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Evaluating variability and stability using measures for nonlinear dynamics may provide additional insight into the structure of the locomotor system, reflecting the neuromuscular system's organization of gait. This is in particular of interest when this system is affected by a respiratory disease and it's extrapulmonary manifestations. This study assessed stride-to-stride fluctuations and gait stability in patients with chronic obstructive pulmonary disease (COPD) during a self-paced, treadmill 6-minute walk test (6MWT) and its association with clinical outcomes. In this cross-sectional study, eighty patients with COPD (age 62±7y; forced expiratory volume in first second 56±19%predicted) and 39 healthy older adults (62±7y) were analyzed. Gait parameters including stride-to-stride fluctuations (coefficient of variation (CoV), predictability (sample entropy) and stability (Local Divergence Exponent (LDE)) were calculated over spatiotemporal parameters and center of mass velocity. Independent t-test, Mann-Whitney U test and ANCOVA analyses were conducted. Correlations were calculated between gait parameters, functional mobility using Timed Up and Go Test, and quadriceps muscle strength using dynamometry. Patients walked slower than healthy older adults. After correction for Speed, patients demonstrated increased CoV in stride length (F(1,116) = 5.658, p = 0.019), and increased stride length predictability (F(1,116) = 3.959, p = 0.049). Moderate correlations were found between mediolateral center of mass velocity LDE and normalized maximum peak torque (ρ = -0.549). This study showed that patients with COPD demonstrate alterations in stride length fluctuations even when adjusted for walking speed, highlighting the potential of nonlinear measures to detect alterations in gait function in patients with COPD. Association with clinical outcomes were moderate to weak, indicating that these clinical test are less discriminative for gait alterations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Pulmonary rehabilitation (PR) improves lower-limb muscle function in patients with chronic obstructive pulmonary disease (COPD). However, it remains unclear whether patients improve gait characteristics, in particular stride-to-stride fluctuations that are associated with fall risks. This study aims to identify whether, and to what extent, PR affects positively gait characteristics in COPD. In this prospective observational study, 44 COPD patients (aged: 62 ± 7 years; Forced expiratory volume in 1 s 56 ± 20% predicted) performed self-paced, treadmill 6-min-walk tests (Gait Real-time Analysis Interactive Lab) before and after PR, while spatiotemporal parameters and center of mass position were recorded (100 Hz, Vicon Nexus). Standard deviation, coefficient of variation, predictability (sample entropy), and consistency in organization (local divergence exponent) were calculated. Sub-analysis was performed to identify gait differences between good and poor responders (<30 m change in a 6-min-walk distance). Patients demonstrated shorter stride times ( p = 0.001) and improved lower-limb muscle function ( p < 0.001) following PR. The good responders had a greater increase in stride length ( p < 0.001) and a greater decrease in stride time ( p < 0.001) compared to the poor responders. Current PR improved stride time in patients, while movement patterns within stride-to-stride fluctuations did not change. Training programs specifically targeting balance issues and gait function may be beneficial in improving gait characteristics in COPD.

Background and Aim: Overground gait assessment is limited by the analysis of multiple strides or both spatiotemporal gait characteristics, while fixed speed treadmill walking restricts natural gait speed variations. The Gait Real-time Analysis Interactive Lab (GRAIL)-based 6-minute walk test (6MWT) enables 3D motion analysis and self-paced treadmill walking, and could provide insight in gait alterations in patients with chronic obstructive pulmonary disease (COPD). The aim of this study is to compare spatiotemporal gait characteristics between patients with COPD and healthy elderly during the GRAIL-based 6MWT., Materials and Methods: Eighty COPD patients (60% male; 62±7 years; FEV1:56±19% predicted) and 38 healthy elderly (63% male; 62±6 years; FEV1:119±17% predicted) performed two GRAIL-based 6MWTs. Mean differences and coefficient of variation of spatiotemporal gait characteristics were calculated using the trial with the largest walk distance. Sub-analyses were conducted to account for walking speed differences between groups, and muscle strength and COPD severity within the patient group., Results: COPD patients showed increased temporal gait characteristics, decreased stride and step lengths, and increased gait variability compared to healthy elderly (p<0.01). Stride length variability remained increased in COPD after correction for walking speed (MD:0.98%, CI:0.36-1.61, p = 0.003). Reduced quadriceps strength did not translate into altered gait characteristics, while COPD severity is associated with stride time (left MD:-0.02s, CI:-0.04-0.01, p = 0.003; right MD:-0.02s, CI:-0.04-0.01, p = 0.003)., Discussion: COPD patients performed the GRAIL-based 6MWT differently compared to healthy elderly. Further research should use other variability measures to investigate gait characteristics in COPD, to assess subtle alterations in gait and to enable development of rehabilitation strategies to improve gait, and possibly balance and fall risk in COPD. Other lower limb muscle groups should be considered when investigating gait alterations in COPD., Conclusion: COPD patients have different gait characteristics compared to healthy elderly. Independent of walking speed, COPD patients demonstrate increased stride length variability during the GRAIL-based 6MWT compared to healthy elderly.

