3q29 duplications: A cohort of 46 patients and a literature review.

Duplications of the 3q29 cytoband are rare chromosomal copy number variations (CNVs) (overlapping or recurrent ~1.6 Mb 3q29 duplications). They have been associated with highly variable neurodevelopmental disorders (NDDs) with various associated features or reported as a susceptibility factor to the development of learning disabilities and neuropsychiatric disorders. The smallest region of overlap and the phenotype of 3q29 duplications remain uncertain. We here report a French cohort of 31 families with a 3q29 duplication identified by chromosomal microarray analysis (CMA), including 14 recurrent 1.6 Mb duplications, eight overlapping duplications (>1 Mb), and nine small duplications (<1 Mb). Additional genetic findings that may be involved in the phenotype were identified in 11 patients. Focusing on apparently isolated 3q29 duplications, patients present mainly mild NDD as suggested by a high rate of learning disabilities in contrast to a low proportion of patients with intellectual disabilities. Although some are de novo, most of the 3q29 duplications are inherited from a parent with a similar mild phenotype. Besides, the study of small 3q29 duplications does not provide evidence for any critical region. Our data suggest that the overlapping and recurrent 3q29 duplications seem to lead to mild NDD and that a severe or syndromic clinical presentation should warrant further genetic analyses.

Effect of nusinersen after 3 years of treatment in 57 young children with SMA in terms of SMN2 copy number or type.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder due to an autosomal recessive mutation in the survival motor neuron 1 gene (SMN1), causing degeneration of the anterior horn cells of the spinal cord and resulting in muscle atrophy. This study aimed to report on the 36-month follow-up of children with SMA treated with nusinersen before the age of 3 years. Changes in motor function, nutritional and ventilatory support, and orthopedic outcomes were evaluated at baseline and 36 months after intrathecal administration of nusinersen and correlated with SMA type and SMN2 copy number. RESULTS: We found that 93% of the patients gained new motor skills during the 3 years-standing without help for 12 of 37 and walking with help for 11 of 37 patients harboring three SMN2 copies. No patients with two copies of SMN2 can stand alone or walk. Patients bearing three copies of SMN2 are more likely to be spared from respiratory, nutritional, and orthopedic complications than patients with two SMN2 copies. CONCLUSION: Children with SMA treated with nusinersen continue to make motor acquisitions at 3 years after initiation of treatment. Children with two SMN2 copies had worse motor, respiratory, and orthopedic outcomes after 3 years of treatment than children with three copies.

[The Schwartz-Jampel syndrome]. / Le syndrome de Schwartz-Jampel.

The Schwartz-Jampel syndrome (SJS, OMIM #255800) is an ultra-rare genetic disease characterized by myotonic manifestations combined with bone and cartilage abnormalities. Following an autosomal recessive mode of inheritance, its prevalence is more significant in highly-inbred areas. The unraveling of the HSPG2 gene encoding a protein of the basal lamina enabled a better nosological delineation of the syndrome. The diagnosis is usually strongly suspected at the clinical level and then confirmed by molecular biology. To date, the treatment remains essentially symptomatic.

Title: Le syndrome de Schwartz-Jampel. Abstract: Le syndrome de Schwartz-Jampel (SJS, OMIM #255800) est une affection génétique ultra-rare définie par des manifestations myotoniques et des anomalies ostéo-articulaires. Transmis selon un mode autosomique récessif, sa prévalence est plus élevée dans les zones de forte endogamie. La découverte du gène HSPG2 codant une protéine de la lame basale a permis de mieux en délimiter les contours nosologiques. Le diagnostic est généralement très fortement suspecté cliniquement puis confirmé en biologie moléculaire. Le traitement reste à ce jour essentiellement symptomatique.

Semi-automatic muscle segmentation in MR images using deep registration-based label propagation.

Fully automated approaches based on convolutional neural networks have shown promising performances on muscle segmentation from magnetic resonance (MR) images, but still rely on an extensive amount of training data to achieve valuable results. Muscle segmentation for pediatric and rare diseases cohorts is therefore still often done manually. Producing dense delineations over 3D volumes remains a time-consuming and tedious task, with significant redundancy between successive slices. In this work, we propose a segmentation method relying on registration-based label propagation, which provides 3D muscle delineations from a limited number of annotated 2D slices. Based on an unsupervised deep registration scheme, our approach ensures the preservation of anatomical structures by penalizing deformation compositions that do not produce consistent segmentation from one annotated slice to another. Evaluation is performed on MR data from lower leg and shoulder joints. Results demonstrate that the proposed few-shot multi-label segmentation model outperforms state-of-the-art techniques.

