Helical tomotherapy craniospinal irradiation in primary brain tumours: Toxicities and outcomes in a peadiatric and adult population.

Objective: As craniospinal irradiation (CSI) is delivered more frequently by helical tomotherapy (HT) with few reports about late effects, we analysed all patients treated in our centre over an 11-year period. Methods and materials: Our study included all patients that underwent CSI by HT, between September 2009 and January 2020, in the Department of Radiation Oncology of the Toulouse Cancer Institute. Acute radiotherapy toxicities were reported and medium- to long-term outcomes analysed. Results: Among the 79 patients included, 70.9 % were younger than 18 years at diagnosis, the median age was 13 (range: 1-52) at the time of radiation therapy, 67.1 % of patients had medulloblastoma. Half of them (49.4 %) had a metastatic disease at diagnosis. The median dose of CSI was 36 Gy (range, 18-36). Seventy-seven patients received a radiation boost to the original location of the primary tumour (97.5 %), 32 patients also received a boost to their metastatic sites (40.5 %). Median follow-up was 55.5 months (95 %CI = [41.2; 71.8]). The 3-year event-free survival rate was 66.3 % (95 %CI = [54.2; 75.9]). Most patients presented with acute haematological toxicities during CSI (85.9 %), predominantly severe thrombocytopenia (39.7 %). Among the 64 patients assessed for medium- and long-term outcomes, 52 survived and 47 were alive and disease-free at the latest follow-up visit on record. There were 3.8 % secondary tumours: two meningiomas and one diffuse intrinsic pontine glioma. Adult and paediatric patients respectively presented with secondary cataract (4.3 % vs 22.0 %), persistent hearing disorders (26.1 % vs 29.3 %), pulmonary or cardiac late effects (4.3 % vs 2.4 %), hormonal pituitary gland deficiencies (30.0 % vs 56.8 %) and psycho-cognitive disorders (56.5 % vs 53.7 %). Conclusion: CSI dispensed by HT, did not result in any additional acute or late toxicities when compared to 3D-CSI. There was no increase in the secondary tumour rate compared to that reported in the literature.

Optimizing an exercise training program in pediatric brain tumour survivors: Does timing postradiotherapy matter?

Background: While exercise training (ET) programs show positive outcomes in cognition, motor function, and physical fitness in pediatric brain tumor (PBT) survivors, little is known about the optimal timing of intervention. The aim of this work was to explore the feasibility and benefits of ET based on its timing after radiotherapy. Methods: This retrospective analysis (ClinicalTrials.gov, NCT01944761) analyzed data based on the timing of PBT survivors' participation in an ET program relative to their completion of radiotherapy: <2 years (n = 9), 2-5 years (n = 10), and > 5 years (n = 13). We used repeated measures analysis of variance to compare feasibility and efficacy indicators among groups, as well as correlation analysis between ET program timing postradiotherapy and preliminary treatment effects on cognition, motor function and physical fitness outcomes. Results: Two to five years postradiotherapy was the optimal time period in terms of adherence (88.5%), retention (100%), and satisfaction (more fun, more enjoyable and recommend it more to other children). However, the benefits of ET program on memory recognition (r = -0.379, P = .047) and accuracy (r = -0.430, P = .032) decreased with increased time postradiotherapy. Motor function improved in all groups, with greater improvements in bilateral coordination (P = .043) earlier postradiotherapy, and in running (P = .043) later postradiotherapy. The greatest improvement in pro-rated work rate occurred in the < 2-year group (P = .008). Conclusion: Participation in an ET program should be offered as part of routine postradiotherapy care in the first 1-2 years and strongly encouraged in the first 5 years.

Long-term outcomes of paediatric Guillain-Barré syndrome.

