Performance fatigability in adults with spinal muscular atrophy treated long-term with nusinersen.

INTRODUCTION/AIMS: Persons with spinal muscular atrophy (pwSMA) report progressive muscle weakness but also reduced endurance when performing repetitive tasks in daily life, referred to as "performance fatigability" (PF). Data regarding the effects of the new disease-modifying drugs on PF are scarce. Thus, our main objective was to examine PF in adult ambulatory pwSMA treated long-term with nusinersen. METHODS: Six-minute walk test (6MWT) data from 14 adult pwSMA treated with nusinersen for up to 70 months were retrospectively analyzed to determine PF. Performance fatigability was defined as the percentage change in the distance covered between the last and first minute of the 6MWT. In addition, relationships between PF and other clinical features were assessed. RESULTS: Performance fatigability was found in 12/14 pwSMA (85.7%) prior to treatment. The mean distance walked in the sixth minute (71.1 m) was shorter than the distance covered in the first minute (81.8 m), corresponding to a mean PF of 13.1% (95% confidence interval (CI): 6.5-19.6, p = .0007). During treatment with nusinersen, there was a mean reduction in PF of 5.6% (95% CI: -10.0 to -1.3, p = .0148). We found no relationship between PF and fatigue as measured by the Fatigue Severity Scale. DISCUSSION: This study demonstrates the presence of PF as an independent component of motor impairment and as a potential therapeutic target in our cohort of adult ambulatory pwSMA. Furthermore, the observations in our cohort suggest that nusinersen may have a beneficial effect on PF.

Oral functions in adult persons with spinal muscular atrophy compared to a healthy control group: a prospective cross-sectional study with a multimodal approach.

BACKGROUND: Oral function tests have been shown to reliably detect impaired bulbar function in adults with spinal muscular atrophy (SMA). Although not routinely recorded, it is known that persons with SMA are affected to varying degrees. Detecting differences in bite and tongue force, endurance, and maximum mouth opening has become particularly promising since the introduction of causal therapy for SMA. This study aimed to compare oral function among adult persons with SMA with different SMA types, walking abilities, and treatment status to a healthy control group. METHODS: Data from oral function tests conducted on 58 persons with SMA and 45 healthy individuals were analyzed. Differences in oral function between SMA subgroups were pairwise tested and compared to the healthy control group using Wilcoxon rank sum tests. RESULTS: In an overall comparison, three out of five oral function tests revealed lower values for the SMA group compared to the control group. Subgroup analyses indicated lower scores for most oral function tests in non-ambulatory, untreated patients with SMA type 2 compared to controls. Ambulatory, treated patients with SMA type 3 achieved strength and endurance values comparable to those of healthy individuals. CONCLUSIONS: The impairment of oral function varies across persons with SMA. Routine measurement of oral function is warranted to determine individual bulbar involvement stages. Further evaluation should be scheduled if indicators such as restricted maximum mouth opening arise. Trial registration DRKS, DRKS00015842. Registered 30 July 2019, https://drks.de/register/de/trial/DRKS00015842/preview .

Predictors for long-term relapse of orthodontic treatment in patients with cleft lip and palate. A clinical follow-up study.

OBJECTIVES: To identify predictors for long-term relapse of orthodontic therapy in patients with cleft lip and palate (CLP). MATERIALS AND METHODS: Patients with uni- and bilateral non-syndromal CLP were followed up at least two years after completion of their orthodontic therapy. Plaster casts of the start of treatment (T1), after completion of treatment (T2), and at follow-up (T3) were measured using the modified Huddart Bodenham Index. Characteristics of multidisciplinary therapy were taken from the patient files. Potentially influencing factors of relapse were investigated using logistic regression analyses and Spearman correlations. RESULTS: In total 58.07% of the included 31 patients showed a stable treatment outcome at follow-up after an average of 6.9 years. Even if relapse occurred, 61.54% of these patients still showed improvement regarding their occlusion compared to baseline. Predictors for the occurrence of relapse were the severity of dysgnathia at baseline (p = 0.039) and the extent of therapeutic change (p = 0.041). The extent of therapeutic change was additionally a predictor for the extent of post-therapeutic relapse (ρ = 0.425; p = 0.019). CONCLUSIONS: Patients with CLP benefit from their orthodontic therapy in the long term despite an increased tendency to relapse. CLINICAL RELEVANCE: Results of this long-term study could be used to adapt the treatment concept for patients with CLP and reinforce the significance of a patient-centered orthodontic treatment concept for affected patients.

