Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller’s dementia infantilis, a rare subtype of autism spectrum disorder

International audienceAbstractBackgroundDeletions and mutations involving the SHANK3 gene lead to a nonspecific clinical presentation with moderate to profound intellectual disability, severely delayed or absent speech, and autism spectrum disorders (ASD).Better knowledge of the clinical spectrum of SHANK3 haploinsufficiency is useful to facilitate clinical care monitoring and to guide molecular diagnosis, essential for genetic counselling.Case presentationHere, we report a detailed clinical description of a 10-year-old girl carrying a pathogenic interstitial 22q13.3 deletion encompassing only the first 17 exons of SHANK3.The clinical features displayed by the girl strongly suggested the diagnosis of dementia infantilis, described by Heller in 1908, also known as childhood disintegrative disorder.ConclusionOur present case confirms several observations according to which regression may be part of the clinical phenotype of SHANK3 haploinsufficiency. Therefore, we think it is crucial to look for mutations in the gene SHANK3 in patients diagnosed for childhood disintegrative disorder or any developmental disorder with a regressive pattern involving social and communicative skills as well as cognitive and instinctual functions, with onset around 3 years

On the Approximation Ratio of the MST-based Heuristic for the Energy-Efficient Broadcast Problem in Static Ad-Hoc Radio Networks

We present a new analysis of the approximation ratio of the MST-based heuristic [1] for the Minimum Energy Broadcast Problem in Ad-Hoc Radio Networks

Pre- and Intraoperative Visualization of GRPR-Expressing Solid Tumors: Preclinical Profiling of Novel Dual-Modality Probes for Nuclear and Fluorescence Imaging

Image-guided surgery using a gastrin-releasing peptide receptor (GRPR)-targeting dual-modality probe could improve the accuracy of the resection of various solid tumors. The aim of this study was to further characterize our four previously developed GRPR-targeting dual-modality probes that vary in linker structures and were labeled with indium-111 and sulfo-cyanine 5. Cell uptake studies with GRPR-positive PC-3 cells and GRPR-negative NCI-H69 cells confirmed receptor specificity. Imaging and biodistribution studies at 4 and 24 h with 20 MBq/1 nmol [111In]In-12-15 were performed in nude mice bearing a PC-3 and NCI-H69 xenograft, and showed that the probe with only a pADA linker in the backbone had the highest tumor-to-organ ratios (T/O) at 24 h after injection (T/O > 5 for, e.g., prostate, muscle and blood). For this probe, a dose optimization study with three doses (0.75, 1.25 and 1.75 nmol; 20 MBq) revealed that the maximum image contrast was achieved with the lowest dose. Subsequently, the probe was successfully used for tumor excision in a simulated image-guided surgery setting. Moreover, it demonstrated binding to tissue sections of human prostate, breast and gastro-intestinal stromal tumors. In summary, our findings demonstrate that the developed dual-modality probe has the potential to aid in the complete surgical removal of GRPR-positive tumors

Deep Reactive Ion Etching of Through Silicon Vias

This chapter contains sections titled: • Introduction • DRIE Equipment and Characterization • DRIE Processing • Practical Solutions in Via Etching • Concluding Remarks • Appendix A: Glossary of Abbreviations • Appendix B: Examples of DRIE Recipes • Reference

Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients

Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies

A Mutation Associated with CMT2A Neuropathy Causes Defects in Fzo1 GTP Hydrolysis, Ubiquitylation, and Protein Turnover

Charcot-Marie-Tooth disease type 2A (CMT2A) is caused by mutations in the gene MFN2 and is one of the most common inherited peripheral neuropathies. Mfn2 is one of two mammalian mitofusin GTPases that promote mitochondrial fusion and maintain organelle integrity. It is not known how mitofusin mutations cause axonal degeneration and CMT2A disease. We used the conserved yeast mitofusin FZO1 to study the molecular consequences of CMT2A mutations on Fzo1 function in vivo and in vitro. One mutation (analogous to the CMT2A I213T substitution in the GTPase domain of Mfn2) not only abolishes GTP hydrolysis and mitochondrial membrane fusion but also reduces Mdm30-mediated ubiquitylation and degradation of the mutant protein. Importantly, complexes of wild type and the mutant Fzo1 protein are GTPase active and restore ubiquitylation and degradation of the latter. These studies identify diverse and unexpected effects of CMT2A mutations, including a possible role for mitofusin ubiquitylation and degradation in CMT2A pathogenesis, and provide evidence for a novel link between Fzo1 GTP hydrolysis, ubiquitylation, and mitochondrial fusion