AIM: To study long-term sequelae in children with Guillain-Barré syndrome (GBS). METHOD: This was a prospective observational study with children from two French tertiary centres. Data were from clinical and several standardized scales or questionnaires. RESULTS: Fifty-one patients were included with a median follow-up of 6 years 4 months (range 3-20 years) after the acute phase. The sequelae rate was 67% (95% confidence interval [CI] 53-78) and did not vary with time. Most children had minor sequelae (Guillain-Barré Syndrome Disability Score [GBSDS] = 1); only one was unable to run (GBSDS = 2). The most frequent complaints were paraesthesia (43%), pain (35%), and fatigue (31%). The neurological examination was abnormal in 18% of children, autonomy was compromised in 14%, and symptoms of depression occurred in 34%. The factors associated with late-onset sequelae were correlated with severity during the initial phase (i.e. initial GBSDS >4, odds ratio 6.6, 95% CI 1.8-33; p = 0.009). The predictive factors of more severe late-onset conditions were initial severity (p = 0.002) and sex (female patients; p = 0.01). INTERPRETATION: Two-thirds of children with GBS had late-onset sequelae following an episode, often minor, but sometimes with continuing effects on their everyday lives. Particularly affected were those who had severe GBS during the acute phase and who lost the ability to walk. WHAT THIS PAPER ADDS: Two-thirds of children with Guillain-Barré syndrome (GBS) had persistent sequelae. Sequelae were often minor, but daily repercussions of them were sometimes serious. Sequelae were significantly associated with severe GBS during the acute phase.

The long-term impact of irradiation on functional connectivity in brain circuits involved in memory processes after pediatric posterior fossa tumor.

PURPOSE: Memory is one of the main specific cognitive domains impaired with attention and processing speed after a pediatric brain tumor. This work explored the long-term impact of radiotherapy in children with posterior fossa tumor (PFT) on brain connectivity in neural circuits involved in memory using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: A total of 20 irradiated and 15 non-irradiated PFT survivors, and 21 healthy controls, prospectively included in the IMPALA study (NCT04324450), performed memory tests assessing episodic, procedural, and working memories and were subjected to an rs-fMRI. We manually contoured main structures involved in memory to explore connectivity at rest in a seed-to-voxel analysis. The groups were compared and differences in connectivity were correlated with behavioral scores and irradiation doses. RESULTS: The performance of all mnesic tasks was lower in PFT survivors with a greater alteration in working and episodic memory in irradiated patients. Irradiated survivors had atypical connectivities in all memory circuits compared to controls and in cortico-caudate and cortico-cerebellar circuits compared to non-irradiated survivors. Non-irradiated survivors had only atypical connectivities in the cortico-cerebellar circuits compared to controls. In irradiated survivors, atypical connectivities in cortico-hippocampal circuits were linked with episodic memory scores and dose of irradiation to the left hippocampus and in cortico-striatal circuits with procedural memory scores and dose of irradiation to the striatum. CONCLUSION: The results of this study highlight that irradiation has a long-term impact on brain connectivity in brain circuits involved in memory after pediatric PFT with a specific radiation-dose effect in supratentorial structures.

Confirmatory validation of the french version of the Duchenne Muscular Dystrophy module of the pediatric quality of life inventory (PedsQLTM3.0DMDfv).

Duchenne Muscular Dystrophy (DMD) is a neuromuscular disease that inevitably leads to total loss of autonomy. The new therapeutic strategies aim to both improve survival and optimise quality of life. Evaluating quality of life is nevertheless a major challenge. No DMD-specific quality of life scale to exists in French. We therefore produced a French translation of the English Duchenne Muscular Dystrophy module of the Pediatric Quality of Life Inventory (PedsQLTMDMD) following international recommendations. The study objective was to carry out a confirmatory validation of the French version of the PedsQLTMDMD for paediatric patients with DMD, using French multicentre descriptive cross-sectional data. The sample consisted of 107 patients. Internal consistency was acceptable for proxy-assessments, with Cronbach's alpha coefficients above 0.70, except for the Treatment dimension. For self-assessments, internal consistency was acceptable only for the Daily Activities dimension. Our results showed poor metric qualities for the French version of the PedsQLTMDMD based on a sample of about 100 children, but these results remained consistent with those of the original validation. This confirms the interest of its use in clinical practice.

Impact of a pediatric posterior fossa tumor and its treatments on motor procedural learning.