Fixed orthodontic appliances and adolescents' peer relations in school : A social network analysis using cross-sectional survey data.

PURPOSE: Studies from the 1970s and 1980s, but also recent investigations on social media suggest that wearing a fixed orthodontic appliance can be a cause of bullying and social exclusion. With the greater uptake of orthodontic treatment in recent decades, it can be assumed that fixed braces are increasingly perceived as normal or even socially desirable. This study investigated how wearing visible fixed braces affects adolescents' social position in their peer networks using cross-sectional survey data. METHODS: A total of 3002 students in the seventh grade (ages 12/13) at 39 secondary schools were asked about their social relationships in school. These directed network data were used to compare different indegrees (friendship, popularity and victimisation) of students with and without fixed braces. Statistical analyses were performed using ordinary least squares multiple regression models with school cohort fixed effects. RESULTS: In all, 19% of the surveyed students indicated that they wear visible fixed braces. Girls with fixed braces were slightly more likely to be nominated for friendship and popularity and slightly less likely to be nominated for victimisation than girls without fixed braces (p < 0.05). These associations also remained stable when controlling for socioeconomic differences. Among boys, all observed associations were statistically insignificant. CONCLUSION: We found no evidence that wearing fixed braces in adolescence is socially sanctioned by peers. Rather, female students with fixed braces even tend to hold a slightly more favourable position in their peer networks than girls without braces do. These analyses exemplify how network-analytic approaches can be successfully applied in interdisciplinary research at the intersection of sociology, epidemiology and medicine.

Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores.

BACKGROUND: Nonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome-wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is explained by rare penetrant variants. METHODS: To identify new candidate genes, we searched for highly penetrant de novo variants (DNVs) in 50 nsCL/P patient/parent-trios with a low polygenic risk for the phenotype (discovery). We prioritized DNV-carrying candidate genes from the discovery for resequencing in independent cohorts of 1010 nsCL/P patients of diverse ethnicities and 1574 population-matched controls (replication). Segregation analyses and rare variant association in the replication cohort, in combination with additional data (genome-wide association data, expression, protein-protein-interactions), were used for final prioritization. CONCLUSION: In the discovery step, 60 DNVs were identified in 60 genes, including a variant in the established nsCL/P risk gene CDH1. Re-sequencing of 32 prioritized genes led to the identification of 373 rare, likely pathogenic variants. Finally, MDN1 and PAXIP1 were prioritized as top candidates. Our findings demonstrate that DNV detection, including polygenic risk score analysis, is a powerful tool for identifying nsCL/P candidate genes, which can also be applied to other multifactorial congenital malformations.

Does maxillary sinus size affect the risk for zygomatic complex fractures?

The purpose of the study was to measure the maxillary sinus sizes in patients with and without zygomatic bone fractures. In this cross-sectional study computed tomography data of a case group of consecutive treated patients with displaced zygomatic bone fractures were compared to a control group with mandibular fractures. Maxillary sinus sizes were measured in width, height, depth, and volume. We compared sinus sizes between the case and control group, followed by a subgroup analysis of slightly and severely displaced fractures using T-tests. We identified 89 cases, thereof 46 with slightly and 43 with severely displaced fractures. The control group consisted of 110 patients. The mean sinus volume of the case group (19,313 mm3 ± 5237) was significantly larger than in the control group (17,645 mm3 ± 4760; p = 0.02). Subgroup analyses revealed that this difference in volume was more pronounced between patients with severely displaced fractures (20,354 mm3 ± 5416; p = 0.003) and the control group. In two-dimensional measures, only sinus height was significantly greater in the case group (37.41 mm ± 4.25 vs. 35.33 mm ± 4.88; p = 0.002). The same holds for the subgroup with severely displaced fractures (38.27 mm ± 3.91; p = 0.001). Sinus width and depth showed no significant differences between the groups. A maxillary sinus volume larger than 20,000 mm3 is a predictive risk factor for a displaced zygomatic bone fracture. Greater sinus height indicates a larger surface area of the zygomaticomaxillary buttress that decreases the resistance to facial trauma.

