Biallelic SEMA3A defects cause a novel type of syndromic short stature.

Chromosomal microarray testing is commonly used to identify disease causing de novo copy number variants in patients with developmental delay and multiple congenital anomalies. In such a patient we now observed an 150 kb deletion on chromosome 7q21.11 affecting the first exon of the axon guidance molecule gene SEMA3A (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3A). This deletion was inherited from the healthy father, but considering the function of SEMA3A and phenotypic similarity to the knock-out mice, we still assumed a pathogenic relevance and tested for a recessive second defect. Sequencing of SEMA3A in the patient indeed revealed the de novo in-frame mutation p.Phe316_Lys317delinsThrSerSerAsnGlu. Cloning of the mutated allele in combination with two informative SNPs confirmed compound heterozygosity in the patient. While the altered protein structure was predicted to be benign, aberrant splicing resulting in a premature stop codon was proven by RT-PCR to occur in about half of the transcripts from this allele. Expression profiling in human fetal and adult cDNA panels, confirmed a high expression of SEMA3A in all brain regions as well as in adult and fetal heart and fetal skeletal muscle. Normal intellectual development in the patient was surprising but may be explained by the remaining 20% of SEMA3A expression level demonstrated by quantitative RT-PCR. We therefore report a novel autosomal recessive syndrome characterized by postnatal short stature with relative macrocephaly, camptodactyly, septal heart defect and several minor anomalies caused by biallelic mutations in SEMA3A.

Treatment with Nusinersen - Challenges Regarding the Indication for Children with SMA Type 1.

The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is challenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 based on different clinical case scenarios.

Virtual endoscopy on a portable navigation system for ENT surgery.

Virtual endoscopy is considered as an ideal aid assessing the complex anatomy of patients and has already been evaluated in several clinical studies. However, due to the increasing quality of modern CT- and MRT-images, present virtual-endoscopy software relies on powerful hardware. In this contribution virtual endoscopy on a portable navigation system for ENT surgery is proposed. The portable navigation system features a tablet pc to ensure a device that does not need much space in the operating room.

Automatic correction of registration errors in surgical navigation systems.

Surgical navigation systems are used widely among all fields of modern medicine, including, but not limited to ENT- and maxillofacial surgery. As a fundamental prerequisite for image-guided surgery, intraoperative registration, which maps image to patient coordinates, has been subject to many studies and developments. While registration methods have evolved from invasive procedures like fixed stereotactic frames and implanted fiducial markers toward surface-based registration and noninvasive markers fixed to the patient's skin, even the most sophisticated registration techniques produce an imperfect result. Due to errors introduced during the registration process, the projection of navigated instruments into image data deviates up to several millimeter from the actual position, depending on the applied registration method and the distance between the instrument and the fiducial markers. We propose a method that allows to automatically and continually improve registration accuracy during intraoperative navigation after the actual registration process has been completed. The projections of navigated instruments into image data are inspected and validated by the navigation software. Errors in image-to-patient registration are identified by calculating intersections between the virtual instruments' axes and surfaces of hard bone tissue extracted from the patient's image data. The information gained from the identification of such registration errors is then used to improve registration accuracy by adding an additional pair of registration points at every location where an error has been detected. The proposed method was integrated into a surgical navigation system based on paired points registration with anatomical landmarks. Experiments were conducted, where registrations with deliberately misplaced point pairs were corrected with automatic error correction. Results showed an improvement in registration quality in all cases.

Official measurement protocol and accuracy results for an optical surgical navigation system (NPU).

Image-guided surgical navigation is on the rise in many different areas of modern medicine and is already an established standard in some disciplines like ear nose and throat (ENT) or maxillofacial surgery. When evaluating surgical navigation systems the absolute accuracy of the device is of major concern to the surgeon. The following work presents two different ways of measuring the accuracy of surgical navigation systems using the example of the KARL STORZ Navigation Panel Unit (NPU). According to these protocols the FDA approval of the NPU navigation system was prepared. In a first series of experiments the accuracy under realistic surgical conditions is evaluated with a phantom of a human head, which is manufactured in rapid-prototyping processes. In another series of experiments a custom registration board is used, which provides means to evaluate the accuracy under optimal conditions and also allows further measurements regarding the registration error, that are not possible with the phantom. In the experiments an accuracy of 1.44 mm ± 0.18 mm was measured in the surgical setup and 0.63 mm ± 0.07 mm under ideal conditions.

Design and accuracy evaluation of a new navigated drill system for computer assisted ENT-surgery.

In this article a new navigated drill system for computer assisted ear, nose and throat (ENT) surgery is presented. The navigated drill and the microscope probe are part of a surgical navigation system for ENT-surgery. In particular, the accuracy of the new navigated drill is compared to an existing navigated drill experimentally under conditions close to the surgical workflow. For the technical accuracy experiment, the new navigated drill in combination with the new microscope probe and a particular navigated measurement board have been integrated, together with the current navigated drill, in a navigation system by a special navigation software with measuring function, based on a standard ENT navigation software. The developed navigated measurement board provided the implementation of reproducible experiments and the direct accuracy comparison of the two navigated instruments under the same conditions. Thereby, N = 15 accuracy experiments are performed with both navigated drill systems with three possible tracker positions. The distance between the planned and the touched points were calculated and compared. The average distances from the planned points to the touched points with the new navigated drill is in the left tracker position 1.10 mm, in the middle tracker position 1.14 mm and in the right tracker position 1.59 mm. In comparison to the existing drill, the new navigated drill, measured with each tracker position, is 0.62 mm more accurate.

Evaluation of baculovirus-derived recombinant 53-kDa protein of Trichinella spiralis for detection of Trichinella-specific antibodies in domestic pigs by ELISA.

The complete gene encoding the 53-kDa protein derived from Trichinella spiralis was cloned and expressed using a baculovirus-based system. Characterization of a purified fusion protein consisting of the 53-kDa protein and the glutathione S-transferase protein showed unspecific reactivity with swine pre-immune serum in both enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Subsequently, a purified C-terminal 6xHis-tagged 53-kDa protein was used in an ELISA. The evaluation of the test using a negative serum panel showed a high specificity for the ELISA. Serum panels of pigs infected with T. spiralis of two independent experiments showed that pigs of one experiment were tested positive by the ELISA, whereas all sera of the second experiment were negative, indicating a low sensitivity of the ELISA. Furthermore, experimental evidence was found by using mass spectroscopy and Western blot analysis that the 53-kDa protein was not part of the excretory/secretory antigen of T. spiralis as shown in this study.