected persons as early as possible, when they can benefit the most from enzyme replacement therapy.

Mutation spectrum and phenotypic manifestation in FSHD Greek patients.

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic myopathy with a remarkable intra- and inter-familial clinical heterogeneity. This study reports the clinical and genetic analysis of 133 individuals from 71 unrelated Greek families based on a revised clinical severity score (rCSS) index which was developed for clinical assessment regarding the disease progression. A high ratio (31/62, 50%) of probands' family members was found to be asymptomatic or minimally affected gene carriers of a contracted 4q allele. Moreover, a notable clinical variability of FSHD is reported concerning the detection of an identical de novo 13 b EcoRI fragment in monozygotic twins, as well as indications of founder effect. This is the first survey that presents data of FSHD families from an East Mediterranean country supporting the speculation that the prevalence of disease might be significantly underestimated and that synergistic factors could play an essential role on the progression of the disease.

Late onset glycogen storage disease type II: pitfalls in the diagnosis.

BACKGROUND/AIMS: Glycogen storage disease type II (GSD-II) is a lysosomal disorder caused by acid α glucosidase (GAA) deficiency. The infantile form is easier to recognize compared with the milder adult form that may manifest as myopathy without specific clinical characteristics. The aim of this study is to highlight frequent diagnostic errors in adult GSD-II patients. CASE REPORTS: We report four patients with confirmed GSD-II who were at first diagnosed with hypothyroid myopathy, connective tissue disorder, an underlying liver disease and muscular dystrophy, respectively. CONCLUSION: Internists but even neurologists with low suspicion may misdiagnose GSD-II. The early respiratory involvement and the characteristic laboratory abnormalities in a myopathic patient should include GAA deficiency in the differential diagnosis especially in the era of enzyme replacement therapy.

Adult Pompe disease: clinical manifestations and outcome of the first Greek patients receiving enzyme replacement therapy.

OBJECTIVE: Pompe disease is an autosomal recessive lysosomal disorder caused by α-glucosidase deficiency. A specific treatment for the disease with enzyme replacement therapy is currently available. The aim of the present study is to describe the clinical manifestations and the effect of treatment in the first Greek patients with the adult form of the disease. METHODS: Five Greek patients with adult onset Pompe disease aged between 40 and 73 years received 20 mg/kg Myozyme intravenously at two weekly intervals over a different period. Clinical and functional parameters were longitudinally registered. RESULTS: Proximal muscle weakness and respiratory insufficiency were the most common manifestations of the disease, but their severity was different even among patients with similar genotype. The effect of treatment varied with most patients experiencing some improvement in muscle strength and fatigability, while the most severely affected patient did not benefit and stopped therapy. CONCLUSION: No clear genotype-phenotype correlation emerges from our study. The different effect of treatment on our patients seems to be mainly related to their pre-treatment condition and can be reliably assessed only on a long term basis.

Body composition analysis in late-onset Pompe disease.

Pompe disease is an inherited metabolic disorder caused by α-glycosidase deficiency. The adult onset form is mainly characterized by progressive proximal muscle weakness and respiratory dysfunction. The aim of the present study is to evaluate body composition in adult patients before and after enzyme replacement therapy (ERT). Body composition was examined at baseline by means of dual x-ray absorptiometry (DXA) in nine adult patients and after different time periods in six of them who received ERT. Total BMD (bone mineral density) was initially mildly decreased in two patients, while femoral neck BMD was decreased in five patients. On the other hand fat mass was increased in the majority of patients, while body mass index (BMI) was high in four. ERT administration did not seem to induce obvious BMD changes in any patient. Conclusively, the greater femoral neck BMD involvement may be attributed to the lower mechanical load applied by the selectively weakened muscles, whereas the increased fat mass may be the result of metabolic and nutritional derangement.

Effect of pulmonary rehabilitation on muscle remodelling in cachectic patients with COPD.

