The phenotype of recurrent 10q22q23 deletions and duplications.

The genomic architecture of the 10q22q23 region is characterised by two low-copy repeats (LCRs3 and 4), and deletions in this region appear to be rare. We report the clinical and molecular characterisation of eight novel deletions and six duplications within the 10q22.3q23.3 region. Five deletions and three duplications occur between LCRs3 and 4, whereas three deletions and three duplications have unique breakpoints. Most of the individuals with the LCR3-4 deletion had developmental delay, mainly affecting speech. In addition, macrocephaly, mild facial dysmorphisms, cerebellar anomalies, cardiac defects and congenital breast aplasia were observed. For congenital breast aplasia, the NRG3 gene, known to be involved in early mammary gland development in mice, is a putative candidate gene. For cardiac defects, BMPR1A and GRID1 are putative candidate genes because of their association with cardiac structure and function. Duplications between LCRs3 and 4 are associated with variable phenotypic penetrance. Probands had speech and/or motor delays and dysmorphisms including a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip. In conclusion, duplications between LCRs3 and 4 on 10q22.3q23.2 may lead to a distinct facial appearance and delays in speech and motor development. However, the phenotypic spectrum is broad, and duplications have also been found in healthy family members of a proband. Reciprocal deletions lead to speech and language delay, mild facial dysmorphisms and, in some individuals, to cerebellar, breast developmental and cardiac defects.

Metaphyseal chondromatosis combined with D-2-hydroxyglutaric aciduria in four patients.

We report four patients who presented with a severe form of metaphyseal chondromatosis in association with D-2-hydroxyglutaric aciduria (D-2-HGA). All patients showed splaying columns of irregular ossification defects with bulbous metaphyses of the long tubular bones, as well as remarkable involvement of the short tubular and flat bones. The vertebral bodies revealed platyspondyly with irregular, stippled endplates. D-2-HGA has been described as a neurometabolic disorder manifesting a broad range of impairment in mental and motor development. Although hydroxyglutaric acid was excreted in high amounts in the urine of all four patients described herein, no significant neurologic abnormalities were evident. This unusual combination of characteristic skeletal and metabolic abnormalities has rarely been reported. Thus, our report will facilitate the recognition of this distinctive entity, and we suggest that a urine organic acid screening be obtained in patients who present with generalized enchondromatosis.

De novo LMNA mutations cause a new form of congenital muscular dystrophy.

OBJECTIVE: To describe a new entity of congenital muscular dystrophies caused by de novo LMNA mutations. METHODS: Fifteen patients presenting with a myopathy of onset in the first year of life were subjected to neurological and genetic evaluation. Histopathological and immunohistochemical analyses were performed for all patients. RESULTS: The 15 patients presented with muscle weakness in the first year of life, and all had de novo heterozygous LMNA mutations. Three of them had severe early-onset disease, no motor development, and the rest experienced development of a "dropped head" syndrome phenotype. Despite variable severity, there was a consistent clinical pattern. Patients typically presented with selective axial weakness and wasting of the cervicoaxial muscles. Limb involvement was predominantly proximal in upper extremities and distal in lower extremities. Talipes feet and a rigid spine with thoracic lordosis developed early. Proximal contractures appeared later, most often in lower limbs, sparing the elbows. Ten children required ventilatory support, three continuously through tracheotomy. Cardiac arrhythmias were observed in four of the oldest patients but were symptomatic only in one. Creatine kinase levels were mild to moderately increased. Muscle biopsies showed dystrophic changes in nine children and nonspecific myopathic changes in the remaining. Markedly atrophic fibers were common, most often type 1, and a few patients showed positive inflammatory markers. INTERPRETATION: The LMNA mutations identified appear to correlate with a relatively severe phenotype. Our results further broaden the spectrum of laminopathies and define a new disease entity that we suggest is best classified as a congenital muscular dystrophy (LMNA-related congenital muscular dystrophy, or L-CMD).

Nurture versus nature: long-term impact of forced right-handedness on structure of pericentral cortex and basal ganglia.