Sliding behaviour and surface quality after static air polishing of conventional and modern bracket materials : In vitro analysis.

OBJECTIVES: As part of orthodontic treatment, air polishing is routinely used for professional tooth cleaning. Thus, we investigated the effects of static powder polishing on sliding behaviour and surface quality of three different bracket materials (polymer, ceramic, metal), including a 3D-printed bracket. METHODS: Two bracket types of each material group were polished with an air-polishing device using sodium bicarbonate. Exposure times were set at 10, 20, and 60 s; the application distance was 5 mm. The force loss due to sliding resistance was tested with an orthodontic measurement and simulation system (OMSS) using a 0.016 inchâ€¯× 0.022 inch stainless steel archwire. Untreated brackets served as control. Polishing effects and slot precision were evaluated using an optical digital and scanning electron microscope. RESULTS: Sliding behaviour and slot precision differed significantly between and within the groups. Prior to polishing, polymer brackets showed the least force loss, ceramic brackets the highest. With progressive polishing time, the resistance increased significantly with titanium brackets (26 to 37%) and decreased significantly with steel brackets (36 to 25%). Polymer brackets showed the smallest changes in force loss with respect to polishing duration. Slot precision showed the largest differences between material groups and was primarily manufacturer-dependent with hardly any changes due to the polishing time. CONCLUSION: Powder polishing can positively or negatively affect the sliding properties of the bracket-archwire complex but is more dependent on the bracket-archwire material combination (i.e., manufacture-dependent slot precision). For titanium brackets, resistance only increased after 60 s of polishing. For ceramic brackets, effective reduction was observed after 10 s of polishing. Polymer brackets, including the 3D-printed brackets, showed better sliding properties than ceramic or metal brackets even after polishing for 60 s. Removal of plaque and dental calculus should lead to a noticeable improvement of the sliding properties and outweighs structural defects that may develop.

A new digital measurement system for assessing the lip in patients with cleft lip and palate (CLP).

Objective: In order to better and more objectively assess and compare the aesthetics of the lip, we offer an inovative, digital measurement method. Patients and method: Patients were divided into 2 groups:a) patients with unilateral CLP andb) patients with bilateral CLP.Based on standardised photos from 3 different directions, lip symmetry and aesthetics were assessed. A new digital measurement system was used, which was integrated into a proven clinical programme. Different symmetry indices were compared with a non-cleft control group. In addition, the function was investigated and a standardised questionnaire was used. Results: In total, 92 patients with operated CLP could be recruitetd and showed significant residual asymmetry compared to the control group with 49 patients. The results were more symmetrical in group b) than in group a). In contrast, scar width and scar aesthetics as well as orofacial function were better in group a). The preoperative cleft width showed a positive correlation with the postoperative scar width and scar aesthetics. Socioeconomic factors were not related to surgical outcome. Satisfaction of affected children and parents correlated with objectively assessed scar aesthetics and function. There was no correlation between satisfaction and symmetry or cleft width or scar width. Conclusion: The presented measurement system can be used excellently and effectively in clinical routine, especially for the inexperienced examiner, for fast and yet detailed, objective recording of findings. The measurement results can be analyzed comparatively and interpreted predictively for diagnostics, planning and therapy.

Inadvertent side effects of fixed lingual retainers : An in vitro study.

