Long-term burden of informal caregiver 7-years after severe childhood traumatic brain injury in the traumatisme grave de l'Enfant (TGE) study.

OBJECTIVE: To investigate reported burden by the Primary Family Caregiver (PFC) 7-years after severe pediatric traumatic brain injury in the TGE (Traumatisme Grave de l'Enfant) longitudinal study. METHODS: Subjective burden was estimated with the Zarit Burden Inventory (ZBI) in 36 PFC (parents), who rated their own health status (Medical Outcome Study Short Form-12), family functioning and their child's level of care and needs (Pediatric/Adult Care And Needs Scale [PCANS/CANS]). Data collection included: child and PFC sociodemographic characteristics, injury-related factors, 'objective' (e.g. overall level of disability: Glasgow Outcome Scale - Extended, GOS-E/GOS-E-Peds) and 'subjective' outcomes (e.g. participation, behavior, executive functions, quality of life and fatigue). RESULTS: 25% of PFC reported mild-moderate burden, and 19% moderate-severe burden. Higher burden correlated with worse outcomes in all 'subjective' PFC-rated outcomes, and with self-reported participation. The ZBI correlated strongly with CANS/PCANS and GOS-E/GOS-E-Peds. Overall level of disability and PFC-reported executive functioning explained 62% of the ZBI variance. For equal levels of disability, burden was higher when PFC reported a 'negative' picture of their child. CONCLUSION: Significant PFC-reported burden 7-years post-injury was associated with overall disability and 'subjective' PFC-rated outcomes. Factors influencing parental burden in the long term should be identified and psychological support implemented over time.

Molecular characterization of pathogenic OTOA gene conversions in hearing loss patients.

Bi-allelic loss-of-function variants of OTOA are a well-known cause of moderate-to-severe hearing loss. Whereas non-allelic homologous recombination-mediated deletions of the gene are well known, gene conversions to pseudogene OTOAP1 have been reported in the literature but never fully described nor their pathogenicity assessed. Here, we report two unrelated patients with moderate hearing-loss, who were compound heterozygotes for a converted allele and a deletion of OTOA. The conversions were initially detected through sequencing depths anomalies at the OTOA locus after exome sequencing, then confirmed with long range polymerase chain reactions. Both conversions lead to loss-of-function by introducing a premature stop codon in exon 22 (p.Glu787*). Using genomic alignments and long read nanopore sequencing, we found that the two probands carry stretches of converted DNA of widely different lengths (at least 9 kbp and around 900 bp, respectively).

Bi-allelic loss of ERGIC1 causes relatively mild arthrogryposis.

Arthrogryposis describes the presence of multiple joint-contractures. Clinical severity of this phenotype is variable, and more than 400 causative genes have been proposed. Among these, ERGIC1 is a recently reported candidate encoding a putative transmembrane protein of the ER-Golgi interface. Two homozygous missense variants have been reported in patients with relatively mild non-syndromic arthrogryposis. In a consanguineous family with two affected siblings presenting congenital arthrogryposis and some facial dysmorphism we performed prenatal array-CGH, postnatal targeted exome and genome sequencing. Genome sequencing identified a homozygous 22.6 Kb deletion encompassing the promoter and first exon of ERGIC1. mRNA quantification showed the complete absence of ERGIC1 expression in the two affected siblings and a decrease in heterozygous parents. Our observations validate the pathogenic role of ERGIC1 in congenital arthrogryposis and demonstrate that complete loss of function causes a relatively mild phenotype. These findings will contribute to improve genetic counseling of ERGIC1 mutations.

Domains of genome-wide gene expression dysregulation in Down's syndrome.

Trisomy 21 is the most frequent genetic cause of cognitive impairment. To assess the perturbations of gene expression in trisomy 21, and to eliminate the noise of genomic variability, we studied the transcriptome of fetal fibroblasts from a pair of monozygotic twins discordant for trisomy 21. Here we show that the differential expression between the twins is organized in domains along all chromosomes that are either upregulated or downregulated. These gene expression dysregulation domains (GEDDs) can be defined by the expression level of their gene content, and are well conserved in induced pluripotent stem cells derived from the twins' fibroblasts. Comparison of the transcriptome of the Ts65Dn mouse model of Down's syndrome and normal littermate mouse fibroblasts also showed GEDDs along the mouse chromosomes that were syntenic in human. The GEDDs correlate with the lamina-associated (LADs) and replication domains of mammalian cells. The overall position of LADs was not altered in trisomic cells; however, the H3K4me3 profile of the trisomic fibroblasts was modified and accurately followed the GEDD pattern. These results indicate that the nuclear compartments of trisomic cells undergo modifications of the chromatin environment influencing the overall transcriptome, and that GEDDs may therefore contribute to some trisomy 21 phenotypes.

