Late Onset Pompe Disease with Novel Mutations and Atypical Phenotypes

Background: Late onset Pompe disease (LOPD) is rare and generally manifests predominantly as progressive limb girdle muscle weakness. It is linked to the pathogenic mutations in GAA gene, which leads to glycogen accumulation in various tissues. Materials and methods: We describe the unusual clinical, biochemical, histopathological and genetic characteristics of 5 cases of LOPD. Results: The first case had progressive anterior horn cell like disease (AHCD) that evolved later to classical limb girdle syndrome and respiratory failure, the second patient had rigid spine syndrome with gastrointestinal manifestations, the third had limb girdle weakness superimposed with episodic prolonged worsening and respiratory failure, the fourth had large fibre sensory neuropathy without primary muscle involvement and the fifth presented with classical limb girdle muscle weakness. Two homozygous missense mutations c.1461C > A (p.Phe487Leu) and c.1082C > T (p.Pro361Leu) in the GAA gene were identified in case 1 and 2 respectively. Case 3 was compound heterozygous with inframe c.1935_1940del (p.Val646_Cys647del) and an intronic splice effecting variant c.-32-13T > G. Compound heterozygous missense variants c.971C > T (p.Pro324Leu) and c.794G > A (p.Ser265Asn) were identified in case 4. Case 5 had a frameshift insertion c.1396dupG (p.Val466GlyfsTer40) and a synonymous splice affecting variant c.546G > T(p.Thr182=). Conclusion: We are describing for the first time from India on LOPD with unusual phenotypes identified. A high degree of clinical suspicion and diagnosing rare phenotypes of Pompe disease is imperative to consider early initiation of Enzyme Replacement Therapy (ERT).

Development of the Pectoral Lobed Fin in the Australian Lungfish Neoceratodus forsteri

The evolutionary transition from paired fins to limbs involved the establishment of a set of limb muscles as an evolutionary novelty. In parallel, there was a change in the topography of the spinal nerves innervating appendicular muscles, so that distinct plexuses were formed at the bases of limbs. However, the key developmental changes that brought about this evolutionary novelty have remained elusive due to a lack of data on the development of lobed fins in sarcopterygian fishes. Here, we observed the development of the pectoral fin in the Australian lungfish Neoceratodus forsteri (Sarcopterygii) through synchrotron radiation X-ray microtomography. Neoceratodus forsteri is a key taxon for understanding the fin-to-limb transition due to its close phylogenetic relationships to tetrapods and well-developed lobed fins. At the onset of the fin bud in N. forsteri, there is no mesenchyme at the junction between the axial body wall and the fin bud, which corresponds to the embryonic position of the brachial plexus formed in the mesenchyme in tetrapods. Later, concurrent with the cartilage formation in the fin skeleton, the fin adductor and abductor muscles become differentiated within the surface ectoderm of the fin bud. Subsequently, the girdle muscle, which is homologous to the tetrapod serratus muscle, newly develops at the junction between the axial body wall and the fin. Our study suggests that the acquisition of embryonic mesenchyme at the junction between the axial body wall and the appendicular bud opened the door to the formation of the brachial plexus and the specialization of individual muscles in the lineage that gave rise to tetrapods.

TBE in Lithuania

The first case of tick-borne encephalitis (TBE) in Lithuania, diagnosed by clinical and epidemiologic criteria only, was reported in 1953. A forest worker became ill with the disease in April after a tick bite, had a typical clinical presentation with shoulder girdle muscle paralysis and bulbar syndrome, and died after 12 days from the start of clinical symptoms. Autopsy data were compatible with viral encephalitis.1 Serological diagnosis of TBE in Lithuania was started in 1970.2

Skeletal muscle status, autonomic balance and short-term results of cardiac surgery

Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Research Institute for Complex Issues of Cardiovascular Diseases The aim - investigate the association of the lower extremities skeletal muscle state, status autonomic nervous system (ANS) and short-term results of the cardiac operations. Design Study included 64 patients, who underwent planned cardiac surgery. All subjects before surgery performed a routine laboratory and instrumental examinations, six-minute walk test (6MWT), and static-dynamic tests on the training device. ANS was carried out, using ORTOexpert software. Were formed 2 groups – with the combined endpoint CEP (n = 9) and without CEP (n = 55). CEP included: perioperative development stroke, myocardial infarction, persistent arrhythmias and heart block, multiple organ dysfunction syndrome, death. Results Not found difference between the groups in gender, age, in main clinical data and laboratory tests indicators, and in endurance of the skeletal muscles or the 6MWT. In the CEP group, strength of skeletal muscles of the upper and lower extremities was lower, initially more pronounced sympathetic activation and larger values of the power of the frequency spectrum (TF). Stress index (IS) was lower in the CEP group, but after transitioning orthostatic position it surpassed the number without CEP. One-factor logistic regression analysis established factors associated with the development of CEP - poor muscle status, peripheral atherosclerosis; high EuroSCORE, cardiopulmonary bypass duration (CBD) and ANS disbalance. Multivariate regression analysis to establish the relationship of poor skeletal muscle status, pronounced sympathicotonia and a high incidence of postoperative complications. Logistic regression analisys Odds ratio [ -95%; +95%CL] p One-factor logistic regression Stenosis ICA ≥ 30% 9,545 [1,030; 88,467] ,043 Shoulder Girdle Muscle Strength (Kg) 0,893 [0,786; 1,001] ,048 Knee extensors strength (kg) 1,012 [0,997; 1,029] ,098 Amo (basic) 0,958 [0,920; 0,998] ,037 IS (basic) 0,996 [0,990; 1,000] ,096 EuroSCORE (points) 1,643 [1,003; 2,694] ,043 CBD (min) 1,010 [1,001; 1,022] ,068 Multiple-factor logistic regression p=,001 LF/HF 1,175 [0,972; 1,420] ,088 Amo (basic) 0,950 [0,905; 0,997] ,034 Shoulder Girdle Muscle Strength (Kg) 0,863 [0,750; 0,993] ,036 LF/HF-ratio Low frecuency/High frecuency Amo-mode amplitude