INTRODUCTION: Posterior fossa tumor (PFT) survivors have difficulty learning new skills. Procedural memory is a skill learning system that allows, through training, the automatization of procedures and progressive improvement of performance. It underlies most of the motor procedures in everyday life that we perform automatically, such as riding a bike or writing. Motor procedural memory is divided into two components: motor sequence learning involving mainly cortico-striatal networks, and motor adaptation involving mainly cortico-cerebellar networks. The aim of this work was to explore the impact of a tumor and its treatment during childhood on procedural learning hypothesizing that sequence learning would be impaired in PFT survivors who have been treated with radiotherapy, whereas motor adaptation would be impaired in all PFT survivors. METHOD: 22 irradiated survivors of PFT, 17 non-irradiated survivors and 21 healthy controls from the IMPALA study (NCT04324450) performed a motor sequence learning task and a motor adaptation task. Doses received by striatal and cerebellar structures were reported from the initial dosimetry plans. RESULTS: Sequence learning was preserved in both tumor groups, but at the individual level 7/22 irradiated, and 4/17 non-irradiated participants failed to learn the motor sequence. Motor adaptation was impaired in both tumor groups, predominantly in the irradiated group. CONCLUSION: This study sheds new light on the long-term impact of PFT treatments in childhood on a rarely-studied part of memory, which is perceptual-motor procedural learning. Our results suggest that the cerebellum and striatum could be considered as organs at risk with regard to procedural learning.

Unusual circumstance for craniopharyngioma discovery on meningoencephalitis: a pediatric case report.

BACKGROUND: Craniopharyngioma is a rare condition in children, but it is the most frequent tumor that occurs in the hypothalamic pituitary region. Chemical meningitis has been described as an uncommon postoperative complication, but no chemical meningitis due to a spontaneous rupture leading to craniopharyngioma diagnosis in children has been reported. CASE PRESENTATION: This is a case of a 13-year-old boy presenting with fever, vomiting and headache for two days. The CT scan revealed a suprasellar lesion, and lumbar puncture showed aseptic meningitis. The cerebral MRI suggested a craniopharyngioma and the cerebrospinal fluid cholesterol concentration was abnormally high. A thorough medical history indicated some visual disturbance, which improved at the onset of meningitis, and an inflection of the growth curve. The anatomopathological analysis of the tumor confirmed the diagnosis of craniopharyngioma. CONCLUSIONS: This case is the first to report the discovery of a craniopharyngioma with meningoencephalitis caused by the rupture of a craniopharyngioma cyst in a child. Diagnosis was facilitated by determining the cholesterol level in the cerebrospinal fluid, as well as fine anamnesis to identify visual and growth disturbances.

Arterial Spin Labeling Perfusion in Pediatric Brain Tumors: A Review of Techniques, Quality Control, and Quantification.

Arterial spin labeling (ASL) is a magnetic resonance imaging (MRI) technique for measuring cerebral blood flow (CBF). This noninvasive technique has added a new dimension to the study of several pediatric tumors before, during, and after treatment, be it surgery, radiotherapy, or chemotherapy. However, ASL has three drawbacks, namely, a low signal-to-noise-ratio, a minimum acquisition time of 3 min, and limited spatial summarize current resolution. This technique requires quality control before ASL-CBF maps can be extracted and before any clinical investigations can be conducted. In this review, we describe ASL perfusion principles and techniques, summarize the most recent advances in CBF quantification, report technical advances in ASL (resting-state fMRI ASL, BOLD fMRI coupled with ASL), set out guidelines for ASL quality control, and describe studies related to ASL-CBF perfusion and qualitative and semi-quantitative ASL weighted-map quantification, in healthy children and those with pediatric brain tumors.

Post-CMV Guillain-Barré Syndrome with Anti-GM2 Antibodies: Two Cases and a Review of the Literature.