Self- and parent-reported Quality of Life 7 years after severe childhood traumatic brain injury in the Traumatisme Grave de l'Enfant cohort: associations with objective and subjective factors and outcomes.

PURPOSE: To investigate self- and parent-reported Health-Related Quality-of-Life (HRQoL) and their associations after severe childhood traumatic brain injury (TBI) in the Traumatisme Grave de l'Enfant (TGE) cohort. METHODS: Self- (n = 34) and/or parent-reports (n = 25) of HRQoL were collected for 38 participants (age 7-22 years) 7 years after severe childhood TBI. The collected data included sociodemographic characteristics, injury severity indices, and overall disability and functional outcome at 3-months, 1- and 2-years post-injury. At 7-years post-injury, data were collected in the TBI group and in a control group (n = 33): overall disability (Glasgow Outcome Scale Extended), intellectual ability (IQ), and questionnaires assessing HRQoL (Pediatric Quality of Life Inventory), executive functions (Behavior Rating Inventory of Executive Functions), behavior (Child Behavior Checklist), fatigue (Multidimensional Fatigue Scale) and participation (Child and Adolescent Scale of Participation). RESULTS: Parent- and self-reports of HRQoL were significantly lower in the TBI group than in the control group. Parent-rated HRQoL was not associated with objectively assessed factors, whereas self-reported HRQoL was associated with gender (worse in females) and initial functional outcome. All questionnaire scores completed by the same informant (self or parent) were strongly inter-correlated. CONCLUSIONS: Reported HRQoL 7-years after severe childhood TBI is low compared to controls, weakly or not-related to objective factors, such as injury severity indices, clinically assessed functional outcomes, or IQ, but strongly related to reports by the same informant of executive deficits, behavior problems, fatigue, and participation.

Self- and Parent-Reported Fatigue 7 Years After Severe Childhood Traumatic Brain Injury: Results of the Traumatisme Grave de l'Enfant Prospective Longitudinal Study.

OBJECTIVE: To investigate presence of and factors associated with self- and parent-reported fatigue 7 years after severe childhood traumatic brain injury (TBI) in the prospective longitudinal study TGE (Traumatisme Grave de l'Enfant-severe childhood trauma). METHODS: Self-reports and/or parent reports on the Multidimensional Fatigue Scale were collected for 38 participants (aged 7-22 years) 7 years after severe childhood TBI, and 33 controls matched for age, gender, and parental educational level. The data collected included sociodemographic characteristics, age at injury and injury severity scores, overall disability (Glasgow Outcome Scale Extended), intellectual outcome (Wechsler scales), and questionnaires assessing executive functions, health-related quality of life, behavior, and participation. RESULTS: Fatigue levels were significantly worse in the TBI than in the control group, especially for cognitive fatigue. Correlations of reported fatigue with age at injury, gender, TBI severity, and intellectual ability were moderate and often not significant. Fatigue was significantly associated with overall level of disability (Glasgow Outcome Scale Extended) and with all questionnaires completed by the same informant. CONCLUSION: High levels of fatigue were reported by 30% to 50% of patients 7 years after a severe childhood TBI. Reported fatigue explained more than 60% of the variance of reported health-related quality of life by the same informant (patient or parent).

Language, intellectual and educational outcomes after moderate-to-severe traumatic brain injury sustained before the age of 18 months.