PURPOSE: To better understand the side effects of fixed lingual retainers by means of an in vitro study in a two-tooth model determining the three-dimensional (3D) force-moment components acting at adjacent teeth combined with different composite-wire interfaces. METHODS: Triple-stranded round retainer wires were embedded in cured disks of flowable composite. At one side the composite-wire interface was untreated and checked to be absolutely fix. At the other side the composite-wire interface was configured as either an isolated compound with (1) petroleum jelly coating, or an adhered compound with (2) no manipulation, (3) ethanol degreasing or (4) ethanol degreasing and rectangular bending of the wire ends. The 3D force-moment components were registered, while the intertooth distance was increased in steps of 0.01 mm leading to increasing tension of the wire. Measurements were repeated after artificially aging the specimens. RESULTS: Retainer wire specimens with adhered compound (2, 3, 4) showed negative vestibulo-oral moments ranging maximally each between -0.3 and -0.9 Nmm in opposite direction to positive moments of 1.9 Nmm for specimens with isolated compound 1. Significant tipping moments occurred in the group with isolated compound at lower forces than in those groups with adhered compound. Similar effects were observed after artificial aging. CONCLUSION: Side effects emerge under specific circumstances: an altered adhesive compound combined with the presence of oral forces. Compounds with lost adhesion at the composite-wire interface showed rotational moments in the direction of the wire windings even during low tensile forces similar to those that may occur in clinical settings. Opposite rotational moments leading to unwinding of the wire may occur in cases with adhered compounds at higher tensile forces. Utilization of round triple-stranded retainer wires without bent ends are of higher risk to induce inadvertent side effects.

Does one size fit all? A qualitative study about the need for individualized information transfer for orthognathic patients.

AIMS: For any orthodontic-orthognathic treatment, it is crucial that patients are provided with enough and proper information in order to make evidence-based decisions- not only prior to treatment start, but also throughout the course of therapy. Thus, the objectives of this qualitative study were to identify information needs of patients undergoing combined orthodontic-orthognathic treatment. Additionally, professionals' perspectives were evaluated. METHODS: A qualitative research approach was chosen in order to determine crucial aspects of information needs before and throughout treatment. With respect to a purposive sampling strategy and thematic saturation, we conducted ten semi-structured interviews with patients who had finished their orthodontic-orthognathic surgery treatments (five women, five men; being 21 to 34 years old). The indications for the combination treatment were severe skeletal Class IIs to Class IIIs with various vertical and transverse discrepancies. In addition, a multidisciplinary focus-group with six professionals from the maxillofacial surgery and orthodontic department (three women, three men; being 30 to 38 years old) helped to reflect about the experts' point of views. After transcription, data was categorized and analyzed by Mayring's content analysis. RESULTS: We identified three key themes. During this analysis, we focused on theme (1) 'information transfer' with its corresponding categories 'information needs' - depending on different treatment stages -, 'source of information' and 'doctor-patient-communication'. The affected patients ranked individualized patient information and empathetic doctor-patient-communication high. This was mostly in line with the professionals' point of view. Verbal communication was seen as being the best way to communicate throughout treatment. The role of the internet as a source of information was seen diversely. CONCLUSION: This qualitative study highlights the need for individualized patient information and reveals both met and unmet information needs by patients. Although evidence-based written information is highly necessary for orthognathic patients and their families alike, it cannot replace an empathetic way of direct verbal doctor-patient-communication. It seems crucial to give specific individualized information at different treatment stages, starting at a thoroughly interdisciplinary screening at the very beginning.

Looking good but tweeting bad? The social perception of orthodontic-related posts on Twitter and Instagram.