INTRODUCTION: Guillain-Barré syndrome (GBS) is an acute post-infectious inflammatory polyneuropathy of ubiquitous distribution. Cytomegalovirus (CMV) is the virus that is most frequently involved. All ages are affected but rare pediatric cases seem to show some distinctive features in terms of specificity and severity. Specific antibodies that target the peripheral nervous system have been identified in several forms of GBS in adults, such as anti-GM2 ganglioside antibodies in post-CMV GBS, which in most instances present as demyelinating polyneuropathies, with a more favorable progression and fewer complications. MATERIALS AND METHODS: This is a retrospective report on two cases of post-CMV GBS with a demyelinating disorder and positive for anti-GM2 IgM. The review of the literature examines five other cases of children with post-CMV GBS with anti-GM2 IgM. RESULTS: In terms of progression, our two cases of post-CMV GBS with a demyelinating disorder and anti-GM2 IgM are similar to the five other cases described in the literature. The CMV infection was asymptomatic or paucisymptomatic and involved girls (6/7), often presenting severe motor forms with frequent loss of the ability to walk (4/6), facial involvement (⅗), little respiratory involvement (⅙), and favorable progression with adapted treatment. CONCLUSION: Post-CMV GBS with anti-GM2 IgM is a specific clinical spectrum that seems to affect children as it affects adults with a predominance among females, demyelination, and severe motor involvement, but a good prognosis. On the other hand, unlike adults, the use of assisted ventilation does not seem to be more frequent.

A review of long-term deficits in memory systems following radiotherapy for pediatric posterior fossa tumor.

INTRODUCTION: In recent years, progress in pediatric posterior fossa tumor (PFT) treatments has improved survival rates. However, the majority of survivors present neurocognitive sequelae that impact academic achievement. METHODS: This review examines the literature from 2000 to 2020 on long-term outcomes in different memory systems for survivors of pediatric PFT, considering the impact of radiotherapy which is a well-known prognostic factor for global neurocognitive function. RESULTS: Of the 43 articles selected, 31 explored working memory, 19 episodic memory, 9 semantic memory and 2 procedural memory. Irradiated survivors had scores of <-2 standard deviation (SD) (n = 4 studies/25) or between -2SD and -1SD (n = 7 studies/25) for working memory; <-1SD for anterograde memory (n = 11/13), with a progressive decline in these two memory systems; <-1SD (n = 4/7) in semantic memory, and a deficit in perceptual-motor procedural learning (n = 1/1). Reducing craniospinal irradiation dose, limiting tumor bed boosts, and using proton therapy seem to have had a beneficial effect with better preservation of the memory score and a reduction in the decline over time. Non-irradiated survivors had memory systems that were less affected, with preservation of anterograde memory and maintenance of long-term stability. CONCLUSION: Memory deficits are a core feature in survivors of pediatric PFT, especially when treatment requires radiotherapy. To limit these effects, dose constraints for specific brain areas involved in memory should be defined. During long-term follow-up, specific attention is essential to identify these deficits in order to limit their impact on the quality of life.

Unexpected Intermediate Nerve Conduction Velocity Findings in Charcot-Marie-Tooth Syndromes Classified as Demyelinated or Axonal in a Pediatric Population.

INTRODUCTION: Among the hereditary motor and sensory neuropathies (HMSN), demyelinating forms are the best characterized, with a clear predominance of CMT1A. The axonal and intermediate forms are less described. The aim of this study is to report the genetic diagnosis of Charcot-Marie-Tooth (CMT) according to the nerve conduction velocity (NCV) findings in a pediatric population. METHODS: We retrospectively described a population of HMSN children with a confirmed genetic diagnosis of demyelinated, intermediate, or axonal forms. We compared the results of the genetic analyses with those of motor NCV in median nerve according to whether they were below 25 m/s (demyelinating group); between 25 and 45 m/s (intermediate group), or above 45 m/s (axonal group). RESULTS: Among the 143 children with an HMSN, 107 had a genetic diagnosis of which 61 had an electromyogram. On NCV findings: seven (11%) pertain to the axonal group, 20 (32%) to the intermediate group, and 34 (55%) to the demyelinating group. When NCV was above 45 m/s, CMT2A was the predominant genetic diagnosis (70%) when NCV were below 25 m/s, CMT1A was the predominant genetic diagnosis (71%). Intermediate NCV findings group was the more heterogeneous with seven genetic CMT subgroups (60% CMT1A, CMT1B, CMT1X, CMT2A, CMT2N, CMT4G). CONCLUSION: Taking NCV values between 25 and 45 m/s to define an intermediate group of CMT in children leads to the inclusion of non-typically "intermediate", especially CMT1A. We emphasize the broad spectrum of NCV in CMT1A that justified the systematic search of PMP22 duplication/deletion screening before next generation sequencing panel.