Background: The 6-minute walk test (6MWT) in a regular hallway is commonly used to assess functional exercise capacity in patients with chronic obstructive pulmonary disease (COPD). However, treadmill walking might provide additional advantages over overground walking, especially if virtual reality and self-paced treadmill walking are combined. Therefore, this study aimed to assess the reproducibility and validity of the 6MWT using the Gait Real-time Analysis Interactive Lab (GRAIL) in patients with COPD and healthy elderly., Methodology/results: Sixty-one patients with COPD and 48 healthy elderly performed two 6MWTs on the GRAIL. Patients performed two overground 6MWTs and healthy elderly performed one overground test. Differences between consecutive 6MWTs and the test conditions (GRAIL vs. overground) were analysed. Patients walked further in the second overground test (24.8 m, 95% CI 15.2-34.4 m, p<0.001) and in the second GRAIL test (26.8 m, 95% CI 13.9-39.6 m). Healthy elderly improved their second GRAIL test (49.6 m, 95% CI 37.0-62.3 m). The GRAIL 6MWT was reproducible (intra-class coefficients = 0.65-0.80). The best GRAIL 6-minute walk distance (6MWD) in patients was shorter than the best overground 6MWD (-27.3 ± 49.1 m, p<0.001). Healthy elderly walked further on the GRAIL than in the overground condition (23.6 ± 41.4 m, p<0.001). Validity of the GRAIL 6MWT was assessed and intra-class coefficient values ranging from 0.74-0.77 were found., Conclusion: The GRAIL is a promising system to assess the 6MWD in patients with COPD and healthy elderly. The GRAIL 6MWD seems to be more comparable to the 6MWDs assessed overground than previous studies on treadmills have reported. Furthermore, good construct validity and reproducibility were established in assessing the 6MWD using the GRAIL in patients with COPD and healthy elderly., Competing Interests: The authors have declared that no competing interests exist.

Sedentary behavior (sitting/lying at low energy expenditure while awake) is emerging as an important risk factor that may compromise the health-related quality of life (HRQoL) of colorectal cancer (CRC) survivors. We examined associations of sedentary time with HRQoL in CRC survivors, 2-10 years post-diagnosis. In a cross-sectional study, stage I-III CRC survivors (n = 145) diagnosed (2002-2010) at Maastricht University Medical Center+, the Netherlands, wore the thigh-mounted MOX activity monitor 24 h/day for seven consecutive days. HRQoL outcomes were assessed by validated questionnaires (EORTC QLQ-C30, WHODAS II, Checklist Individual Strength, and Hospital Anxiety and Depression Scale). Confounder-adjusted linear regression models were used to estimate associations with HRQoL outcomes of MOX-derived total and prolonged sedentary time (in prolonged sedentary bouts ≥ 30 min), and usual sedentary bout duration, corrected for waking wear time. On average, participants spent 10.2 h/day sedentary (SD, 1.6), and 4.5 h/day in prolonged sedentary time (2.3). Mean usual sedentary bout duration was 27.3 min (SD, 16.8). Greater total and prolonged sedentary time, and longer usual sedentary bout duration were associated with significantly (P < 0.05) lower physical functioning, and higher disability and fatigue scores. Greater prolonged sedentary time and longer usual sedentary bout duration also showed significant associations with lower global quality of life and role functioning. Associations with distress and social functioning were non-significant. Sedentary time was cross-sectionally associated with poorer HRQoL outcomes in CRC survivors. Prospective studies are needed to investigate whether sedentary time reduction is a potential target for lifestyle interventions aiming to improve the HRQoL of CRC survivors.