BACKGROUND: Social media plays a major role in the daily life of adolescents and has become highly interesting for healthcare research as well. The aim of this study was to explore the social perception of orthodontic-related posts on Twitter and Instagram by young adults. METHODS: 401 orthodontic-related posts were collected during a 30-day period and categorized with regard to specific characteristics - their content and the social networking site (SNS) being used as well as the presence or absence of a selfie. In order to investigate the social perception of these posts, 42 young adults rated the emotional states of the SNS users using the Self-Assessment Manikin (SAM)-Tool. A total of 4211 poster-rater observations pertaining to the three SAMs dimensions pleasure, arousal and dominance were analyzed by using linear and multinomial logistic regression analyses. RESULTS: The investigated characteristics of the collected posts had significant effects on the perceived emotional state of the SNS users. Besides significant SNS-associated differences, there were also effects that were independent of the SNS being used: Receiving orthodontic appliances was more often associated with rather negative emotions (p < 0.001), while users who posted about the removal of such braces were more often perceived as joyful (p < 0.001). Interestingly, users whose posts contained selfies with visible braces were perceived as significantly more positive and stronger in comparison to users who did not post a picture of themselves (p < 0.05). CONCLUSION: This research gives insights into the social perception of orthodontic-related posts on SNS. While users' emotional states were perceived highly differential on both SNS, orthodontic-related content also revealed significant effects on social perception. Because selfies with visible braces were associated with positive feelings by young adults, a modern and SNS-related way of coping with a temporary supposed impairment like fixed orthodontic appliances might have been revealed through this research.

Comparative in vitro analysis of the sliding resistance of a modern 3D-printed polymer bracket in combination with different archwire types.

OBJECTIVES: To analyse the sliding resistance of a modern 3D-printed polymer bracket combined with different archwire types and to compare the results with conventionally used polymeric, ceramic and metal brackets. It was of further interest which bracket-archwire combination could be best qualified for clinical use. MATERIALS AND METHODS: The sliding behaviour was tested using an orthodontic measurement and simulation system (OMSS) for the use of two bracket types of the polymer, ceramic and metal group in combination with a 0.016 inch × 0.022 inch and 0.017 inch × 0.025 inch archwire of nickel-titanium (NiTi), titanium-molybdenum alloy (TMA) and stainless steel. Six bracket types were combined with six different archwire types and compared to each other. RESULTS: The sliding resistance showed significant differences between various the bracket-archwire complexes. The combination of 3D-printed polymer brackets with both steel archwire cross-sections showed the least values of sliding resistance (average 23-29%), while the combination of ceramic brackets with TMA archwires presented the highest (average 47%). CONCLUSIONS: The present study could show that modern 3D-printed bracket materials can have similar or even better mechanical properties than conventional ones regarding sliding resistance. Although the combination of bracket and archwire material is decisive for low sliding resistance values, the selection of the bracket material seems to have a greater influence than the selection of the archwire material or its cross section. CLINICAL RELEVANCE: It might be possible in future to combine aesthetic and biomechanical requirements for aesthetic brackets by using 3D-printing technology.

Reducing the Burden of Care: Multidisciplinary Management of Late-Manifested Crouzon Syndrome-A Case Report.

The therapy of patients with Crouzon syndrome involves a multidisciplinary team. In most cases, this therapy is extensive, time-consuming, and exhausting for the patient. This case report illustrates a temporally coordinated therapy plan that succeeds in reducing the burden of care. Showing typical extraoral characteristics of Crouzon syndrome, the patient had a frontal and left-sided crossbite, and impaction of the maxillary canines. Multidisciplinary therapy included the extraction of multiple teeth, midface distraction at Le Fort III level, and alignment of the impacted teeth. Before starting, during, and after completion of the treatment, the patient's oral health-related quality of life was assessed using COHIP-19. The combination of different treatment steps significantly reduced the duration of therapy. The therapy improved not only the patient's oro- and craniofacial function, but also the patient's facial appearance in a short treatment period. The patient's quality of life improved considerably during this time. In the treatment of severe craniofacial anomalies, the highest priority should be given to keeping the burden of care low. All measures should encourage young patients' appropriate psychosocial development despite extensive therapies, ensuring at the same time medically satisfactory treatment results.

Extending the allelic spectrum at noncoding risk loci of orofacial clefting.