Atypical connectivity in the cortico-striatal network in NF1 children and its relationship with procedural perceptual-motor learning and motor skills.

INTRODUCTION: Neurofibromatosis type 1 (NF1) is considered a model of neurodevelopmental disorder because of the high frequency of learning deficits, especially developmental coordination disorder. In neurodevelopmental disorder, Nicolson and Fawcett formulated the hypothesis of an impaired procedural learning system that has its origins in cortico-subcortical circuits. Our aim was to investigate the relationship between cortico-striatal connectivity and procedural perceptual-motor learning performance and motor skills in NF1 children. METHODS: Seventeen NF1 and 18 typically developing children aged between 8 and 12 years old participated in the study. All were right-handed and did not present intellectual or attention deficits. In all children, procedural perceptual-motor learning was assessed using a bimanual visuo-spatial serial reaction time task (SRTT) and motor skills using the Movement Assessment Battery for Children (M-ABC). All participants underwent a resting-state functional MRI session. We used a seed-based approach to explore cortico-striatal connectivity in somatomotor and frontoparietal networks. A comparison between the groups' striato-cortical connectivity and correlations between connectivity and learning (SRTT) and motor skills (M-ABC) were performed. RESULTS: At the behavioral level, SRTT scores are not significantly different in NF1 children compared to controls. However, M-ABC scores are significantly impaired within 9 patients (scores below the 15th percentile). At the cerebral level, NF1 children present a higher connectivity in the cortico-striatal regions mapping onto the right angular gyrus compared to controls. We found that the higher the connectivity values between these regions, differentiating NF1 and controls, the lower the M-ABC scores in the whole sample. No correlation was found for the SRTT scores. CONCLUSION: NF1 children present atypical hyperconnectivity in cortico-striatal connections. The relationship with motor skills could suggest a sensorimotor dysfunction already found in children with developmental coordination disorder. These abnormalities are not linked to procedural perceptual-motor learning assessed by SRTT.

A prospective behavioral and imaging study exploring the impact on long-term memory of radiotherapy delivered for a brain tumor in childhood and adolescence.

BACKGROUND: Posterior fossa tumors represent two thirds of brain tumors in children. Although progress in treatment has improved survival rates over the past few years, long-term memory impairments in survivors are frequent and have an impact on academic achievement. The hippocampi, cerebellum and cerebellar-cortical networks play a role in several memory systems. They are affected not only by the location of the tumor itself and its surgical removal, but also by the supratentorial effects of complementary treatments, particularly radiotherapy. The IMPALA study will investigate the impact of irradiation doses on brain structures involved in memory, especially the hippocampi and cerebellum. METHODS/DESIGN: In this single-center prospective behavioral and neuro-imaging study, 90 participants will be enrolled in three groups. The first two groups will include patients who underwent surgery for a posterior fossa brain tumor in childhood, who are considered to be cured, and who completed treatment at least 5 years earlier, either with radiotherapy (aggressive brain tumor; Group 1) or without (low-grade brain tumor; Group 2). Group 3 will include control participants matched with Group 1 for age, sex, and handedness. All participants will perform an extensive battery of neuropsychological tests, including an assessment of the main memory systems, and undergo multimodal 3 T MRI. The irradiation dose to the different brain structures involved in memory will be collected from the initial radiotherapy dosimetry. DISCUSSION: This study will provide long-term neuropsychological data about four different memory systems (working memory, episodic memory, semantic memory, and procedural memory) and the cognitive functions (attention, language, executive functions) that can interfere with them, in order to better characterize memory deficits among the survivors of brain tumors. We will investigate the correlations between neuropsychological and neuroimaging data on the structural (3DT1), microstructural (DTI), functional (rs-fMRI), vascular (ASL) and metabolic (spectroscopy) impact of the tumor and irradiation dose. This study will thus inform the setting of dose constraints to spare regions linked to the development of cognitive and memory functions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04324450, registered March 27, 2020, updated January 25th, 2021. Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT04324450.