Aims/hypothesis: The study investigated cross-sectional associations of total amount and patterns of sedentary behaviour with glucose metabolism status and the metabolic syndrome., Methods: We included 2,497 participants (mean age 60.0 ± 8.1 years, 52% men) from The Maastricht Study who were asked to wear an activPAL accelerometer 24 h/day for 8 consecutive days. We calculated the daily amount of sedentary time, daily number of sedentary breaks and prolonged sedentary bouts (≥30 min), and the average duration of the sedentary bouts. To determine glucose metabolism status, participants underwent an oral glucose tolerance test. Associations of sedentary behaviour variables with glucose metabolism status and the metabolic syndrome were examined using multinomial logistic regression analyses., Results: Overall, 1,395 (55.9%) participants had normal glucose metabolism, 388 (15.5%) had impaired glucose metabolism and 714 (28.6%) had type 2 diabetes. The odds ratio per additional hour of sedentary time was 1.22 (95% CI 1.13, 1.32) for type 2 diabetes and 1.39 (1.27, 1.53) for the metabolic syndrome. No significant or only weak associations were seen for the number of sedentary breaks, number of prolonged sedentary bouts or average bout duration with either glucose metabolism status or the metabolic syndrome., Conclusions/interpretation: An extra hour of sedentary time was associated with a 22% increased odds for type 2 diabetes and a 39% increased odds for the metabolic syndrome. The pattern in which sedentary time was accumulated was weakly associated with the presence of the metabolic syndrome. These results suggest that sedentary behaviour may play a significant role in the development and prevention of type 2 diabetes, although longitudinal studies are needed to confirm our findings.

Shprintzen-Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys-Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFβ activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). This implicates that the initial molecular testing could be focused on mutation analysis of the first half of exon 1 of SKI. As the majority of the known mutations are located in the R-SMAD binding domain of SKI, our study further emphasizes the importance of TGFβ signaling in the pathogenesis of SGS.

Objectives: To report clinical implementation of cell-free DNA (cfDNA) analysis of maternal blood in screening for trisomies 21, 18 and 13 in twin pregnancies and examine variables that could influence the failure rate of the test., Methods: cfDNA testing was performed in 515 twin pregnancies at 10-28 weeks' gestation. The failure rate of the test to provide results was compared with that in 1847 singleton pregnancies, and logistic regression analysis was used to determine which factors among maternal and pregnancy characteristics were significant predictors of test failure., Results: Failure rate of the cfDNA test at first sampling was 1.7% in singletons and 5.6% in twins. Of those with a test result, the median fetal fraction in twins was 8.7% (range, 4.1-30.0%), which was lower than that in singletons (11.7% (range, 4.0-38.9%)). Multivariable regression analysis demonstrated that twin pregnancy, higher maternal weight and conception by in-vitro fertilization provided significant independent prediction of test failure. Follow-up was available in 351 (68.2%) of the twin pregnancies and comprised 334 with euploid fetuses, 12 discordant for trisomy 21 and five discordant for trisomy 18. In all 323 euploid cases with a result, the risk score for each trisomy was < 1:10 000. In 11 of the 12 cases with trisomy 21 and in the five with trisomy 18, the cfDNA test gave a high-risk result, but in one case of trisomy 21, the score was < 1:10 000., Conclusion: In twin pregnancies screening by cfDNA testing is feasible, but the failure rate is higher and detection rate may be lower than in singletons., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

Patients with renal diseases associated with salt-losing tubulopathies categorized as Gitelman and classic form of Bartter syndrome have undergone genetic screening for possible mutation capture in two different genes: SLC12A3 and CLCNKB. Clinical symptoms of these two diseases may overlap. Bartter syndrome and Gitelman syndrome are autosomal recessive salt-losing tubulopathies with hypokalemia, metabolic alkalosis, hyperreninemia, hyperplasia of the juxtaglomerular apparatus, hyperaldosteronism, and, in some patients, hypomagnesemia. Here we describe four patients from an inbred family with a novel missense variant in the CLCNKB gene. All of patients are asymptomatic; yet they have the typical metabolic abnormality of salt losing tubulopathies. One of those patients had hypomagnesaemia while others not. Clinical and laboratory data of all patients was described. All 4 patients have a homozygous c.490G > T missense variant in exon 5 of the CLCNKB gene. This variant alters a glycine into a cysteine on amino acid position 164 of the resulting protein (p.Gly164Cys). The c.490G > T variant is a novel variant not previously described in other patients nor controls. Polyphen analysis predicts the variation to be possibly damaging. Analysis of SLC12A3 was normal. Here in we are describing a novel homozygous c.490G > T missense variation was identified in exon 5 of the CLCNKB gene was identified in an Emirati patients with a mild manifestation of Bartter - Gitelman syndrome.