Genome-wide association studies (GWAS) have generated unprecedented insights into the genetic etiology of orofacial clefting (OFC). The moderate effect sizes of associated noncoding risk variants and limited access to disease-relevant tissue represent considerable challenges for biological interpretation of genetic findings. As rare variants with stronger effect sizes are likely to also contribute to OFC, an alternative approach to delineate pathogenic mechanisms is to identify private mutations and/or an increased burden of rare variants in associated regions. This report describes a framework for targeted resequencing at selected noncoding risk loci contributing to nonsyndromic cleft lip with/without cleft palate (nsCL/P), the most frequent OFC subtype. Based on GWAS data, we selected three risk loci and identified candidate regulatory regions (CRRs) through the integration of credible SNP information, epigenetic data from relevant cells/tissues, and conservation scores. The CRRs (total 57 kb) were resequenced in a multiethnic study population (1061 patients; 1591 controls), using single-molecule molecular inversion probe technology. Combining evidence from in silico variant annotation, pedigree- and burden analyses, we identified 16 likely deleterious rare variants that represent new candidates for functional studies in nsCL/P. Our framework is scalable and represents a promising approach to the investigation of additional congenital malformations with multifactorial etiology.

Impact of Maternal Smoking on Nonsyndromic Clefts: Sex-Specific Associations With Side and Laterality.

OBJECTIVE: To compare the incidence of right-sided versus left-sided, and unilateral versus bilateral, nonsyndromic clefting in the affected offspring of smoking and nonsmoking mothers. DESIGN: Self-report data on periconceptual and first trimester smoking behavior were collected from 842 mothers of children with nonsyndromic orofacial clefting. Differences in the incidence of left- versus right-sided clefts, and of unilateral versus bilateral clefts, were analyzed between the children of smoking and nonsmoking mothers. SETTING: Interviews and clinical examinations took place at 8 specialist centers in Germany. PATIENTS AND PARTICIPANTS: Children with nonsyndromic clefts were recruited during the course of surgical or orthodontic treatment, or within the context of the annual control consultation. Patients with cleft palate only or missing data were excluded. The final cohort comprised 842 patients (540 males and 302 females) with unilateral or bilateral clefts. The respective mothers were interviewed. MAIN OUTCOME MEASURE: Side and laterality of nonsyndromic clefts were the main outcome measures. RESULTS: Children of smoking mothers more often had right-sided clefts than children of nonsmoking mothers (42% right-sided clefts in children of smoking mothers vs 31% of nonsmoking mothers). Children of smoking mothers more often had bilateral clefts than children of nonsmoking mothers (35% bilateral clefts in children of smoking mothers vs 29% of nonsmoking mothers). Sex-specific analyses confirmed substantially and statistically significant associations only for girls. CONCLUSIONS: The results suggest that maternal smoking is a sex-specific, exogenous determinant of laterality and side in nonsyndromic clefts.

Prenatal Diagnosis of Robin Sequence: Sensitivity, Specificity, and Clinical Relevance of an Index for Micrognathia.

OBJECTIVE: Micrognathia in connection with glossoptosis (called Robin sequence) may lead to life-threatening respiratory problems immediately after birth. An objective detection during prenatal routine ultrasound sonography is possible using an index that relates fetal lower jaw length to femur length or gestational age. The aim of this study was to test the method's sensitivity and specificity and to discuss its predictive power concerning neonatal respiratory insufficiency. DESIGN: Patients with subjectively identified suspicious signs in the sagittal profile view were included in the study: Two-dimensional serial ultrasound scans of their fetal mandible were used to measure the lower jaw lengths and compare them to predicted values according to an index, derived from 313 healthy fetuses. Follow-up data provided additional information on the clinical appearance of the newborns. RESULTS: The index showed a high sensitivity: 15 of the 16 cases with a micrognathia were correctly diagnosed (sensitivity of 93.75%). Follow-up data showed that newborns with similar index values differed in terms of their upper airway obstruction and treatment need. CONCLUSION: Fetal mandibular micrognathia can be objectively evaluated with the help of the index. The method allows an early detection of micrognathia, which helps to take the necessary steps for proper treatment of potential life-threatening respiratory impairment. Observations ranging outside the prediction interval could prompt the ultrasonographer to check for other associated malformations.