Does a conflict between inborn motor preferences and educational standards during childhood impact the structure of the adult human brain? To examine this issue, we acquired high-resolution T1-weighted magnetic resonance scans of the whole brain in adult "converted" left-handers who had been forced as children to become dextral writers. Analysis of sulcal surfaces revealed that consistent right- and left-handers showed an interhemispheric asymmetry in the surface area of the central sulcus with a greater surface contralateral to the dominant hand. This pattern was reversed in the converted group who showed a larger surface of the central sulcus in their left, nondominant hemisphere, indicating plasticity of the primary sensorimotor cortex caused by forced use of the nondominant hand. Voxel-based morphometry showed a reduction of gray matter volume in the middle part of the left putamen in converted left-handers relative to both consistently handed groups. A similar trend was found in the right putamen. Converted subjects with at least one left-handed first-degree relative showed a correlation between the acquired right-hand advantage for writing and the structural changes in putamen and pericentral cortex. Our results show that a specific environmental challenge during childhood can shape the macroscopic structure of the human basal ganglia. The smaller than normal putaminal volume differs markedly from previously reported enlargement of cortical gray matter associated with skill acquisition. This indicates a differential response of the basal ganglia to early environmental challenges, possibly related to processes of pruning during motor development.

Devenir et prise en charge des enfants grands prématurés [Neurodevelopmental outcome of very premature infants].

Very preterm infants are at risk of neurodevelopmental impairments, which may affect motor development, intelligence and behavior. Neurodevelopmental follow-up is offered to these children who represent 1% of Swiss births, and may show abnormal motor tone, which sometimes resolves spontaneously or evolves in cerebral palsy. Standardized tests explore intellectual functioning and may allow the diagnosis of specific learning impediments. Finally, behavior is assessed with standardized questionnaires which can reveal hyperactivity with or without attention deficit, impaired social relations, psychiatric troubles or autism, all more frequent amongst preterm children.

Development of motor speed and associated movements from 5 to 18 years.

AIM: To study the development of motor speed and associated movements in participants aged 5 to 18 years for age, sex, and laterality. METHOD: Ten motor tasks of the Zurich Neuromotor Assessment (repetitive and alternating movements of hands and feet, repetitive and sequential finger movements, the pegboard, static and dynamic balance, diadochokinesis) were administered to 593 right-handed participants (286 males, 307 females). RESULTS: A strong improvement with age was observed in motor speed from age 5 to 10, followed by a levelling-off between 12 and 18 years. Simple tasks and the pegboard matured early and complex tasks later. Simple tasks showed no associated movements beyond early childhood; in complex tasks associated movements persisted until early adulthood. The two sexes differed only marginally in speed, but markedly in associated movements. A significant laterality (p<0.001) in speed was found for all tasks except for static balance; the pegboard was most lateralized, and sequential finger movements least. Associated movements were lateralized only for a few complex tasks. We also noted a substantial interindividual variability. INTERPRETATION: Motor speed and associated movements improve strongly in childhood, weakly in adolescence, and are both of developmental relevance. Because they correlate weakly, they provide complementary information.

Neuromotor development in children. Part 3: motor performance in 3- to 5-year-olds.

AIM: The aim of this cross-sectional study was to provide normative data (ordinal scores and timed performances) for gross and fine motor tasks in typically developing children between 3 and 5 years of age using the Zurich Neuromotor Assessment (ZNA). METHOD: Typically developing children (n=101; 48 males, 53 females) between 3 and 5 years of age were enrolled from day-care centres in the greater Zurich area and tested using a modified version of the ZNA; the tests were recorded digitally on video. Intraobserver reliability was assessed on the videos of 20 children by one examiner. Interobserver reliability was assessed by two examiners. Test-retest reliability was performed on an additional 20 children. The modelling approach summarized the data with a linear age effect and an additive term for sex, while incorporating informative missing data in the normative values. Normative data for adaptive motor tasks, pure motor tasks, and static and dynamic balance were calculated with centile curves (for timed performance) and expected ordinal scores (for ordinal scales). RESULTS: Interobserver, intraobserver, and test-retest reliability of tasks were moderate to good. Nearly all tasks showed significant age effects, whereas sex was significant only for stringing beads and hopping on one leg. INTERPRETATION: These results indicate that timed performance and ordinal scales of neuromotor tasks can be reliably measured in preschool children and are characterized by developmental change and high interindividual variability.

Relationship of aerobic fitness and motor skills with memory and attention in preschoolers (Ballabeina): a cross-sectional and longitudinal study.