It is known that non-cachectic patients with chronic obstructive pulmonary disease (COPD) respond well to pulmonary rehabilitation, but whether cachectic COPD patients are capable of adaptive responses is both important and unknown. 10 cachectic and 19 non-cachectic COPD patients undertook high-intensity cycling training, at the same relative intensity, for 45 min x day(-1), 3 days x week(-1) for 10 weeks. Before and after rehabilitation vastus lateralis muscle biopsies were analysed morphologically and for the expression of muscle remodelling factors (insulin-like growth factor (IGF)-I, myogenic differentiation factor D (MyoD), tumour necrosis factor (TNF)-alpha, nuclear factor (NF)-kappaB and myostatin) and key components of ubiquitin-mediated proteolytic systems (muscle ring finger protein (MURF)-1 and Atrogin-1). Rehabilitation improved peak work-rate and the 6-min walk distance similarly in non-cachectic (18+/-3% and 42+/-13 m, respectively) and cachectic (16+/-2% and 53+/-16 m, respectively) patients, but quality of life only improved in non-cachectic COPD. Mean muscle fibre cross-sectional area increased in both groups, but significantly less in cachectic (7+/-2%) than in non-cachectic (11+/-2%) patients. Both groups equally decreased the proportion of type IIb fibres and increased muscle capillary/fibre ratio. IGF-I mRNA expression increased in both groups, but IGF-I protein levels increased more in non-cachectic COPD. MyoD was upregulated, whereas myostatin was downregulated at the mRNA and protein level only in non-cachectic patients. Whilst rehabilitation had no effect on TNF-alpha expression, it decreased the activation of the transcription factor NF-kappaB in both groups by the same amount. Atrogin-1 and MURF-1 expression were increased in cachectic COPD, but it was decreased in non-cachectic patients. Cachectic COPD patients partially retain the capacity for peripheral muscle remodelling in response to rehabilitation and are able to increase exercise capacity as much as those without cachexia, even if they exhibit both quantitative and qualitative differences in the type of muscle fibre remodelling in response to exercise training.

[Macrophagic myofascitis vs atypical Whipple's disease]. / Makrophagische Myofasziitis vs. atypischer M. Whipple.

A 39-year-old man presented pronounced asthenia and diffuse myalgias 8 months after a vaccination against the tetanus toxoid. Muscle biopsy disclosed infiltration of the perimysium and endomysium by densely packed, PAS-positive macrophages. Tropheryma whippelii detection in blood and faeces allowed the initial assumption of atypical Whipple's disease with isolated muscle involvement. However, the histological detection of aluminium-containing macrophages by means of Morin stain immunofluorescence established the diagnosis of macrophagic myofascitis in an obviously asymptomatic T. whippelii carrier.

Seven cases of Pompe disease from Greece.

We present seven cases of Pompe disease (McKusick 232300; glycogen storage disease type II; acid maltase deficiency) from Greece. The onset of symptoms varied from early childhood to late adulthood, and the patients had quite variable duration of disease. All but one of them had muscle weakness and all had mildly to highly elevated serum creatine kinase. The diagnosis in all cases was confirmed by the finding of acid alpha-glucosidase (EC 3.2.1.3/20) deficiency in cultured skin fibroblasts. Thirteen mutant alleles were identified and nine different pathogenic mutations were encountered. Four were new: c.2071_2072insAGCCG leads to frameshift and total loss of function; c.1856G > A (p.Ser619Asn) leads to 90-95% loss of function; and the splice-site mutations c.1552-3C > G and c.2331+4A > G reduce the number of correct splicing events by more than 90%. The splice-site mutation c.-32-13T > G (IVS1-13T > G) was encountered four times and seems equally common among Greek and other caucasians. The other mutations: c.925G > A (p.Gly309Arg), c.[307T > G; 271G > A] (p.Cys103Gly; Asp91Asn), c.271del and c.1655T > C (p.Leu552Pro) have been reported earlier. Our study highlights the heterogeneity of Pompe disease in Greece and provides tools for diagnosis and carrier detection.

Relationship between shot put performance and triceps brachii fiber type composition and power production.