As the classical first trimester Down syndrome screening (FTS, combination test) has a false-negative rate of 20-25% and > 95% of the abnormal FTS results are false-positive, we evaluated the new Non-Invasive Prenatal Test (NIPT) in Belgium and the Netherlands. The study population consisted of 3000 consecutive pregnancies in Belgium and the Netherlands in which NIPT was performed using the Harmony test. In 57 (1.9%) of the 3000 pregnancies an abnormal NIPT result was found. This included 51 fetuses with trisomy 21, 4 fetuses with trisomy 18 and 2 fetuses with trisomy 13. In 47 of the 57 the NIPT result was confirmed by genetic testing of material obtained by amniocentesis or chorionic biopsy, and no false-positive results were recorded. The false-negative rate as determined on more than 2000 women that had delivered at the time of reporting was low, and so far only 2 false-negative results were reported (one trisomy 18 and one trisomy 21). The failure rate where no NIPT result could be obtained after repeated sampling was 0.90%. In this large clinical series, NIPT using the Harmony test proves to be a very reliable prenatal test to detect fetal trisomies 21, 18 and 13 in maternal blood in Belgium and the Netherlands.

Background: Higher plantar pressures play an important role in the development of plantar foot ulceration in diabetic polyneuropathy and earlier studies suggest that higher pressures under the forefoot may be related to a decrease in lower leg muscle strength. Therefore, in this randomised controlled trial we evaluated whether lower-extremity strength training can reduce plantar pressures in diabetic polyneuropathy., Methods: This study was embedded in an unblinded randomised controlled trial. Participants had diabetes and polyneuropathy and were randomly assigned to the intervention group (n = 48) receiving strength training during 24 weeks, or the control group (n = 46) receiving no intervention. Plantar pressures were measured in both groups at 0, 12, 24 and 52 weeks. A random intercept model was applied to evaluate the effects of the intervention on peak pressures and pressure-time-integrals, displacement of center-of-pressure and the forefoot to rearfoot pressure-time-integral-ratio., Results: Plantar pressure patterns were not affected by the strength training. In both the intervention and control groups the peak pressure and the pressure-time-integral under the forefoot increased by 55.7 kPa (95% CI: 14.7, 96.8) and 2.0 kPa.s (95% CI: 0.9, 3.2) over 52 weeks, respectively. Both groups experienced a high number of drop-outs, mainly due to deterioration of health status and lower-extremity disabilities., Conclusions: Plantar pressures under the forefoot increase progressively over time in people with diabetic polyneuropathy, but in this study were not affected by strength training. Future intervention studies should take this increase of plantar pressure into account and alternative interventions should be developed to reduce the progressive lower extremity problems in these patients., Trial Registration: This study was embedded in a clinical trial with trial number NCT00759265.

Cornelia de Lange syndrome (CdLS) is a dominantly inherited congenital malformation disorder, caused by mutations in the cohesin-loading protein NIPBL for nearly 60% of individuals with classical CdLS, and by mutations in the core cohesin components SMC1A (~5%) and SMC3 (<1%) for a smaller fraction of probands. In humans, the multisubunit complex cohesin is made up of SMC1, SMC3, RAD21 and a STAG protein. These form a ring structure that is proposed to encircle sister chromatids to mediate sister chromatid cohesion and also has key roles in gene regulation. SMC3 is acetylated during S-phase to establish cohesiveness of chromatin-loaded cohesin, and in yeast, the class I histone deacetylase Hos1 deacetylates SMC3 during anaphase. Here we identify HDAC8 as the vertebrate SMC3 deacetylase, as well as loss-of-function HDAC8 mutations in six CdLS probands. Loss of HDAC8 activity results in increased SMC3 acetylation and inefficient dissolution of the ‘used’ cohesin complex released from chromatin in both prophase and anaphase. SMC3 with retained acetylation is loaded onto chromatin, and chromatin immunoprecipitation sequencing analysis demonstrates decreased occupancy of cohesin localization sites that results in a consistent pattern of altered transcription seen in CdLS cell lines with either NIPBL or HDAC8 mutations.