BACKGROUND: The debate about a possible relationship between aerobic fitness and motor skills with cognitive development in children has recently re-emerged, because of the decrease in children's aerobic fitness and the concomitant pressure of schools to enhance cognitive performance. As the literature in young children is scarce, we examined the cross-sectional and longitudinal relationship of aerobic fitness and motor skills with spatial working memory and attention in preschool children. METHODS: Data from 245 ethnically diverse preschool children (mean age: 5.2 (0.6) years, girls: 49.4%) analyzed at baseline and 9 months later. Assessments included aerobic fitness (20 m shuttle run) and motor skills with agility (obstacle course) and dynamic balance (balance beam). Cognitive parameters included spatial working memory (IDS) and attention (KHV-VK). All analyses were adjusted for age, sex, BMI, migration status, parental education, native language and linguistic region. Longitudinal analyses were additionally adjusted for the respective baseline value. RESULTS: In the cross-sectional analysis, aerobic fitness was associated with better attention (r=0.16, p=0.03). A shorter time in the agility test was independently associated with a better performance both in working memory (r=-0.17, p=0.01) and in attention (r=-0.20, p=0.01). In the longitudinal analyses, baseline aerobic fitness was independently related to improvements in attention (r=0.16, p=0.03), while baseline dynamic balance was associated with improvements in working memory (r=0.15, p=0.04). CONCLUSIONS: In young children, higher baseline aerobic fitness and motor skills were related to a better spatial working memory and/or attention at baseline, and to some extent also to their future improvements over the following 9 months. TRIAL REGISTRATION: clinicaltrials.gov NCT00674544.

Visuo-motor and cognitive procedural learning in children with basal ganglia pathology.

We investigated procedural learning in 18 children with basal ganglia (BG) lesions or dysfunctions of various aetiologies, using a visuo-motor learning test, the Serial Reaction Time (SRT) task, and a cognitive learning test, the Probabilistic Classification Learning (PCL) task. We compared patients with early (<1 year old, n=9), later onset (>6 years old, n=7) or progressive disorder (idiopathic dystonia, n=2). All patients showed deficits in both visuo-motor and cognitive domains, except those with idiopathic dystonia, who displayed preserved classification learning skills. Impairments seem to be independent from the age of onset of pathology. As far as we know, this study is the first to investigate motor and cognitive procedural learning in children with BG damage. Procedural impairments were documented whatever the aetiology of the BG damage/dysfunction and time of pathology onset, thus supporting the claim of very early skill learning development and lack of plasticity in case of damage.

The hotel industry and its importance in the technical and economic development of a region : the Lake Geneva case (1852-1914)

The historiography dedicated to tourism has emphasised how some socio-economic evolutions such as urbanisation, mechanisation of transport or the advent of leisure time in society have supported pleasure trips and therefore the development of the hotel industry. On the contrary, the research has too often neglected or at least minimised the impact of the hotel sector on a region's development. This contribution seeks to fill this gap by analysing the Geneva Lake region, one of the most important birthplaces of the European tourism. In this space not much touched by the first industrial revolution, the hotel business has in fact played the role of an economic motor, stimulating investment and employment. This dynamism provoked a domino effect on several other sectors of the economy (industry, bulding sector, banking). To please their customers, the hoteliers have not only given impulses on housing modernisation, but also to the revitalisation of transport, energy and communication networks. The necessity to remain on the state-of-the-art of technical issues, with the concern of competitiveness, has called forth an acceleration of the technology transfer and stimulated the constitution of technical know-how.

Doublecortin-positive cells in the adult primate cerebral cortex and possible role in brain plasticity and development.

We have demonstrated that cortical cell autografts might be a useful therapy in two monkey models of neurological disease: motor cortex lesion and Parkinson's disease. However, the origin of the useful transplanted cells obtained from cortical biopsies is not clear. In this report we describe the expression of doublecortin (DCX) in these cells based on reverse-transcription polymerase chain reaction (RT-PCR) and immunodetection in the adult primate cortex and cell cultures. The results showed that DCX-positive cells were present in the whole primate cerebral cortex and also expressed glial and/or neuronal markers such as glial fibrillary protein (GFAP) or neuronal nuclei (NeuN). We also demonstrated that only DCX/GFAP positive cells were able to proliferate and originate progenitor cells in vitro. We hypothesize that these DCX-positive cells in vivo have a role in cortical plasticity and brain reaction to injury. Moreover, in vitro these DCX-positive cells have the potential to reacquire progenitor characteristics that confirm their potential for brain repair.

Relationship of aerobic fitness and motor skills with memory and attention in preschoolers (Ballabeina): A cross-sectional and longitudinal study.