Circulating miR-206 as a Biomarker for Patients Affected by Severe Limb Girdle Muscle Dystrophies

Limb-girdle muscular dystrophies (LGMD) are clinically and genetically heterogeneous conditions, presenting with a wide clinical spectrum, leading to progressive proximal weakness caused by loss of muscle fibers. MiR-206 is a member of myomiRNAs, a group of miRNAs with important function in skeletal muscle. Our aim is to determine the value of miR-206 in detecting muscle disease evolution in patients affected by LGMD. We describe clinical features, disease history and progression of eleven patients affected by various types of LGMD: transportinopathy, sarcoglycanopathy and calpainopathy. We analyzed the patients’ mutations and we studied the circulating miR-206 in serum by qRT-PCR; muscle MRI was done with a 1.5 Tesla apparatus. The severe evolution of disease type is associated with the expression levels of miR-206, which was significantly elevated in our LGMD patient cohort in comparison with a control group. In particular, we observed an over-expression of miR-206 that was 50–80 folds elevated in two patients with a severe and early disease course in the transportinopathy and calpainopathy sub-types. The functional impairment was observed clinically and muscle loss and atrophy documented by muscle MRI. This study provides the first evidence that miR-206 is associated with phenotypic expression and it could be used as a prognostic indicator of LGMD disease progression.

Muscle biopsy: what and why and when?

Skeletal muscle biopsy remains an important investigative tool in the diagnosis of a variety of muscle disorders. Traditionally, someone with a limb-girdle muscle weakness, myopathic changes on electrophysiology and raised serum creatine kinase (CK) would have a muscle biopsy. However, we are living through a genetics revolution, and so do all such patients still need a biopsy? When should we undertake a muscle biopsy in patients with a distal, scapuloperoneal or other patterns of muscle weakness? When should patients with myositis, rhabdomyolysis, myalgia, hyperCKaemia or a drug-related myopathy have a muscle biopsy? What does normal muscle histology look like and what changes occur in neurogenic and myopathic disorders? As with Kipling’s six honest serving men, we hope that by addressing these issues we can all become more confident about when to request a muscle biopsy and develop clearer insights into muscle pathology.

TBE in Lithuania

The first case of tick-borne encephalitis (TBE) in Lithuania, diagnosed by clinical and epidemiologic criteria only, was reported in 1953. A forest worker became ill with the disease in April after a tick bite, had a typical clinical presentation with shoulder girdle muscle paralysis and bulbar syndrome, and died after 12 days from the start of clinical symptoms. Autopsy data were compatible with viral encephalitis.1 Serological diagnosis of TBE in Lithuania was started in 1970.2

SUN-076 Somatic and Neurodevelopmental Outcome and Muscle Tone in 5 to 9 Year Old Children Born After Intracytoplasmic Sperm Injection

Introduction: Assessing the development and health status of children born after assisted reproductive techniques is very important. This also applies to somatic and neurological development. Little is known on the development of muscle tone in children. Aim of our study was to evaluate the somatic and neurological development in children born after intracytoplasmic sperm injection (ICSI) with special focus on proximal muscle tone. Material and methods: A group of 82 singletons (ICSI) aged 5–9 years (42 M, 40 F) and a control group of 82 singletons spontaneously conceived (SC), all with low morbidity, were compared by age and sex. Comprehensive assessment by endocrinologist, clinical anthropologist and pediatric neurologist was performed. Results: Both ICSI and SC children had normal somatic development. In the standard neurological testing, motor development did not differ significantly in ICSI children compared with the general population. Nevertheless, some coordination abnormalities tested by diadochokinesis and by the finger-nose test, were found in all but 7 ICSI children (ICSI in 91 % versus SC in 9 %; p<0.001). A prominent hypotonia of upper girdle muscles tested by the scarf sign was found in all but 4 ICSI children (ICSI in 95 % versus SC in 61 %; p<0.001). In the contrary, no difference was found for lower girdle muscle tone in ICSI versus SC children. Any of the factors tested for possible relationship to upper girdle muscle hypotonia was not found to be significant. Conclusions: As far as we know, this study is the first evaluation of proximal muscle tone in ICSI children aged 5 - 9 years. Subtle changes in the neurological status were revealed comparing ICSI and SC children, i. e. the prominent upper girdle muscle hypotonia and the coordination changes. The hypotonia can be explained by a slight change in the muscle tone maturation and movement coordination. The ICSI method very likely does not have any negative effect on the neurodevelopmental outcome of children. Nevertheless, the development of muscle tone and coordination in ICSI children should be monitored. Early diagnosis of these abnormalities helps to early initiation of appropriate therapy and thus avoids possible complications.