Background: Aneurysms-osteoarthritis syndrome (AOS) is a new autosomal dominant syndromic form of thoracic aortic aneurysms and dissections characterised by the presence of arterial aneurysms and tortuosity, mild craniofacial, skeletal and cutaneous anomalies, and early-onset osteoarthritis. AOS is caused by mutations in the SMAD3 gene., Methods: A cohort of 393 patients with aneurysms without mutation in FBN1, TGFBR1 and TGFBR2 was screened for mutations in SMAD3. The patients originated from The Netherlands, Belgium, Switzerland and USA. The clinical phenotype in a total of 45 patients from eight different AOS families with eight different SMAD3 mutations is described. In all patients with a SMAD3 mutation, clinical records were reviewed and extensive genetic, cardiovascular and orthopaedic examinations were performed., Results: Five novel SMAD3 mutations (one nonsense, two missense and two frame-shift mutations) were identified in five new AOS families. A follow-up description of the three families with a SMAD3 mutation previously described by the authors was included. In the majority of patients, early-onset joint abnormalities, including osteoarthritis and osteochondritis dissecans, were the initial symptom for which medical advice was sought. Cardiovascular abnormalities were present in almost 90% of patients, and involved mainly aortic aneurysms and dissections. Aneurysms and tortuosity were found in the aorta and other arteries throughout the body, including intracranial arteries. Of the patients who first presented with joint abnormalities, 20% died suddenly from aortic dissection. The presence of mild craniofacial abnormalities including hypertelorism and abnormal uvula may aid the recognition of this syndrome., Conclusion: The authors provide further insight into the phenotype of AOS with SMAD3 mutations, and present recommendations for a clinical work-up.

Background: To date, detailed analyses of walking patterns using accelerometers during the 6-min walk test (6MWT) have not been performed in patients with chronic obstructive pulmonary disease (COPD). Therefore, it remains unclear whether and to what extent COPD patients have an altered walking pattern during the 6MWT compared to healthy elderly subjects., Methodology/principal Findings: 79 COPD patients and 24 healthy elderly subjects performed the 6MWT wearing an accelerometer attached to the trunk. The accelerometer features (walking intensity, cadence, and walking variability) and subject characteristics were assessed and compared between groups. Moreover, associations were sought with 6-min walk distance (6MWD) using multiple ordinary least squares (OLS) regression models. COPD patients walked with a significantly lower walking intensity, lower cadence and increased walking variability compared to healthy subjects. Walking intensity and height were the only two significant determinants of 6MWD in healthy subjects, explaining 85% of the variance in 6MWD. In COPD patients also age, cadence, walking variability measures and their interactions were included were significant determinants of 6MWD (total variance in 6MWD explained: 88%)., Conclusions/significance: COPD patients have an altered walking pattern during 6MWT compared to healthy subjects. These differences in walking pattern partially explain the lower 6MWD in patients with COPD.

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by congenital cataracts, renal tubular dysfunction, cognitive problems and maladaptive behavior. The syndrome is caused by pathogenic DNA variations in the X-linked OCRL1 gene. A 24-month-old boy was referred to our hospital with delayed motor milestones, hypotonia, involuntary purposeless movements of hands and feet, congenital cataract, severe feeding difficulties, and failure to thrive. Physical examination at the age of 24 months revealed a body weight of 7350 g (-5.1 SDS). Length was 71 cm (-5.1 SDS) and head circumference 45 cm (-3.9 SDS). He had deep-set small eyes, frontal bossing, flat occiput, parietal prominence, bilateral congenital cataract, cryptorchid left testis, joint hypermobility, decreased muscle tone, and hyporeflexia. Biochemical analysis revealed the characteristic findings of renal Fanconi syndrome. Genetic analysis showed a novel pathogenic DNA variation (c.1528C>T) in exon 15 of the OCRL1 gene. Clinical findings and genetic analysis confirmed the diagnosis of OCRL syndrome., (©Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.)

The Keratitis-Ichthyosis-Deafness syndrome (KIDS) is an autosomal dominant ectodermal dysplasia characterized by ocular, skin, and ear anomalies, including keratitis, palmoplantar keratoderma, and congenital hearing loss. Most cases are due to mutations in the GJB2 gene encoding connexin 26. The Dandy-Walker malformation (DWM) is a developmental anomaly of the midline of the cerebellum with complete or partial agenesis of the vermis and cystic dilatation of the fourth ventricle. The association of KID syndrome with DWM has been reported a few times, but thought to be coincidental. We report 4 additional patients with KIDS and DWM, supporting the possibility that this is an association and not a coincidental finding. This also suggests that the GJB2 gene may have a role in other cases with DWM of, as yet, unknown etiology.

