Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head-to-tail binding

Mitokondriaalinen resessiivinen ataksiasyndrooma ja valproaattihoidon toksisuus

Mitokondriaalinen resessiivinen ataksiasyndrooma (MIRAS) voi ilmetä lapsuus-, nuoruus- tai aikuisiällä. Tauti johtuu polymeraasi gamma -geenin mutaatioista. Oireisto vaihtelee lasten enkefaliitin tyyppisestä akuutista taudinkuvasta nuorten vaikeahoitoiseen epilepsiaan ja migreenityyppiseen päänsärkyyn sekä aikuisiän ataksiaan, ääreishermorappeumaan, psykiatrisiin oireisiin ja älyllisten toimintojen heikkenemiseen. Epilepsiaa tulee hoitaa aktiivisesti, koska se on tärkein potilaan ennustetta huonontava tekijä. Akuuttina status epilepticuksena alkava MIRAS on tärkeä tunnistaa, koska valproaattihoito aiheuttaa näille potilaille lähes poikkeuksetta akuutin, jopa maksansiirtoa vaativan maksavaurion. Suomessakin on vuosien varrella kuollut toistakymmentä lasta ja nuorta valproaatin indusoiman MIRAS-maksavaurion vuoksi. English summary: Mitochondrial recessive ataxia syndrome (MIRAS) and valproate toxicity The clinical phenotypes vary considerably and can be divided into three groups: 1) childhood-onset encephalopathy and hepatopathy, 2) juvenile onset refractory epilepsy and migraine-like headaches, and 3) adult-onset ataxia and neuropathy with additional symptoms such as psychiatric symptoms and cognitive impairment. The life-threatening MIRAS epilepsy should be actively treated, as it is associated with poor prognosis. The form of MIRAS, starting as acute, treatment resistant epilepsy, is important to diagnose, since valproate therapy almost always leads to acute liver failure requiring liver transplantation

A multicenter study on Leigh syndrome: Disease course and predictors of survival

Background: Leigh syndrome is a progressive neurodegenerative disorder, associated with primary or secondary dysfunction of the mitochondrial oxidative phosphorylation. Despite the fact that Leigh syndrome is the most common phenotype of mitochondrial disorders in children, longitudinal natural history data is missing. This study was undertaken to assess the phenotypic and genotypic spectrum of patients with Leigh syndrome, characterise the clinical course and identify predictors of survival in a large cohort of patients. Methods. This is a retrospective study of patients with Leigh syndrome that have been followed at eight centers specialising in mitochondrial diseases in Europe; Gothenburg, Rotterdam, Helsinki, Copenhagen, Stockholm, Brussels, Bergen and Oulu. Results: A total of 130 patients were included (78 males; 52 females), of whom 77 patients had identified pathogenic mutations. The median age of disease onset was 7 months, w

Accommodating to English-medium instruction in teacher education in Finland

This study analyses teacher educators’ and student teachers’ perceptions of teaching and learning situations in an international English as a lingua franca (ELF) context in an English-medium instruction (EMI) teacher education programme in Finland. The analysis of semi-structured interviews revealed that the participants perceived a partial reversal of traditional teacher and student roles; students assisted voluntarily and teaching became reciprocal. Some teachers reflected on having used typical strategies in ELF context such as code-switching to further communication and engage students. However, teachers’ lack of fluency was sometimes considered causing frustration among students and affected negatively their feeling of being professional teacher educators. Nevertheless, by increasing more learner-led activities, ELF can positively affect teacher education pedagogy.Peer reviewe

Solvent-Induced Reversal of Activities between Two Closely Related Heterogeneous Catalysts in the Aldol Reaction

The relative rates of the aldol reaction catalyzed by supported primary and secondary amines can be inverted by 2 orders of magnitude, depending on the use of hexane or water as a solvent. Our analyses suggest that this dramatic shift in the catalytic behavior of the supported amines does not involve differences in reaction mechanism, but is caused by activation of imine to enamine equilibria and stabilization of iminium species. The effects of solvent polarity and acidity were found to be important to the performance of the catalytic reaction. This study highlights the critical role of solvent in multicomponent heterogeneous catalytic processes