Objective: The aim of this study was to assess long-term outcomes in terms of oral language, intellectual ability, education, following very early moderate-to-severe TBI. Methods: Children who had been hospitalized in rehabilitation after moderate-to-severe TBI sustained before 18 months of age were contacted once they had reached school age. Detailed oral language and intellectual ability assessment were performed, and information on ongoing education was collected. Results: 52 children met inclusion criteria; 21 (40.4%) participated [13 males, mean age 7.5 years (SD = 1.9), age at injury 0.7 years (SD = 0.5), time since injury 6.8 years (SD = 1.8)]. Performance was in the clinical range (<-2SD) for: syntactic comprehension (67%; mean z-scores -2.6; SD = 3.1), syntactic expression (62%; -2.1; SD = 1.3), lexical stock extent (57%; -1.5; SD = 1.5), lexical access skills (48%; -1.9; SD = 2), and semantic organization (32%; -0.9; SD = 1.2). Full-scale IQ was <90 for 91%. Only eight children followed mainstream education without adaptations. Performance on all language tests (except lexical stock extent) was significantly poorer for children with a personal school aid or those in specialized education. Conclusions: Early moderate-to-severe TBI causes significant delayed language (especially syntactic aspects of language) and cognitive disabilities, with consequences on long-term educational outcome. These children require long-term follow-up and timely interventions.

Assessment of memory functioning over two years following severe childhood traumatic brain injury: results of the TGE cohort.

The aims of this study were (1) to prospectively measure memory functioning following severe childhood Traumatic Brain Injury (TBI), and its evolution over 2 years; (2) to assess demographic and medical factors associated with memory function and recovery; (3) to explore relations between memory and other TBI outcomes. Methods: Children (aged 0-15 years; n= 65) consecutively admitted in a single trauma center over a 3-year period, who survived severe non-inflicted TBI, were included in a prospective longitudinal study. Memory was assessed in 38 children aged 5-15 years at injury, using the Children's Memory Scale at 3, 12, and 24 months post-injury. Results: Mean general memory score was low at 3 months (M = 90.2, SD = 20.3) but within the normal range at 12 and 24 months (M = 100.6, SD = 23.1 and M = 108.6, SD = 24.1, respectively), with high variability. Improvement was stronger for immediate visual memory than for other memory indices. Lower general memory score was associated with higher injury severity, lower intellectual ability and functional status, higher overall disability, and ongoing education. Conclusion: Memory functioning is highly variable following severe childhood TBI, related to injury severity and functional, cognitive and educational outcomes; improvement is significant during the first-year post-injury, but varies according to the type of memory.

Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.

The Hedgehog (Hh) family of secreted proteins act as morphogens to control embryonic patterning and development in a variety of organ systems. Post-translational covalent attachment of cholesterol and palmitate to Hh proteins are critical for multimerization and long range signaling potency. However, the biological impact of lipid modifications on Hh ligand distribution and signal reception in humans remains unclear. In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene. This mutation occurred in the conserved membrane bound O-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH. Consistent with the patient phenotype, HHAT was found to be expressed in the somatic cells of both XX and XY gonads at the time of sex determination, and Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans. In the developing testis, HHAT is not required for Sertoli cell commitment but plays a role in proper testis cord formation and the differentiation of fetal Leydig cells. Altogether, these results shed new light on the mechanisms of action of Hh proteins. Furthermore, they provide the first clinical evidence of the essential role played by lipid modification of Hh proteins in human testicular organogenesis and embryonic development.

Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome.

Some neonates with Down syndrome (DS) are diagnosed with self-regressing transient myeloproliferative disorder (TMD), and 20% to 30% of those progress to acute megakaryoblastic leukemia (AMKL). We performed exome sequencing in 7 TMD/AMKL cases and copy-number analysis in these and 10 additional cases. All TMD/AMKL samples contained GATA1 mutations. No exome-sequenced TMD/AMKL sample had other recurrently mutated genes. However, 2 of 5 TMD cases, and all AMKL cases, showed mutations/deletions other than GATA1, in genes proven as transformation drivers in non-DS leukemia (EZH2, APC, FLT3, JAK1, PARK2-PACRG, EXT1, DLEC1, and SMC3). One patient at the TMD stage revealed 2 clonal expansions with different GATA1 mutations, of which 1 clone had an additional driver mutation. Interestingly, it was the other clone that gave rise to AMKL after accumulating mutations in 7 other genes. Data suggest that GATA1 mutations alone are sufficient for clonal expansions, and additional driver mutations at the TMD stage do not necessarily predict AMKL progression. Later in infancy, leukemic progression requires "third-hit driver" mutations/somatic copy-number alterations found in non-DS leukemias. Putative driver mutations affecting WNT (wingless-related integration site), JAK-STAT (Janus kinase/signal transducer and activator of transcription), or MAPK/PI3K (mitogen-activated kinase/phosphatidylinositol-3 kinase) pathways were found in all cases, aberrant activation of which converges on overexpression of MYC.

Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families.

Rare, atypical, and undiagnosed autosomal-recessive disorders frequently occur in the offspring of consanguineous couples. Current routine diagnostic genetic tests fail to establish a diagnosis in many cases. We employed exome sequencing to identify the underlying molecular defects in patients with unresolved but putatively autosomal-recessive disorders in consanguineous families and postulated that the pathogenic variants would reside within homozygous regions. Fifty consanguineous families participated in the study, with a wide spectrum of clinical phenotypes suggestive of autosomal-recessive inheritance, but with no definitive molecular diagnosis. DNA samples from the patient(s), unaffected sibling(s), and the parents were genotyped with a 720K SNP array. Exome sequencing and array CGH (comparative genomic hybridization) were then performed on one affected individual per family. High-confidence pathogenic variants were found in homozygosity in known disease-causing genes in 18 families (36%) (one by array CGH and 17 by exome sequencing), accounting for the clinical phenotype in whole or in part. In the remainder of the families, no causative variant in a known pathogenic gene was identified. Our study shows that exome sequencing, in addition to being a powerful diagnostic tool, promises to rapidly expand our knowledge of rare genetic Mendelian disorders and can be used to establish more detailed causative links between mutant genotypes and clinical phenotypes.

Behavior problems 7 years after severe childhood traumatic brain injury: Results of the Traumatisme Grave de L'Enfant study.

PURPOSE/OBJECTIVE: To investigate the occurrence of behavioral problems 7 years after severe pediatric traumatic brain injury (TBI), and their evolution from 3 months to 7 years postinjury. METHOD/DESIGN: Thirty-four participants, 38% girls, M (SD) age at injury 7.6 (4.7) years, age at assessment 15 (4.6) years, underwent comprehensive assessments 7 years after severe TBI from March 2014 to March 2016 and were matched to a control group by age, gender, and parental education. A subgroup of 20 participants had available behavioral assessments at 3, 12, and 24 months postinjury. Internalizing, externalizing, and total behavioral problems were assessed with self- and parent reports of the Achenbach's Behavioral Checklist. Additional data included sociodemographic background, initial injury severity, and specific outcomes assessed concurrently 7 years postinjury. RESULTS: Compared to controls: (a) a significant proportion of participants with severe TBI fell above the clinical cutoff for self- (42%) and parent-reported (36%) externalizing problems, but not for self- (33%) or parent-reported (45%) internalizing problems; (b) withdrawn/depressed, intrusive behavior, and somatic complaints were significantly higher in self-reports; and (c) rule-breaking behavior, attention, and social problems were significantly higher in parent reports. Parent-reported internalizing problems were associated with older age at injury, whereas externalizing problems correlated with greater injury severity and concurrent levels of greater overall disability, lower intellectual ability, and poorer family functioning. In multiple hierarchical regression analyses, overall disability and worse family functioning significantly predicted externalizing problems. Parent-reported internalizing and externalizing problems persisted over time. CONCLUSIONS/IMPLICATIONS: These results highlight the importance of long-term follow-up and individualized behavioral interventions for children who sustained severe TBI. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

TNPO3 protects HIV-1 replication from CPSF6-mediated capsid stabilization in the host cell cytoplasm.