Cerebral palsy due to perinatal injury to cerebral white matter is usually not caused by genetic mutations, but by ischemia and/or inflammation. Here, we describe an autosomal-recessive type of tetraplegic cerebral palsy with mental retardation, reduction of cerebral white matter, and atrophy of the cerebellum in an inbred sibship. The phenotype was recorded and evolution followed for over 20 years. Brain lesions were studied by diffusion tensor MR tractography. Homozygosity mapping with SNPs was performed for identification of the chromosomal locus for the disease. In the 14 Mb candidate region on chromosome 7q22, RNA expression profiling was used for selecting among the 203 genes in the area. In postmortem brain tissue available from one patient, histology and immunohistochemistry were performed. Disease course and imaging were mostly reminiscent of hypoxic-ischemic tetraplegic cerebral palsy, with neuroaxonal degeneration and white matter loss. In all five patients, a donor splice site pathogenic mutation in intron 14 of the AP4M1 gene (c.1137+1G-->T), was identified. AP4M1, encoding for the mu subunit of the adaptor protein complex-4, is involved in intracellular trafficking of glutamate receptors. Aberrant GluRdelta2 glutamate receptor localization and dendritic spine morphology were observed in the postmortem brain specimen. This disease entity, which we refer to as congenital spastic tetraplegia (CST), is therefore a genetic model for congenital cerebral palsy with evidence for neuroaxonal damage and glutamate receptor abnormality, mimicking perinatally acquired hypoxic-ischemic white matter injury.

Background: Patients with diabetic polyneuropathy (DPN) are often confronted with ulceration of foot soles. Increased plantar pressure under the forefoot has been identified as a major risk factor for ulceration. This study sets out to test the hypothesis that changes in gait characteristics induced by DPN related muscle weakness are the origin of the elevated plantar pressures., Methods: Three groups of subjects participated: people diagnosed with diabetes without polyneuropathy (DC), people diagnosed with diabetic polyneuropathy (DPN) and healthy, age-matched controls (HC). In all subjects isometric strength of plantar and dorsal flexors was assessed. Moreover, joint moments at ankle, knee and hip joints were determined while walking barefoot at a velocity of 1.4 m/s. Simultaneously plantar pressure patterns were measured., Results: Compared to HC-subjects, DPN-participants walked with a significantly increased internal plantar flexor moment at the first half of the stance phase. Also in DPN-subjects the maximal braking and propelling force applied to the floor was decreased. Moreover, in DPN-subjects the ratio of forefoot-to-rear foot plantar pressures was increased. Body-mass normalized strength of dorsal flexors showed a trend to be reduced in people with diabetes, both DC and DPN, compared to HC-subjects. Plantar flexors tended to be less weak in DC compared to HC and in DPN relative to DC., Conclusion: The results of this study suggest that adverse plantar pressure patterns are associated with redistribution of joint moments, and a consequent reduced capacity to control forward velocity at heel strike.

Noncompaction of the ventricular myocardium is associated with de novo mutation in the beta-myosin heavy chain gene Budde et al. (2007) PLoS ONE 2: e1362 Homozygosity for a novel splice site mutation in the cardiac myosin-binding protein C gene causes severe neonatal hypertrophic cardiomyopathy Xin et al. (2007) Am J Med Genet 143: 2662-2667 Alpha-cardiac actin mutations produce atrial septal defects Matsson et al. (2008) Hum Mol Genet 17: 256-265.

Many human syndromes associated with hearing loss are caused by disease genes located on the X chromosome, but few X-linked loci for non-syndromic hearing loss have been reported. Surprisingly, a Y-linked locus has been identified, representing one of the only disease loci on the Y chromosome. This study reviews the different sex-linked genes and loci on the X- and Y chromosome leading to syndromic and especially non-syndromic hearing loss.

We report a three-generation family with nine patients affected by a combination of cardiac abnormalities and left isomerism which, to our knowledge, has not been described before. The cardiac anomalies include non-compaction of the ventricular myocardium, bradycardia, pulmonary valve stenosis, and secundum atrial septal defect. The laterality sequence anomalies include left bronchial isomerism, azygous continuation of the inferior vena cava, polysplenia and intestinal malrotation, all compatible with left isomerism. This new syndrome is inherited in an autosomal dominant pattern. A genome-wide linkage analysis suggested linkage to chromosome 6p24.3-21.2 with a maximum LOD score of 2.7 at marker D6S276. The linkage interval is located between markers D6S470 (telomeric side) and D6S1610 (centromeric side), and overlaps with the linkage interval in another family with heterotaxy reported previously. Taken together, the genomic region could be reduced to 9.4 cM (12 Mb) containing several functional candidate genes for this complex heterotaxy phenotype.