Stiff Person Syndrome and Encephalitis with GAD Antibodies with Severe Anterograde Amnesia in an Adolescent: A Case Study and Literature Review.

Antiglutamic acid decarboxylase (GAD65) encephalitis is rare and few pediatric cases have been reported, with variable clinical presentations. A 14-year-old female adolescent was managed in our department. She had been treated for several months for drug-resistant temporal lobe epilepsy and gradually presented major anterograde amnesia with confusion. Upon her arrival at the University Hospital Centre, she showed a classical form of stiff person syndrome. The brain magnetic resonance imaging showed bitemporal hyperintensities and hypertrophy of the amygdala. The blood and cerebrospinal fluid were positive for GAD65 antibodies. At 2 years of immunosuppressive treatment and rehabilitation, the course showed partial improvement of the memory and neuropsychiatric impairment, and epilepsy that continued to be active. GAD65 antibodies are associated with various neurological syndromes, and this presentation combining limbic encephalitis and stiff person syndrome is the first pediatric form published to date; there are also few cases described in adults.

Evaluating next-generation sequencing in neuromuscular diseases with neonatal respiratory distress.

With the exception of infantile spinal muscular atrophy (SMA) and congenital myotonic dystrophy 1 (DM1), congenital myopathies and muscular dystrophies with neonatal respiratory distress pose diagnostic challenges. Next-generation sequencing (NGS) provides hope for the diagnosis of these rare diseases. We evaluated the efficiency of next-generation sequencing (NGS) in ventilated newborns with peripheral hypotonia. We compared the results of our previous study in a cohort of 19 patients analysed by Sanger sequencing from 2007 to 2012, with a diagnostic yield of 26% (5/19), and those of a new retrospective study in 28 patients from 2007 to 2018 diagnosed using MyoPanel, a neuromuscular disease panel, with a diagnostic yield of 43% (12/28 patients). Pathogenic variants were found in five genes: ACTA1 (n = 4 patients), RYR1 (n = 2), CACNA1S (n = 1), NEB (n = 3), and MTM1 (n = 2). Myopanel increased the diagnosis of congenital neuromuscular diseases, but more than half the patients remained undiagnosed. Whole exome sequencing did not seem to fully respond to this diagnostic limitation. Therefore, explorations with whole genome sequencing will be the next step.

Reading Comprehension Impairment in Children With Neurofibromatosis Type 1 (NF1): The Need of Multimodal Assessment of Attention.

Attention span, which has been shown to have an impact on reading quality in many other conditions, is one of the main cognitive disorders of neurofibromatosis type 1 (NF1). The aim of this work is to observe the impact of attention on reading comprehension, in NF1 and non-NF1 children. A multicenter, cross-sectional study was conducted on 150 children (8-12 years old) with or without NF1 (75 NF1 vs 75 non-NF1; 72 female, 78 male), matched for age, sex, handedness, and reading level, thus forming a continuum from good to poor readers in both NF1 and non-NF1 groups. Children with intellectual deficiency or neurologic or psychiatric disorder were excluded. Attentional skills were assessed by combining a parent questionnaire (Child Behavior CheckList) and a performance-based assessment (Conner's Continuous Performance Test-Second Edition). Reading comprehension was assessed through a standardized reading comprehension test (ORLEC Lobrot). The performance-based attention scores were associated with text and sentence comprehension ability (P = .0235 and P = .0164, respectively), while indirect questionnaire attention scores were only associated with sentence comprehension (P = .0263). For both groups, the correlations between questionnaire and performance-based measures were low. We have shown that reading comprehension is greatly influenced by attention in NF1 and non-NF1, even if predictors of good reading comprehension also include IQ score and reading accuracy. Indirect observer-rated questionnaires and direct performance-based measures of attention do not assess the same variables, are linked to different components of reading skills, and are not interchangeable assessments of attention difficulties. Both assessments are complementary and must be used simultaneously, leading to recommendations that support multimodal assessment of attention.

Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy.

BACKGROUND: Congenital nemaline myopathies are rare pathologies characterised by muscle weakness and rod-shaped inclusions in the muscle fibres. METHODS: Using next-generation sequencing, we identified three patients with pathogenic variants in the Troponin T type 1 (TNNT1) gene, coding for the troponin T (TNT) skeletal muscle isoform. RESULTS: The clinical phenotype was similar in all patients, associating hypotonia, orthopaedic deformities and progressive chronic respiratory failure, leading to early death. The anatomopathological phenotype was characterised by a disproportion in the muscle fibre size, endomysial fibrosis and nemaline rods. Molecular analyses of TNNT1 revealed a homozygous deletion of exons 8 and 9 in patient 1; a heterozygous nonsense mutation in exon 9 and retention of part of intron 4 in muscle transcripts in patient 2; and a homozygous, very early nonsense mutation in patient 3.Western blot analyses confirmed the absence of the TNT protein resulting from these mutations. DISCUSSION: The clinical and anatomopathological presentations of our patients reinforce the homogeneous character of the phenotype associated with recessive TNNT1 mutations. Previous studies revealed an impact of recessive variants on the tropomyosin-binding affinity of TNT. We report in our patients a complete loss of TNT protein due to open reading frame disruption or to post-translational degradation of TNT.

Are morphological and structural MRI characteristics related to specific cognitive impairments in neurofibromatosis type 1 (NF1) children?

INTRODUCTION: NF1 children have cognitive disorders, especially in executive functions, visuospatial, and language domains, the pathophysiological mechanisms of which are still poorly understood. MATERIALS AND METHODS: A correlation study was performed from neuropsychological assessments and brain MRIs of 38 NF1 patients and 42 controls, all right-handed, aged 8-12 years and matched in age and gender. The most discriminating neuropsychological tests were selected to assess their visuospatial, metaphonological and visuospatial working memory abilities. The MRI analyses focused on the presence and location of Unidentified Bright Objects (UBOs) (1), volume analysis (2) and diffusion analysis (fractional anisotropy and mean diffusivity) (3) of the regions of interest including subcortical structures and posterior fossa, as well as shape analysis of subcortical structures (4). The level of attention, intelligence quotient, age and gender of the patients were taken into account in the statistical analysis. Then, we studied how diffusion and volumes parameters were associated with neuropsychological characteristics in NF1 children. RESULTS: NF1 children present different brain imaging characteristics compared to the control such as (1) UBOs in 68%, (2) enlarged total intracranial volume, involving all subcortical structures, especially thalamus, (3) increased MD and decreased FA in thalamus, corpus callosum and hippocampus. These alterations are diffuse, without shape involvement. In NF1 group, brain microstructure is all the more altered that volumes are enlarged. However, we fail to find a link between these brain characteristics and neurocognitive scores. CONCLUSION: While NF1 patients have obvious pathological brain characteristics, the neuronal substrates of their cognitive deficits are still not fully understood, perhaps due to complex and multiple pathophysiological mechanisms underlying this disorder, as suggested by the heterogeneity observed in our study. However, our results are compatible with an interpretation of NF1 as a diffuse white matter disease.

The value of screening tests in children with neurofibromatosis type 1 (NF1).

Neurofibromatosis type 1 (NF1) is one of the most prevalent rare diseases. Whilst penetrance is complete by adulthood, its expressivity is extremely variable with potential multi-systemic complications. Although NF1 is diagnosed clinically, molecular analysis has a part to play in the screening of atypical forms and in genetic counselling. The screening of complications is primarily based on a full annual clinical examination and an ophthalmological examination. Targeted paraclinical examinations will be carried out when clinical signs appear (neurological, ophthalmological, cutaneous, endocrinological, orthopaedic and cardiovascular, etc.). The implementation of routine paraclinical examinations, which are stressful for families, expensive and sometimes invasive (MRI under general anaesthetic), is only of minor interest and does not lead to any change in treatment if the child is asymptomatic. Part of the consultation should focus on evaluation of psychomotor development and learning difficulties, which are common features of this condition (50%), and impact the child's quality of life.