BACKGROUND: Despite intensive investigation the mechanism by which HIV-1 reaches the host cell nucleus is unknown. TNPO3, a karyopherin mediating nuclear entry of SR-proteins, was shown to be required for HIV-1 infectivity. Some investigators have reported that TNPO3 promotes HIV-1 nuclear import, as would be expected for a karyopherin. Yet, an equal number of investigators have failed to obtain evidence that supports this model. Here, a series of experiments were performed to better elucidate the mechanism by which TNPO3 promotes HIV-1 infectivity. RESULTS: To examine the role of TNPO3 in HIV-1 replication, the 2-LTR circles that are commonly used as a marker for HIV-1 nuclear entry were cloned after infection of TNPO3 knockdown cells. Potential explanation for the discrepancy in the literature concerning the effect of TNPO3 was provided by sequencing hundreds of these clones: a significant fraction resulted from autointegration into sites near the LTRs and therefore were not bona fide 2-LTR circles. In response to this finding, new techniques were developed to monitor HIV-1 cDNA, including qPCR reactions that distinguish 2-LTR circles from autointegrants, as well as massive parallel sequencing of HIV-1 cDNA. With these assays, TNPO3 knockdown was found to reduce the levels of 2-LTR circles. This finding was puzzling, though, since previous work has shown that the HIV-1 determinant for TNPO3-dependence is capsid (CA), an HIV-1 protein that forms a mega-dalton protein lattice in the cytoplasm. TNPO3 imports cellular splicing factors via their SR-domain. Attention was therefore directed towards CPSF6, an SR-protein that binds HIV-1 CA and inhibits HIV-1 nuclear import when the C-terminal SR-domain is deleted. The effect of 27 HIV-1 capsid mutants on sensitivity to TNPO3 knockdown was then found to correlate strongly with sensitivity to inhibition by a C-terminal deletion mutant of CPSF6 (R2 = 0.883, p < 0.0001). TNPO3 knockdown was then shown to cause CPSF6 to accumulate in the cytoplasm. Mislocalization of CPSF6 to the cytoplasm, whether by TNPO3 knockdown, deletion of the CPSF6 nuclear localization signal, or by fusion of CPSF6 to a nuclear export signal, resulted in inhibition of HIV-1 replication. Additionally, targeting CPSF6 to the nucleus by fusion to a heterologous nuclear localization signal rescued HIV-1 from the inhibitory effects of TNPO3 knockdown. Finally, mislocalization of CPSF6 to the cytoplasm was associated with abnormal stabilization of the HIV-1 CA core. CONCLUSION: TNPO3 promotes HIV-1 infectivity indirectly, by shifting the CA-binding protein CPSF6 to the nucleus, thus preventing the excessive HIV-1 CA stability that would otherwise result from cytoplasmic accumulation of CPSF6.

A diagnostic genetic test for the physical mapping of germline rearrangements in the susceptibility breast cancer genes BRCA1 and BRCA2.

The BRCA1 and BRCA2 genes are involved in breast and ovarian cancer susceptibility. About 2 to 4% of breast cancer patients with positive family history, negative for point mutations, can be expected to carry large rearrangements in one of these two genes. We developed a novel diagnostic genetic test for the physical mapping of large rearrangements, based on molecular combing (MC), a FISH-based technique for direct visualization of single DNA molecules at high resolution. We designed specific Genomic Morse Codes (GMCs), covering the exons, the noncoding regions, and large genomic portions flanking both genes. We validated our approach by testing 10 index cases with positive family history of breast cancer and 50 negative controls. Large rearrangements, corresponding to deletions and duplications with sizes ranging from 3 to 40 kb, were detected and characterized on both genes, including four novel mutations. The nature of all the identified mutations was confirmed by high-resolution array comparative genomic hybridization (aCGH) and breakpoints characterized by sequencing. The developed GMCs allowed to localize several tandem repeat duplications on both genes. We propose the developed genetic test as a valuable tool to screen large rearrangements in BRCA1 and BRCA2 to be combined in clinical settings with an assay capable of detecting small mutations.

Molecular combing reveals allelic combinations in facioscapulohumeral dystrophy.

OBJECTIVE: The genetic variation underlying facioscapulohumeral muscular dystrophy (FSHD), 1 of the most common hereditary neuromuscular disorders, is complex, and associated with the contraction of a repeat array (D4Z4) at the subtelomeric end of chromosome 4q. Nonpathogenic variants of 4q and the presence of a homologous array on chromosome 10q make FSHD diagnosis extremely challenging, at least in individuals with nonstandard D4Z4 arrays. We aimed to improve FSHD molecular analysis by proposing an alternative technique to the Southern blot. METHODS: We applied molecular combing (MC) to directly visualize allelic combinations associated with FSHD. RESULTS: MC enabled the accurate diagnosis of 32 FSHD patients. Unreported haplotypes and rearrangements, as well as somatic mosaicism, which is common in the 10 to 30% of cases that are sporadic, were detectable by MC. INTERPRETATION: MC enables the detailed exploration of the FSHD locus and accurate diagnosis of FSHD, the first Mendelian disease to benefit from this technique. MC is also likely to be applicable to other copy number-variant or repeat expansion-associated human diseases.