Background: The majority of COL2A1 missense mutations are substitutions of obligatory glycine residues in the triple helical domain. Only a few non-glycine missense mutations have been reported and among these, the arginine to cysteine substitutions predominate., Objective: To investigate in more detail the phenotype resulting from arginine to cysteine mutations in the COL2A1 gene., Methods: The clinical and radiographic phenotype of all patients in whom an arginine to cysteine mutation in the COL2A1 gene was identified in our laboratory, was studied and correlated with the abnormal genotype. The COL2A1 genotyping involved DHPLC analysis with subsequent sequencing of the abnormal fragments., Results: Six different mutations (R75C, R365C, R519C, R704C, R789C, R1076C) were found in 11 unrelated probands. Each mutation resulted in a rather constant and site-specific phenotype, but a perinatally lethal disorder was never observed. Spondyloarthropathy with normal stature and no ocular involvement were features of patients with the R75C, R519C, or R1076C mutation. Short third and/or fourth toes was a distinguishing feature of the R75C mutation and brachydactyly with enlarged finger joints a key feature of the R1076C substitution. Stickler dysplasia with brachydactyly was observed in patients with the R704C mutation. The R365C and R789C mutations resulted in classic Stickler dysplasia and spondyloepiphyseal dysplasia congenita (SEDC), respectively., Conclusions: Arginine to cysteine mutations are rather infrequent COL2A1 mutations which cause a spectrum of phenotypes including classic SEDC and Stickler dysplasia, but also some unusual entities that have not yet been recognised and described as type II collagenopathies.

We identified, by homozygosity mapping, a novel locus on 10q21.3-q22.1 for Goldberg-Shprintzen syndrome (GOSHS) in a consanguineous Moroccan family. Phenotypic features of GOSHS in this inbred family included microcephaly and mental retardation, which are both central nervous system defects, as well as Hirschsprung disease, an enteric nervous system defect. Furthermore, since bilateral generalized polymicogyria was diagnosed in all patients in this family, this feature might also be considered a key feature of the syndrome. We demonstrate that homozygous nonsense mutations in KIAA1279 at 10q22.1, encoding a protein with two tetratrico peptide repeats, underlie this syndromic form of Hirschsprung disease and generalized polymicrogyria, establishing the importance of KIAA1279 in both enteric and central nervous system development.

Background: Arterial tortuosity syndrome (ATS) is an uncommon connective tissue disorder of unknown aetiology. The most prominent feature is tortuosity of the large arteries, but lengthening, stenosis, and aneurysm formation are also frequent., Methods: We performed a genomewide screen by homozygosity mapping of three consanguineous multiplex families, two from Morocco, and one from Italy, which included 11 ATS patients. The two families from Morocco may possibly have a common ancestor., Results: We mapped the ATS gene to chromosome 20q13. Recombinations within an extended haplotype of 11 microsatellite markers localised the ATS gene between markers D20S836 and D20S109, an interval of 9.5 cM., Conclusions: Cloning and completing functional and structural analysis of the ATS gene may provide new insights into the molecular mechanisms of elastogenesis.

Amyotrophic lateral sclerosis (ALS) is a late onset, rapidly progressive and ultimately fatal neurological disorder, caused by the loss of motor neurons in the brain and spinal cord. Familial aggregation of ALS, with an age-dependent but high penetrance, is a major risk factor for ALS. Familial ALS (FALS) is clinically and genetically heterogeneous. Three genes and linkage to four additional gene loci have been identified so far and may either predominantly lead to ALS (ALSI-ALS6) or cause multisystem neurodegeneration with ALS as an occasional symptom (tauopathies, ALS-dementia complex). This review presents a tentative classification of the "major" ALS genes and ALS "susceptibility" genes, that may act as susceptibility factors for neurodegeneration in interaction with other genetic or environmental risk factors. Considering that mutations in ALS genes explain approximately 10% of familial as well as sporadic ALS, and most remaining cases of the discase are thought to result form the interaction of several genes and environmental factors, ALS is a paradigm for multifactorial discases.