Background: The debate about a possible relationship between aerobic fitness and motor skills with cognitive development in children has recently re-emerged, because of the decrease in children's aerobic fitness and the concomitant pressure of schools to enhance cognitive performance. As the literature in young children is scarce, we examined the cross-sectional and longitudinal relationship of aerobic fitness and motor skills with spatial working memory and attention in preschool children.Methods: Data from 245 ethnically diverse preschool children (mean age: 5.2 (0.6) years, girls: 49.4%) analyzed at baseline and 9 months later. Assessments included aerobic fitness (20 m shuttle run) and motor skills with agility (obstacle course) and dynamic balance (balance beam). Cognitive parameters included spatial working memory (IDS) and attention (KHV-VK). All analyses were adjusted for age, sex, BMI, migration status, parental education, native language and linguistic region. Longitudinal analyses were additionally adjusted for the respective baseline value.Results: In the cross-sectional analysis, aerobic fitness was associated with better attention (r = 0.16, p = 0.03). A shorter time in the agility test was independently associated with a better performance both in working memory (r = -0.17, p = 0.01) and in attention (r = -0.20, p = 0.01). In the longitudinal analyses, baseline aerobic fitness was independently related to improvements in attention (r = 0.16, p = 0.03), while baseline dynamic balance was associated with improvements in working memory (r = 0.15, p = 0.04).Conclusions: In young children, higher baseline aerobic fitness and motor skills were related to a better spatial working memory and/or attention at baseline, and to some extent also to their future improvements over the following 9 months.

The Smiling Project: development of a new program for gait and balance training

Introduction: The SMILING project, a multicentric project fundedby the European Union, aims to develop a new gait and balance trainingprogram to prevent falls in older persons. The program includes the"SMILING shoe", an innovative device that generates mechanical perturbationwhile walking by changing the soles' inclination. Induced perturbationschallenge subjects' balance and force them to react to avoidfalls. By training specifically the complex motor reactions used to maintainbalance when walking on irregular ground, the program will improvesubjects' ability to react in situation of unsteadiness and reduce theirrisk of falling. Methods: The program will be evaluated in a multicentric,cross-over randomized controlled trial. Overall, 112 subjects (aged≥65 years, ≥1 falls, POMA score 22-26/28) will be enrolled. Subjectswill be randomised in 2 groups: group A begin the training with active"SMILING shoes", group B with inactive dummy shoes. After 4 weeksof training, group A and B will exchange the shoes. Supervised trainingsessions (30 minutes twice a week for 8 weeks) include walkingtasks of progressive difficulties.To avoid a learning effect, "SMILINGshoes" perturbations will be generated in a non-linear and chaotic way.Gait performance, fear of falling, and acceptability of the program willbe assessed. Conclusion: The SMILING program is an innovative interventionfor falls prevention in older persons based on gait and balancetraining using chaotic perturbations. Because of the easy use of the"SMILING shoes", this program could be used in various settings, suchas geriatric clinics or at home.

Vitamin D deficiency: A forgotten treatable cause of motor delay and proximal myopathy.

We report a four-year-old African boy referred for proximal muscle weakness, fatigability and episodic limb pain. Classical causes of structural and metabolic myopathy were initially considered before clinical and biological features of vitamin D deficiency rickets were identified. Prompt treatment with vitamin D and calcium supplementation led to a complete reversal of the muscle symptoms. Rickets-associated myopathy should be included in the differential diagnosis of proximal myopathy, especially in at-risk individuals. Vitamin D deficiency and its prevention remain important health issues in industrialized countries.

RNA interference mitigates motor and neuropathological deficits in a cerebellar mouse model of machado-joseph disease.

Machado-Joseph disease or Spinocerebellar ataxia type 3 is a progressive fatal neurodegenerative disorder caused by the polyglutamine-expanded protein ataxin-3. Recent studies demonstrate that RNA interference is a promising approach for the treatment of Machado-Joseph disease. However, whether gene silencing at an early time-point is able to prevent the appearance of motor behavior deficits typical of the disease when initiated before onset of the disease had not been explored. Here, using a lentiviral-mediated allele-specific silencing of mutant ataxin-3 in an early pre-symptomatic cerebellar mouse model of Machado-Joseph disease we show that this strategy hampers the development of the motor and neuropathological phenotypic characteristics of the disease. At the histological level, the RNA-specific silencing of mutant ataxin-3 decreased formation of mutant ataxin-3 aggregates, preserved Purkinje cell morphology and expression of neuronal markers while reducing cell death. Importantly, gene silencing prevented the development of impairments in balance, motor coordination, gait and hyperactivity observed in control mice. These data support the therapeutic potential of RNA interference for Machado-Joseph disease and constitute a proof of principle of the beneficial effects of early allele-specific silencing for therapy of this disease.