Long-term follow-up of 64 children with classical infantile-onset Pompe disease since 2004: A French real-life observational study.

BACKGROUND: Classical infantile-onset Pompe disease (IOPD) is the most severe form of Pompe disease. Enzyme replacement therapy (ERT) has significantly increased survival but only a few studies have reported long-term outcomes. METHODS: We retrospectively analyzed the outcomes of classical IOPD patients diagnosed in France between 2004 and 2020. RESULTS: Sixty-four patients were identified. At diagnosis (median age 4 months) all patients had cardiomyopathy and most had severe hypotonia (57 of 62 patients, 92%). ERT was initiated in 50 (78%) patients and stopped later due to being ineffective in 10 (21%). Thirty-seven (58%) patients died during follow-up, including all untreated and discontinued ERT patients, and 13 additional patients. Mortality was higher during the first 3 years of life and after the age of 12 years. Persistence of cardiomyopathy during follow-up and/or the presence of heart failure were highly associated with an increased risk of death. In contrast, cross-reactive immunologic material (CRIM)-negative status (n = 16, 26%) was unrelated to increased mortality, presumably because immunomodulation protocols prevent the emergence of high antibody titers to ERT. Besides survival, decreased ERT efficacy appeared after the age of 6 years, with a progressive decline in motor and pulmonary functions for most survivors. CONCLUSIONS: This study reports the long-term follow-up of one of the largest cohorts of classical IOPD patients and demonstrates high long-term mortality and morbidity rates with a secondary decline in muscular and respiratory functions. This decreased efficacy seems to be multifactorial, highlighting the importance of developing new therapeutic approaches targeting various aspects of pathogenesis.

The Impact of Screen Exposure on Attention Abilities in Young Children: A Systematic Review.

BACKGROUND: The neurocognitive consequences of exposure to screens in school-aged children have been the subject of multiple studies. However, the relationship between screen exposure and neurocognitive development, especially attentional functions, remains unclear in preschool children. The aim of this systematic review was to evaluate the immediate and long-term impact of screen exposure on attentional functions in preschoolers. METHODS: Three electronic databases (PubMed, COCHRANE, and SCOPUS) were searched for studies published between January 1, 2000, and November 30, 2020. Two reviewers independently selected studies. Inclusion criteria were observational studies, inclusion of children aged less than seven years with no neurodevelopmental disorders, evaluation of screen time, and evaluation of attentional functions. Data extracted including participants' ages, number of participants, screen exposure time, attention assessment tool, and confounding factors. Study quality was evaluated using the Newcastle-Ottawa Scale. RESULTS: Five cross-sectional studies were included: all reported significant, positive associations between high levels of screen exposure and attention difficulties. Ten longitudinal studies were included: six found a significant impact of earlier screen exposure on subsequent attentional function and four found no relationship. Eight of the studies included evaluated the direction of the relationship between screen exposure and attentional difficulties: seven suggested the relationship is bidirectional. CONCLUSIONS: These findings support current guidelines to limit screen time in preschoolers to prevent the development of attention difficulties.

Early Seizure Recurrence in Children Admitted for Nonfebrile Seizures in the Emergency Department: A Prospective Study.

OBJECTIVE: This study was aimed to determine the rate, timing, and risk factors of acute recurrence of seizures in the children admitted for nonfebrile seizure in the emergency department (ED). METHODS: This multicenter prospective study was conducted in the ED of three hospitals. All consecutive visits of children aged 28 days to 15 years who attended the ED for a nonfebrile seizure for 1 year were included in the study and prospectively followed. The rate of acute seizure recurrence within 24 hours was evaluated and association with potential risk factor was tested. Timing of seizure recurrence was assessed. RESULTS: A total of 181 ED visits were enrolled. Overall, 19.9% (36/181) of children presented acute seizure recurrence, 50% of seizure recurrence occurred during the 2 hours after ED arrival and 70% within 6 hours. Multivariable analysis showed that age of <5 years and seizure recurrence in the emergency department were associated with a significant increase in acute recurrence risk. CONCLUSION: Early seizure recurrence is common in children with nonfebrile seizure, with younger children at higher risk. Based on these findings, acute recurrence risk after a nonfebrile seizure should justify to observe the children admitted for a nonfebrile seizure in the ED, especially young children. A larger study should analyze other risk factors associated with increased risk of acute seizure recurrence and help ED management.

MECP2 Dysautonomia Phenotypes in Boys.