It is commonly accepted that shot put performance is mainly determined by the ability of the lower body to produce power. The purpose of the present study was to investigate the relationship between shot put performance and triceps brachii muscle fiber type composition and strength capacity. Thirteen male physical education students were selected to participate in the study based upon their shot put performance after 5 weeks of shot put technique instruction. At the completion of this technique-instruction period, they performed the following tests: shot put with a 6-kg shot, isokinetic torque measurements of the elbow extensors at 0, 0.52, 1.04, 1.57, 2.09, 3.14, and 4.19 rad.s(-1), maximal strength (1 RM) and explosive-throwing bench-press tests, one-arm seated shot put with 1-, 2-, 3-, 4-, 5- and 6-kg shot. Whole-body and dominant upper-arm bioimpedance measurements were used to estimate whole-body and upper-arm muscle mass. Muscle biopsy samples from the long head of the dominant triceps brachii were obtained and analyzed for fiber type composition with ATPase histochemistry. Shot put performance was significantly correlated with type II fiber area ( r=0.70, P<0.01), one-arm seated shot put (range r=0.60 to r=0.79, P<0.05), elbow extensors' isokinetic torque (range r=0.65 to r=0.78, P<0.05), bench-press tests ( r>0.86, P<0.01) and estimated arm muscle cross-sectional area ( r=0.68, P<0.05). These results suggest that fiber type composition and the functional capacity of triceps brachii muscle (e.g., isokinetic torque) explain a part of shot put performance. The magnitude of the correlation coefficients between shot put and the upper-body power tests suggests that other body parts (e.g., lower extremities) may play a significant role in this event.

Audiological assessment in patients with mitochondrial myopathy.

Mitochondrial myopathies comprise a heterogeneous group of disorders characterized by the presence of ragged red fibres in muscle biopsy. The present study investigates the audiological features in a group of 14 patients in whom diagnosis was histologically confirmed. A complete ENT, neurological and audiological work-up was performed for every patient, including measurement of brainstem auditory evoked potentials (BAEPs). Most patients presented with a varying degree of hearing loss and occasional abnormalities of the latencies and interpeak latencies of the BAEPs, but only the increased latencies of waves I and V have been statistically confirmed. Audiological data suggest non-specific involvement at one or more sites along the auditory pathway.

A new mitochondrial tRNA(Met) gene mutation in a patient with dystrophic muscle and exercise intolerance.

A 30-year-old woman with a novel heteroplasmic U4409C mtDNA mutation in the tRNA(Met) gene presented with growth retardation, muscle weakness, severe exercise intolerance, and lactic acidosis. Muscle biopsy showed unusually severe dystrophic features. The mutation was not present in maternal relatives or 25 healthy subjects. Single-fiber PCR-RFLP analysis of mtDNA showed higher proportion of the mutation in COX-negative than in COX-positive muscle fibers.

Type II glycogenosis and thyroxine binding globulin deficiency in the same family.

An eight-member family is presented with two female members suffering from the juvenile form of acid maltase deficiency (AMD), the diagnosis confirmed by biochemical study of muscle. Biochemical leucocyte investigation revealed reduced a-glucosidase activity in both patients, a brother and the parents. Endocrinological study of the family disclosed reduced levels of thyroxine binding globulin (TBG) in the father and the three daughters. We consider the co-existence of AMD and TBG deficiency interesting, as thyroxine seems to play a role in the activation of acid maltase.

Size and proportion of fiber types in human muscle fascicles.

Size and distribution of 2 histochemical types of muscle fibers within the human muscle fascicle were investigated. Cryostat sections (ATPase, pH 9.4) were studied from 15 quadriceps femoris, 15 biceps brachii and 15 deltoid muscles taken at autopsy from 12 males and 9 females who had no history of neuromuscular disease. The number and the lesser diameter of type 1 and type 2 fibers were counted and percentage and mean diameter of the 2 types of fibers were calculated separately for periphery and interior of randomly selected fascicles. The results showed that a progressive age-related reduction of the diameter of type 2 fibers is observed and the predominance of type 2 fibers in the periphery is a constant finding in all muscles studied, regardless of sex and age.