Van Buchem disease is an autosomal recessive skeletal dysplasia characterised by generalised bone overgrowth, predominantly in the skull and mandible. Clinical complications including facial nerve palsy, optic atrophy, and impaired hearing occur in most patients. These features are very similar to those of sclerosteosis and the two conditions are only differentiated by the hand malformations and the tall stature appearing in sclerosteosis. Using an extended Dutch inbred van Buchem family and two inbred sclerosteosis families, we mapped both disease genes to the same region on chromosome 17q12-q21, supporting the hypothesis that van Buchem disease and sclerosteosis are caused by mutations in the same gene. In a previous study, we positionally cloned a novel gene, called SOST, from the linkage interval and identified three different, homozygous mutations in the SOST gene in sclerosteosis patients leading to loss of function of the underlying protein. The present study focuses on the identification of a 52 kb deletion in all patients from the van Buchem family. The deletion, which results from a homologous recombination between Alu sequences, starts approximately 35 kb downstream of the SOST gene. Since no evidence was found for the presence of a gene within the deleted region, we hypothesise that the presence of the deletion leads to a down regulation of the transcription of the SOST gene by a cis regulatory action or a position effect.

In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%-10% of cases.

Magnetic resonance imaging (MRI) of the brain of fragile X patients, the most frequent form of inherited mental retardation, has revealed abnormalities in the size of specific brain structures, including the cerebellar vermis, the hippocampus, and the ventricular system. We intended to quantify the differences observed in the patient studies in the fragile X knockout mouse model, which is a good model for the disease, paralleling the human disorder in having cognitive deficits, macro-orchidism, and immature dendritic spines. Therefore we set up MRI of the mouse brain which allowed us to measure the size of the brain structures reported to be abnormal in human fragile X patients in the mouse model. We did not find evidence for size alterations in various brain regions of the fragile X mouse model, but the method described may find a wide application in the study of mutant mouse models with neurological involvement.

Identification of the FMR1 gene and the repeat-amplification mechanism causing fragile X syndrome led to development of reliable DNA-based diagnostic methods, including Southern blot hybridization and PCR. Both methods are performed on DNA isolated from peripheral blood cells and measure the repeat size in FMR1. Using an immunocytochemical technique on blood smears, we recently developed a novel test for identification of patients with fragile X syndrome. This method, also called "antibody test," uses monoclonal antibodies against the FMR1 gene product (FMRP) and is based on absence of FMRP in patients' cells. Here we describe a new diagnostic test to identify male patients with fragile X syndrome, on the basis of lack of FMRP in their hair roots. Expression of FMRP in hair roots was studied by use of an FMRP-specific antibody test, and the percentage of FMRP-expressing hair roots in controls and in male fragile X patients was determined. Control individuals showed clear expression of FMRP in nearly every hair root, whereas male fragile X patients lacked expression of FMRP in almost all their hair roots. Mentally retarded female patients with a full mutation showed FMRP expression in only some of their hair roots (<55%), and no overlap with normal female controls was observed. The advantages of this test are (1) plucking of hair follicles does no appreciable harm to the mentally retarded patient, (2) hairs can be sent in a simple envelope to a diagnostic center, and (3) the result of the test is available within 5 h of plucking. In addition, this test enabled us to identify two fragile X patients who did not show the full mutation by analysis of DNA isolated from blood cells.

Non-syndromic hearing impairment is one of the most heterogeneous hereditary conditions, with more than 40 reported gene localisations. We have identified a large Dutch family with autosomal dominant non-syndromic sensorineural hearing impairment. In most patients, the onset of hearing impairment is in the first or second decade of life, with a slow decline in the following decades, which stops short of profound deafness. The hearing loss is bilateral, symmetrical, and only affects low and mid frequencies up to 2000 Hz. In view of the phenotypic similarities of this family with an American family that has been linked to chromosome 4p16.3 (DFNA6), we investigated linkage to the DFNA6 region. Lod score calculations confirmed linkage to this region with two point lod scores above 6. However, as haplotype analysis indicated that the genetic defect in this family is located in a 5.6 cM candidate region that does not overlap the DFNA6 region, the new locus has been named DFNA14.

Recently the gene responsible for Pendred syndrome (PDS) was isolated and several mutations in the PDS gene have been identified in Pendred patients. Here we report the occurrence of two different PDS mutations in an extended inbred Turkish family. The majority of patients in this family are homozygous for a splice site mutation (1143-2A-->G) affecting the 3' splice site consensus sequence of intron 7. However, two affected sibs with non-consanguineous parents are compound heterozygotes for the splice site mutation and a missense mutation (1558T-->G), substituting an evolutionarily conserved amino acid. The latter mutation has been found previously in two Pendred families originating from The Netherlands, indicating that the 1558T-->G mutation may be a common mutation.