BACKGROUND: Recognizing and identifying dysautonomia would facilitate the diagnosis and management of MECP2 mutations in boys. We aimed to explore the prevalence of dysautonomia symptoms in boys with MECP2 mutations. METHOD: We conducted a national, retrospective study (2000-2020) of medical records from boys who were aged less than 18 years when diagnosed with a pathogenic, or likely pathogenic, variant in the MECP2 gene. We systematically looked for dysautonomic signs in the cardiovascular, respiratory, gastrointestinal, and thermoregulatory systems. RESULTS: Nine of the 13 cases had at least one system affected by dysautonomia. Two patient subgroups were identified: (1) patients who were ambulatory with intellectual or learning disabilities (n = 6/13 cases) and (2) patients who were unable to walk normally with severe encephalopathy (n = 7/13 cases). Dysautonomic signs were found in both subgroups: 7 of seven patients in the severe array subgroup and 2 of six in the mild array subgroup. CONCLUSIONS: These results support MECP2 testing and dysautonomia investigations in both young males who present with encephalopathy and those with intellectual disabilities.

A Multidisciplinary Approach to Optimizing Long-Term Functional Prognosis of A Girl With Quadriceps Fibrosis.

The consequences and optimal treatment of quadriceps fibrosis following intramuscular quinine injection during childhood remain unclear. We report here a case of a 17-year-old girl who experienced unilateral quadriceps fibrosis following intramuscular injection of quinine as a baby. This case report describes the evolution of the condition during the child's growth, the long-term impact of early fibrosis on range of motion, muscle volumes, strength, gait, and activities of daily living. Rehabilitation involved orthoses and physiotherapy from the age of 6 years, when her knee flexion was reduced to 90°. A Judet quadricepsplasty was performed at 12 years because of continued loss of knee range with consequences for gait. At 16 years, knee range was satisfactory and gait variables were normalized. Functional evaluations and quality of life scales showed excellent recovery. Isometric strength of the involved quadriceps remained lower than the expected age-matched strength. Magnetic resonance imaging identified amyotrophy of the quadriceps, specifically the vastus intermedius. Despite being a focal impairment, quadriceps fibrosis had wider consequences within the involved limb, the uninvolved limb and functioning. This case report illustrates how children with quadriceps fibrosis can have a good prognosis, with excellent functional results at the end of the growth period, following early and appropriate management.

DNA nuclear targeting sequences for enhanced non-viral gene transfer: An in vitro and in vivo study.

An important bottleneck for non-viral gene transfer commonly relates to translocation of nucleic acids into the nuclear compartment of target cells. So-called 3NFs are optimized short nucleotide sequences able to interact with the transcription factor nuclear factor κB (NF-κB), which can enhance the nuclear import of plasmid DNA (pDNA) carrying such motifs. In this work, we first designed a consistent set of six pDNAs featuring a common backbone and only varying in their 3NF sequences. These constructions were then transfected under various experimental settings. In vitro, cationic polymer-assisted pDNA delivery in five human-derived cell lines showed the potential advantage of 3NF carrying pDNA in diverse cellular contexts. In vivo, naked pDNAs were hydrodynamically delivered to muscle hindlimbs in healthy mice; this direct accurate comparative (in the absence of any gene carrier) revealed modest but consistent trends in favor of the pDNAs equipped with 3NF. In summary, the results reported emphasize the implications of various parameters on NF-κB-mediated pDNA nuclear import; under specific conditions, 3NF can provide modest to substantial advantages for pDNA gene transfer, in vitro as well as in vivo. This study thus further underscores the potential of optimized nuclear import for more efficient non-viral gene transfer applications.

No pain, no gain? Children with cerebral palsy and their experience with physiotherapy.

OBJECTIVES: Recent studies have shown that physiotherapy can induce pain in children and young adults with cerebral palsy (CP). There is a lack of knowledge of children's pain experiences during therapy sessions and the specific causes of pain. The main objective of this study was to better understand the experience of children and young adults with CP during physiotherapy sessions and to analyse the coping strategies used by children and therapists. METHODS: Qualitative study with focus groups. Eighteen children/young adults with CP who experienced pain during physiotherapy were interviewed, using focus groups as a source of data collection in a phenomenological perspective. Data collection and analysis were consecutive to ensure that the data saturation point was reached. The transcripts were coded manually using thematic analysis. First, interesting features of the verbatim were coded, then codes were collated into potential themes and then the themes were checked to ensure they worked in relation to the coded extracts. Multiple coding was performed by 3 different researchers, and results were merged at each step. RESULTS: This study confirmed that among the 18 children interviewed (mean [SD] age 13.17 [4.02] years, 10 girls), physiotherapy, particularly stretching, induced pain. Participants reported that the experience of pain led to a dislike of physiotherapy, although some believed that the pain was necessary to show that the treatment was effective. The use of distraction techniques and the relationship with the physiotherapist were key elements associated with the perception and experience of pain. CONCLUSIONS: This study confirmed that patients with CP experience pain during physiotherapy. Stretching seems to be the main source of pain. Beliefs and practices regarding the concept of pain show that physiotherapists need training in this field.

Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord. Nusinersen has been covered by public healthcare in France since May 2017. The aim of this article is to report results after 1 year of treatment with intrathecal nusinersen in children with SMA types 1 and 2 in France. Comparisons between treatment onset (T0) and after 1 year of treatment (Y1) were made in terms of motor function and need for nutritional and ventilatory support. Motor development milestone achievements were evaluated using the modified Hammersmith Infant Neurologic Examination-Part 2 (HINE-2) for patients under 2 years of age and Motor Function Measure (MFM) scores for patients over 2 years of age. RESULTS: Data on 204 SMA patients (type 1 or 2) were retrospectively collected from the 23 French centers for neuromuscular diseases. One hundred and twenty three patients had been treated for at least 1 year and were included, 34 of whom were classified as type 1 (10 as type 1a/b and 24 as type 1c) and 89 as type 2. Survival motor Neuron 2 (SMN2) copy numbers were available for all but 6 patients. Patients under 2 years of age (n = 30), had significantly higher HINE-2 scores at year 1 than at treatment onset but used more nutritional and ventilatory support. The 68 patients over 2 years of age evaluated with the Motor Function Measure test had significantly higher overall scores after 1 year, indicating that their motor function had improved. The scores were higher in the axial and proximal motor function (D2) and distal motor function (D3) parts of the MFM scale, but there was no significant difference for standing and transfer scores (D1). No child in either of the two groups achieved walking. CONCLUSION: Nusinersen offers life-changing benefits for children with SMA, particularly those with more severe forms of the disorder. Caregiver assessments are positive. Nevertheless, patients remain severely disabled and still require intensive support care. This new treatment raises new ethical challenges.

Clinical Applications of Mobile Health Wearable-Based Sleep Monitoring: Systematic Review.

BACKGROUND: Sleep disorders are a major public health issue. Nearly 1 in 2 people experience sleep disturbances during their lifetime, with a potential harmful impact on well-being and physical and mental health. OBJECTIVE: The aim of this study was to better understand the clinical applications of wearable-based sleep monitoring; therefore, we conducted a review of the literature, including feasibility studies and clinical trials on this topic. METHODS: We searched PubMed, PsycINFO, ScienceDirect, the Cochrane Library, Scopus, and the Web of Science through June 2019. We created the list of keywords based on 2 domains: wearables and sleep. The primary selection criterion was the reporting of clinical trials using wearable devices for sleep recording in adults. RESULTS: The initial search identified 645 articles; 19 articles meeting the inclusion criteria were included in the final analysis. In all, 4 categories of the selected articles appeared. Of the 19 studies in this review, 58 % (11/19) were comparison studies with the gold standard, 21% (4/19) were feasibility studies, 15% (3/19) were population comparison studies, and 5% (1/19) assessed the impact of sleep disorders in the clinic. The samples were heterogeneous in size, ranging from 1 to 15,839 patients. Our review shows that mobile-health (mHealth) wearable-based sleep monitoring is feasible. However, we identified some major limitations to the reliability of wearable-based monitoring methods compared with polysomnography. CONCLUSIONS: This review showed that wearables provide acceptable sleep monitoring but with poor reliability. However, wearable mHealth devices appear to be promising tools for ecological monitoring.

Muscle MRI: A biomarker of disease severity in Duchenne muscular dystrophy? A systematic review.

OBJECTIVE: To assess the evidence of a relationship between muscle MRI and disease severity in Duchenne muscular dystrophy (DMD). METHODS: We conducted a systematic review of studies that analyzed correlations between MRI measurements and motor function in patients with DMD. PubMed, Cochrane, Scopus, and Web of Science were searched using relevant keywords and inclusion/exclusion criteria (January 1, 1990-January 31, 2019). We evaluated article quality using the Joanna Briggs Institute scale. Information regarding the samples included, muscles evaluated, MRI protocols and motor function tests used was collected from each article. Correlations between MRI measurements and motor function were reported exhaustively. RESULTS: Seventeen of 1,629 studies identified were included. Most patients included were ambulant with a mean age of 8.9 years. Most studies evaluated lower limb muscles. Moderate to excellent correlations were found between MRI measurements and motor function. The strongest correlations were found for quantitative MRI measurements such as fat fraction or mean T2. Correlations were stronger for lower leg muscles such as soleus. One longitudinal study reported that changes in soleus mean T2 were highly correlated with changes in motor function. CONCLUSION: The findings of this systematic review showed that MRI measurements can be used as biomarkers of disease severity in ambulant patients with DMD. Guidelines are proposed to help clinicians choose the most appropriate MRI measurements and muscles to evaluate. Studies exploring upper limb muscles, other stages of the disease, and sensitivity of measurements to change are needed.

