Background Alterations in the MYH7 gene can cause cardiac and skeletal myopathies. MYH7 -related skeletal myopathies are extremely rare, and the vast majority of causal variants in the MYH7 gene are predicted to alter the rod domain of the of ß-cardiac myosin molecule, resulting in distal muscle weakness as the predominant manifestation. Here we describe two unrelated patients harboring an in-frame deletion in the MYH7 gene that is predicted to result in deletion of a single amino acid (p.Glu500del) in the head domain of ß-cardiac myosin. Both patients display an unusual skeletal myopathy phenotype with congenital axial stiffness and muscular hypertonus, but no cardiac involvement. Results Clinical data, MRI results and histopathological data were collected retrospectively in two unrelated boys (9 and 3.5 years old). Exome sequencing uncovered the same 3-bp in-frame deletion in exon 15 (c.1498_1500delGAG) of the MYH7 gene of both patients, a mutation which deletes a highly conserved glutamate residue (p.Glu500del) in the relay loop of the head domain of the ß-cardiac myosin heavy chain. The mutation occurred de novo in one patient, whereas mosaicism was detected in blood of the father of the second patient. Both boys presented with an unusual phenotype of prenatal polyhydramnios, congenital axial stiffness and muscular hypertonus. In one patient the phenotype evolved into an axial/proximal skeletal myopathy without distal involvement or cardiomyopathy, whereas the other patient exhibited predominantly stiffness and respiratory involvement. We review and compare all patients described in the literature who possess a variant predicted to alter the p.Glu500 residue in the ß-cardiac myosin head domain, and we provide in-silico analyses of potential effects on polypeptide function. Conclusion The data presented here expand the phenotypic spectrum of mutations in the MYH7 gene and have implications for future diagnostics and therapeutic approaches.

Despite performance improvements of organic photovoltaics, the mechanism of photoinduced electron-hole separation at organic donor-acceptor interfaces remains poorly understood. Inconclusive experimental and theoretical results have produced contradictory models for electron-hole separation in which the role of interfacial charge-transfer (CT) states is unclear, with one model identifying them as limiting separation and another as readily dissociating. Here, polymer-fullerene blends with contrasting photocurrent properties and enthalpic offsets driving separation were studied. By modifying composition, film structures were varied from consisting of molecularly mixed polymer-fullerene domains to consisting of both molecularly mixed and fullerene domains. Transient absorption spectroscopy revealed that CT state dissociation generating separated electron-hole pairs is only efficient in the high energy offset blend with fullerene domains. In all other blends (with low offset or predominantly molecularly mixed domains), nanosecond geminate electron-hole recombination is observed revealing the importance of spatially localized electron-hole pairs (bound CT states) in the electron-hole dynamics. A two-dimensional lattice exciton model was used to simulate the excited state spectrum of a model system as a function of microstructure and energy offset. The results could reproduce the main features of experimental electroluminescence spectra indicating that electron-hole pairs become less bound and more spatially separated upon increasing energy offset and fullerene domain density. Differences between electroluminescence and photoluminescence spectra could be explained by CT photoluminescence being dominated by more-bound states, reflecting geminate recombination processes, while CT electroluminescence preferentially probes less-bound CT states that escape geminate recombination. These results suggest that apparently contradictory studies on electron-hole separation can be explained by the presence of both bound and unbound CT states in the same film, as a result of a range of interface structures.

Nemaline myopathy (NEM) is one of the most prevalent congenital-onset myopathies, characterized by typical rod-like protein accumulations in skeletal myofibers. It has been shown that the there is a wide spectrum of disease severity, ranging from prenatal or neonatal onset with early death in infancy due to respiratory failure, infantile onset with profound weakness, to adult onset with only mild weakness. Different mutations in more than 10 genes cause NEM, suggesting genetic heterogeneity. Thus, conducting clinical trials is challenging. Currently, clinical management in NEM consists of supportive treatments directed towards the specific clinical symptoms of affected individuals. Due to several case reports that suggest beneficial effects of dietary L-tyrosine supplementation, self-administration is common though lack of evidence. Here, we report on four patients with congenital NEM and their self-reported effects of dietary supplementation with L-Tyrosine and motor scores as far as available. In addition, we summarize past and current literature to review frequent practices of dietary supplementation with L-tyrosine.

Nusinersen (Spinraza) was approved by the EMA in 2017 due to the significant improvement of survival and motor function in SMA patients. A rapid initiation of this treatment, ideally in the pre-symptomatic phase, revealed the best outcome. In order to confirm the few already published data showing positive effects of nusinersen on the ability to walk of older patients, 6 ambulatory SMA III patients were followed-up, focusing on walking distance and other motor functions. Data from 6 ambulatory patients with SMA III (age 3 - 14 years) were collected; onset of treatment was between 10/2017 and 02/2018. 3 out of 6 patients received 7 applications of nusinersen, 3 patients received 6 applications. Motor function was tested using Hammersmith Functional Motor Scale Expanded (HFMSE) and 6-minute-walking distance test (6MWD). With two exceptions the test was performed immediately prior to each nusinersen application. In this short observation period (13-18 months) we noted an overall increase (30m-89m) in the walking distance (6MWD) in 5 out of 6 patients. We also observed an increase from 2 to 5 points in the HFMSE in 5 out of 6 patients. The HFMSE dropped by 2 points in a 5 year old boy while his 6MWD increased by 89m. Moreover an improvement of their quality of life has been described by all participants of this study. Our preliminary data show that the nusinersen treatment resulted in an improvement of the walking distance. However, further studies with a larger patient group and/or a longer follow-up observational period are required to verify this observation.