Cross-Dehydrogenative Couplings between Indoles and β-Keto Esters : Ligand-Assisted Ligand Tautomerization and Dehydrogenation via a Proton-Assisted Electron Transfer to Pd(II)

Cross-dehydrogenative coupling reactions between -ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of -ketoesters and indoles. The mechanism of the reaction between a prototypical -ketoester, ethyl 2-oxocyclopentanonecarboxylate and N-methylindole, has been studied experimentally by monitoring the temporal course of the reaction by 1H NMR, kinetic isotope effect studies, and control experiments. DFT calculations have been carried out using a dispersion-corrected range-separated hybrid functional (B97X-D) to explore the basic elementary steps of the catalytic cycle. The experimental results indicate that the reaction proceeds via two catalytic cycles. Cycle A, the dehydrogenation cycle, produces an enone intermediate. The dehydrogenation is assisted by N-methylindole, which acts as a ligand for Pd(II). The compu-tational studies agree with this conclusion, and identify the turnover-limiting step of the dehydrogenation step, which involves a change in the coordination mode of the -keto ester ligand from an O,O’-chelate to an C-bound Pd enolate. This ligand tautom-erization event is assisted by the -bound indole ligand. Subsequent scission of the ’-C–H bond takes place via a proton-assisted electron transfer mechanism, where Pd(II) acts as an electron sink and the trifluoroacetate ligand acts as a proton acceptor, to pro-duce the Pd(0) complex of the enone intermediate. The coupling is completed in cycle B, where the enone is coupled with indole. Pd(TFA)2 and TFA-catalyzed pathways were examined experimentally and computationally for this cycle, and both were found to be viable routes for the coupling step

COL4A1 Mutations Cause Ocular Dysgenesis, Neuronal Localization Defects, and Myopathy in Mice and Walker-Warburg Syndrome in Humans

Muscle-eye-brain disease (MEB) and Walker Warburg Syndrome (WWS) belong to a spectrum of autosomal recessive diseases characterized by ocular dysgenesis, neuronal migration defects, and congenital muscular dystrophy. Until now, the pathophysiology of MEB/WWS has been attributed to alteration in dystroglycan post-translational modification. Here, we provide evidence that mutations in a gene coding for a major basement membrane protein, collagen IV alpha 1 (COL4A1), are a novel cause of MEB/WWS. Using a combination of histological, molecular, and biochemical approaches, we show that heterozygous Col4a1 mutant mice have ocular dysgenesis, neuronal localization defects, and myopathy characteristic of MEB/WWS. Importantly, we identified putative heterozygous mutations in COL4A1 in two MEB/WWS patients. Both mutations occur within conserved amino acids of the triple-helix-forming domain of the protein, and at least one mutation interferes with secretion of the mutant proteins, resulting instead in intracellular accumulation. Expression and posttranslational modification of dystroglycan is unaltered in Col4a1 mutant mice indicating that COL4A1 mutations represent a distinct pathogenic mechanism underlying MEB/WWS. These findings implicate a novel gene and a novel mechanism in the etiology of MEB/WWS and expand the clinical spectrum of COL4A1-associated disorders

Somatosensory processing in neurodevelopmental disorders

The purpose of this article is to review the role of somatosensory perception in typical development, its aberration in a range of neurodevelopmental disorders, and the potential relations between tactile processing abnormalities and central features of each disorder such as motor, communication, and social development. Neurodevelopmental disorders that represent a range of symptoms and etiologies, and for which multiple peer-reviewed articles on somatosensory differences have been published, were chosen to include in the review. Relevant studies in animal models, as well as conditions of early sensory deprivation, are also included. Somatosensory processing plays an important, yet often overlooked, role in typical development and is aberrant in various neurodevelopmental disorders. This is demonstrated in studies of behavior, sensory thresholds, neuroanatomy, and neurophysiology in samples of children with Fragile X syndrome, autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and cerebral palsy (CP). Impaired somatosensory processing is found in a range of neurodevelopmental disorders and is associated with deficits in communication, motor ability, and social skills in these disorders. Given the central role of touch in early development, both experimental and clinical approaches should take into consideration the role of somatosensory processing in the etiology and treatment of neurodevelopmental disorders