Thoracic circumference: A new outcome measure in spinal muscular atrophy type 1?

Since respiratory insufficiency is the first cause of morbidity and mortality in spinal muscular atrophy type 1 (SMA 1), specific respiratory outcome measures are needed to evaluate changes and assess innovative therapies. In this study, thoracic circumference (TC) was used as a proxy for chest growth and an indirect measurement of respiratory function. The anthropometric parameters including TC and head-circumference (HC) were evaluated from birth to 13 months in 19 infants with SMA 1 and 124 control infants. TC was significantly decreased in the SMA 1 group from the first weeks of life. The control group TC/HC ratio = 1 (± 0.04), and was not found to be associated with age. By contrast, it decreased with time in all infants with SMA 1 and those with a TC/HC ratio <0.85 died within 3 months. TC is a simple measurement that provided an index of chest growth and was used as evidence of early, progressive respiratory failure and under-development of the rib-cage in SMA 1. The TC/HC ratio decreased in all patients over time, reflecting the progression of the disease suggesting that TC/HC ratio could be a new measure for SMA 1 for measuring disease severity and prognosis.

From childhood to adulthood: health care use in individuals with cerebral palsy.

AIM: To analyse the health care usage of individuals with cerebral palsy (CP) as a function of age and ambulatory status. METHOD: In total, 970 self-administered questionnaires relating to health care usage were sent, via a clinical network of professionals and institutions, to children and adults with CP in Brittany, France. Frequency of use of different aspects of health care were analysed as a function of age and ambulatory status. Multivariate logistic regression evaluated differences in the frequency of each health care type with age; the transition from childhood to adulthood was specifically analysed. RESULTS: The response rate was 53% (282 adults, 230 children). Use of medication (particularly psychotropic and analgesic) increased with age, while physical-types of health care (rehabilitation, physical medicine and rehabilitation follow-up, and equipment) decreased with age, independently of ambulatory status. Use of other treatments, such as botulinum toxin injections, was not influenced by age. The provision of rehabilitation was particularly affected by the period of transition. INTERPRETATION: Although health care needs change naturally in adulthood, the large decrease in usage of specific types of rehabilitation after the transition to adulthood suggested individuals had difficulty accessing this type of health care after childhood. These results provide objectives for the development of patient-centred, transitional consultations, and longitudinal studies. WHAT THIS PAPER ADDS: Use of medication, particularly psychotropic and analgesic drugs, increased with age in individuals with cerebral palsy. Use of orthoses, physical medicine and rehabilitation physician follow-up, and rehabilitation decreased with age. Transition from childhood to adulthood involved significant changes in health care usage.

Nusinersen in patients older than 7 months with spinal muscular atrophy type 1: A cohort study.

OBJECTIVE: To evaluate the safety and clinical efficacy of nusinersen in patients older than 7 months with spinal muscular atrophy type 1 (SMA1). METHODS: Patients with SMA1 were treated with nusinersen by intrathecal injections as a part of the Expanded Access Program (EAP; NCT02865109). We evaluated patients before treatment initiation (M0) and at 2 months (M2) and 6 months (M6) after treatment initiation. Survival, respiratory, and nutritional data were collected. Motor function was assessed with the modified Hammersmith Infant Neurologic Examination Part 2 (HINE-2) and physiotherapist scales adjusted to patient age (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and the Motor Function Measure 20 or 32). RESULTS: We treated 33 children ranging in age from 8.3 to 113.1 months between December 2016 and May 2017. All patients were alive and were continuing treatment at M6. Median progress on the modified HINE-2 score was 1.5 points after 6 months of treatment (p < 0.001). The need for respiratory support significantly increased over time. There were no statistically significant differences between patients presenting with 2 and those presenting with 3 copies of the survival motor neuron 2 (SMN2) gene. CONCLUSIONS: Our results are in line with the phase 3 study for nusinersen in patients with SMA1 treated before 7 months of age and indicate that patients benefit from nusinersen even at a later stage of the disease. CLINICALTRIALSGOV IDENTIFIER: NCT02865109. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with SMA1 who are older than 7 months, nusinersen is beneficial.