To date, more than 10 genes are known to be causatively involved in nemaline myopathy (NEM). In 2014, a severe form of NEM with prenatal or neonatal onset and substantial risk of death in early childhood, caused by truncating mutations in LMOD3 was identified and denoted as NEM10. In 2018, we reported four unrelated patients from Austria and Germany (Bavaria) with a milder phenotype and disease course. In contrast to the previously described severe phenotype, these patients reached the ability to walk and survived into adulthood. Remarkably, they shared the missense variants c.1648C>T p.(Leu550Phe) and/or c.1004A>G p.(Gln335Arg) in the LMOD3, either in homozygous or compound heterozygous state. The apparent clusters of 2 mild LMOD3 missense variants in Germany and Austria in 4 unrelated families may be explained by a founder effect. One patient showed a distinct phenotype with profound facial weakness, progressive scoliosis with loss of ability to walk independently and reduced vital capacity, suggesting a broader spectrum of disease course. We provide detailed clinical descriptions and updates of these four patients and a review of literature.

Efficient exciton dissociation into mobile charge carries a crucial factor underscoring the performance of organic polymer-based bulk-heterojunction photovoltaic devices. In this paper, we compute the energies of charge-transfer (CT) states of the model donor-acceptor lattice system with varying degrees of structural disorder to investigate how fluctuations in the material properties affect electron-hole separation. We also demonstrate how proper statistical treatment of the CT energies recovers the experimentally observed "hot" and "cold" exciton dissociation pathways. Using a quantum mechanical model for a model heterojunction interface, we recover experimental values for the open-circuit voltage at 50 and 100 meV of site-energy disorder. We find that energetic and conformational disorder generally facilitates charge transfer; however, due to excess energy supplied by photoexcitation, highly energetic electron-hole pairs can dissociate in unfavorable directions, potentially never contributing to the photocurrent while "cold" excitons follow the free energy curve defined at the operating temperature of the device.

In this study, we performed a survey of infantile and late-onset Pompe disease (IOPD and LOPD) in Austria. Paediatric and neuromuscular centres were contacted to provide a set of anonymized clinical and genetic data of patients with IOPD and LOPD. The number of patients receiving enzyme replacement therapy (ERT) was obtained from the pharmaceutical company providing alglucosidase alfa. We found 25 patients in 24 families, 4 IOPD and 21 LOPD with a resulting prevalence of 1:350,914. The most frequent clinical manifestation in LOPD was a lower limb-girdle phenotype combined with axial weakness. Three patients were clinically pauci- or asymptomatic and were diagnosed because of persistent hyperCKemia. Diagnostic delay in LOPD was 7.4 ± 9.7 years. The most common mutation was c.-32-13T > G. All IOPD and 17 symptomatic LOPD patients are receiving ERT. Standardized follow-up was only available in six LOPD patients for the 6-min walk test (6minWT) and in ten for the forced vital capacity (FVC). Mean FVC did not decline (before ERT; 63.6 ± 39.7%; last evaluation during ERT: 61.9 ± 26.9%; P = 0.5) while there was a trend to decline in the mean distance covered by the 6minWT (before ERT: 373.5 ± 117.9 m; last evaluation during ERT: 308.5 ± 120.8 m; P = 0.077). The study shows a lower prevalence of Pompe disease in Austria than in other European countries and corroborates a limb-girdle phenotype with axial weakness as the most common clinical presentation, although asymptomatic hyperCKemia may be the first indication of LOPD.

We present here a formally exact model for electronic transitions between an initial (donor) and final (acceptor) states linked by an intermediate (bridge) state. Our model incorporates a common set of vibrational modes that are coupled to the donor, bridge, and acceptor states and serves as a dissipative bath that destroys quantum coherence between the donor and acceptor. Taking the memory time of the bath as a free parameter, we calculate transition rates for a heuristic 3-state/2 mode Hamiltonian system parameterized to represent the energetics and couplings in a typical organic photovoltaic system. Our results indicate that if the memory time of the bath is of the order of 10-100 fs, a two-state kinetic (i.e., incoherent hopping) model will grossly underestimate overall transition rate.

Extensive research has been conducted on a navigation system for inland vessels at the University of Stuttgart and at the Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg (Focus Max Planck Gesellschaft, Computer at the helm, http://www.mpg.de/942027). As part of this navigation system, a model/based track-keeping controller has been developed. A high performance controller is required because of the reduced space available on rivers and canals. The control structure consists of two components, a feedback and a feedforward block, where the former is provided by a linear quadratic gaussian controller. Both components require the ship dynamics model and thus, the parameter estimation of the underlying model is a key issue to achieve high performance. In this chapter, we firstly consider Monte Carlo simulations to generate data of the closed-loop system and then the parameters of a continuous-time steering dynamics model are identified. The parameter estimation problem is solved applying an instrumental variable method, which takes into account the control structure. Parameter identification using real closed-loop experiments is also considered. Additionally, we evaluate the experiments for parameter estimation through a sensitivity analysis.