Maximum bite force in patients with spinal muscular atrophy during the first year of nusinersen therapy - A pilot study.

OBJECTIVES: Spinal muscular atrophy is a monogenic disease characterized by progressive spinal and bulbar muscle weakness and atrophy. It is caused by the degeneration of alpha-motoneurons. The recent approval of the antisense oligonucleotide nusinersen highlights the need for reliable clinical tools to evaluate motor function in patients with neuromuscular disorders. Measurement of the bulbar neuromuscular function (e.g., bite force) could be an extension to existing motor scales, sensitive to more nuanced changes, especially in symptomatic patients with severely reduced functional abilities. MATERIALS AND METHODS: Maximum bite force measurement was used to quantify changes of the masticatory function in adult monozygotic female twins with SMA type II. Using piezoelectric transducers, 550 observations were recorded for each patient during the first year of nusinersen therapy. RESULTS: During the application of four loading doses of nusinersen, bite force levels steadily increased and reached a statistically significantly higher level compared to the initial state in both patients. Subsequent maintenance doses coincided with smaller or no statistically significant changes in maximum bite force. CONCLUSIONS: This pilot study indicates that the measurement of maximum bite force may be a useful tool to detect changes of the bulbar function in SMA patients. As such, it may supplement existing scales to identify treatment-related changes in motor function.

The Maximum Bite Force for Treatment Evaluation in Severely Affected Adult SMA Patients-Protocol for a Longitudinal Study.

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder characterized by the degeneration of motor neurons in the spinal cord, and comprises a broad clinical spectrum. With the advent of new therapies (e.g., Nusinersen) for patients of all ages and disease stages, sensitive clinical measures are needed to detect slight changes in muscle force even in immobilized, severely affected patients often unable to move limbs. As for these patients, well-established outcome scales set out to evaluate motor function do not work properly, we propose measurement of maximum bite force which is able to detect subtle changes of bulbar function. Requirements for this approach are mentioned, challenges are discussed, and first insights from a pilot study are presented. Finally, a study design is proposed to evaluate the measurement of maximum bite force during the follow up of SMA patients with and without a disease modifying therapy.

Nonsyndromic cleft palate: An association study at GWAS candidate loci in a multiethnic sample.

BACKGROUND: Nonsyndromic cleft palate only (nsCPO) is a common and multifactorial form of orofacial clefting. In contrast to successes achieved for the other common form of orofacial clefting, that is, nonsyndromic cleft lip with/without cleft palate (nsCL/P), genome wide association studies (GWAS) of nsCPO have identified only one genome wide significant locus. Aim of the present study was to investigate whether common variants contribute to nsCPO and, if so, to identify novel risk loci. METHODS: We genotyped 33 SNPs at 27 candidate loci from 2 previously published nsCPO GWAS in an independent multiethnic sample. It included: (i) a family-based sample of European ancestry (n = 212); and (ii) two case/control samples of Central European (n = 94/339) and Arabian ancestry (n = 38/231), respectively. A separate association analysis was performed for each genotyped dataset, and meta-analyses were performed. RESULTS: After association analysis and meta-analyses, none of the 33 SNPs showed genome-wide significance. Two variants showed nominally significant association in the imputed GWAS dataset and exhibited a further decrease in p-value in a European and an overall meta-analysis including imputed GWAS data, respectively (rs395572: PMetaEU = 3.16 × 10-4 ; rs6809420: PMetaAll = 2.80 × 10-4 ). CONCLUSION: Our findings suggest that there is a limited contribution of common variants to nsCPO. However, the individual effect sizes might be too small for detection of further associations in the present sample sizes. Rare variants may play a more substantial role in nsCPO than in nsCL/P, for which GWAS of smaller sample sizes have identified genome-wide significant loci. Whole-exome/genome sequencing studies of nsCPO are now warranted.