Introduction: With "next generation sequencing," a new method is available which offers efficient possibility of parallel sequencing up to 100 gens (> 2,000 exons).

Introduction: Glucose-6-phosphate dehydrogenase deficiency (G6PD) is a common X-linked inherited disorder affecting persons of African, Asian, Mediterranean, or Middle-Eastern descent. The erythrocytes of the patients express an increased vulnerability to oxidative stress. The majority of persons with reduced enzyme activity is asymptomatic, but some have episodic severe hemolysis and others chronic anemia. There are only a few reports of rhabdomyolysis during a hemolytic crisis and one case report of malignant hyperthermia during anesthesia. Case Report: A 17-year-old patient of Middle Eastern origin came to our hospital because of abdominal pain after sports and the ingestion of beans. He had normal hemoglobin and red cell blood count, but moderate thrombopenia, hyperbilirubinemia, and a creatine kinase (CK) of 6,939 U/L. During the next days, the CK went up to 21,753 U/L with extensive high myoglobin of more than 3,000 ng/mL. Lowest erythrocyte count was 4.47 T/L and lowest hemoglobin 13.9 g/dL. Muscle biopsy revealed augmented storage of glycogen. The whole-exome analysis by next generation sequencing (NGS) showed a hemizygous pathogen mutation in the exome 6 (c.563C>T; p.Ser188Phe) of the G6PD gene. Conclusion: In a patient with rhabdomyolysis even without substantial hemolysis, a G6PD should be considered. This diagnosis is essential advising the patient concerning medicine and substance use.

Background: Mutations in the mitochondrial DNA are maternally inherited and may lead to multisystem disorders. A tissue-specific threshold-level of the respective mtDNA-mutation load must be exceeded to give rise to a phenotypic manifestation.

Deletion of a single nucleotide (7630delT) within MT-CO2, the gene of subunit II of cytochrome c oxidase (COX), was identified in a clinically typical MELAS case. The deletion-induced frameshift results in a stop codon close to the 5' end of the reading frame. The lack of subunit II (COII) precludes the assembly of COX and leads to the degradation of unassembled subunits, even those not directly affected by the mutation. Despite mitochondrial proliferation and transcriptional upregulation of nuclear and mtDNA-encoded COX genes (including MT-CO2), a severe COX deficiency was found with all investigations of the muscle biopsy (histochemistry, biochemistry, immunoblotting). The 7630delT mutation in MT-CO2 leads to a lack of COII with subsequent misassembly and degradation of respiratory complex IV despite transcriptional upregulation of its subunits. The genetic and pathobiochemical heterogeneity of MELAS appears to be greater than previously appreciated.

This contribution gives an overview of our recent study of phonon-driven exciton dissociation at semiconductor polymer heterojunctions, using a quantum dynamical analysis based on a linear vibronic coupling model parametrized for three electronic states and 20-30 phonon modes. The decay of the photogenerated exciton towards an interfacial charge transfer state is an ultrafast (femtosecond to picosecond scale) process which initiates the photocurrent generation. We consider several representative interface configurations, which are shown to exhibit an efficient exciton dissociation. The process depends critically on the presence of intermediate states, and on the dynamical interplay between high-frequency (C=C stretch) and low-frequency (ring-torsional) modes. The dynamical mechanism is interpreted in terms of a hierarchical electron-phonon model which allows one to identify generalized reaction coordinates for the nonadiabatic process. This analysis highlights that the electron-phonon coupling is dominated by the high-frequency modes, but the low-frequency modes are crucial in mediating the transition to a charge-separated state. The ultrafast, highly nonequilibrium dynamics is in accordance with spectroscopic observations.

Autosomal recessive Charcot-Marie-Tooth syndrome (AR-CMT) is often characterised by an infantile disease onset and a severe phenotype. Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene are thought to be a common cause of AR-CMT. Mutations in the periaxin (PRX) gene are rare. They are associated with severe demyelination of the peripheral nerves and sometimes lead to prominent sensory disturbances. To evaluate the frequency of GDAP1 and PRX mutations in early onset CMT, we examined seven AR-CMT families and 12 sporadic CMT patients, all presenting with progressive distal muscle weakness and wasting. In one family also prominent sensory abnormalities and sensory ataxia were apparent from early childhood. In three families we detected four GDAP1 mutations (L58LfsX4, R191X, L239F and P153L), one of which is novel and is predicted to cause a loss of protein function. In one additional family with prominent sensory abnormalities a novel homozygous PRX mutation was found (A700PfsX17). No mutations were identified in 12 sporadic cases. This study suggests that mutations in the GDAP1 gene are a common cause of early-onset AR-CMT. In patients with early-onset demyelinating AR-CMT and severe sensory loss PRX is one of the genes to be tested.