Weight gain after childhood traumatic brain injury: a matter of concern.

AIM: The aim of the study was to assess weight changes after traumatic brain injury (TBI) in children and the factors influencing them. METHOD: We conducted a longitudinal observational study of children with TBI of mixed severity who were consecutively admitted to one rehabilitation department (39 children; 23 males, 16 females; median age 8y 7mo; 25th to 75th centiles 3y 7mo-11y 6mo). Weight and height before TBI were obtained from the children's records and were measured monthly for 1 year after TBI. Body mass index (BMI) and BMI z-scores were calculated, and pre-TBI values were compared with the final values using paired tests. Linear mixed-effect interaction models were used to assess the effect of various factors on z-score evolution. RESULTS: Z-score curves revealed early weight loss followed by a rapid increase in weight. The mean BMI gain over the period under study was 0.9 kg/m² (p < 0.001) and the mean z-score gain was 0.4 (p = 0.006). Six children had become overweight by the time of final assessment. Factors associated with a greater rate of increase in the post-TBI z-score were mobility restriction, male sex, and older age. Global pre- to post-TBI weight gain was significantly higher in males (z-score 0.7). Pituitary hormonal testing was available for 17 children at 3 months and for 27 at 1 year. Growth hormone deficiency was detected in one child. INTERPRETATION: Weight gain of children during the first year after TBI was rapid and excessive. Male sex was a risk factor for excessive weight gain.

Shaken Baby Syndrome (SBS) or Pediatric Abusive Head Trauma from Shaking: Guidelines for Interventions During the Perinatal Period from the French National College Of Midwives.

Shaken baby syndrome is the most severe head injury in children. Shaking is an extremely violent gesture, often repeated. The children affected are generally less than a year old, in 2/3 of cases, less than 6 months old. More than 10% of them die, and more than three-quarters of the survivors have long-term effects. Prevention is therefore essential. When a parent (or any person) is strongly upset by an infant's uncalmable crying, the best thing for them to do is to lay the child down in a supine position in his or her bed, leave the room, and then ask for help.

Functional status 1 year after severe childhood traumatic brain injury predicts 7-year outcome: Results of the TGE study.

BACKGROUND: Childhood severe traumatic brain injury (TBI) is a leading cause of long-lasting acquired disability, but predicting long-term functional outcome remains difficult. OBJECTIVES: This study aimed to 1) describe the functional outcome at 1 and 7 years post-TBI; 2) determine the initial and concurrent factors associated with long-term outcome; and 3) evaluate the predictive value of functional status, overall disability level and intellectual ability measured at 1 year post-injury to determine 7-year clinically meaningful outcomes. METHODS: Among the children (<16 years) consecutively included over 3 years in the Traumatisme Grave de l'Enfant (TGE) prospective longitudinal cohort study after accidental severe TBI, we studied the outcomes of 39 survivors at 1 and 7 years post-injury. Overall outcome included disability level (Glasgow Outcome Scale), functional status (Pediatric Injury Functional Outcome Scale), intellectual ability (Wechsler scales), executive functions (Behavior Rating Inventory of Executive Functions), behavior (Child Behavior Checklist) as well as neurological impairments and academic status. RESULTS: Mean (SD) age of the 39 survivors at injury was 7.6 (4.6) years, and long-term evaluation was conducted at a mean of 7.8 years post-injury (range 5.9-9.3); 36% of participants were adults (≥18 years old). Most of the neurological impairments remained stable beyond 1 year after TBI, whereas overall disability level improved significantly from 1 to 7 years but remained highly variable, with almost half of participants presenting significant disability levels (moderate: 26%, or severe: 21%). Almost half of participants had significant cognitive, behavior and/or academic difficulties at 7 years post-TBI. On multivariate regression analysis, functional impairment at 1 year was the best predictor of severe disability at 7 years (F(3,31)=13.18, p < 0.001, sensitivity=100%, specificity=78%). CONCLUSIONS: Our results confirm the significant long-term impact of childhood severe TBI. All children with TBI should benefit from systematic follow-up, especially those with persistent functional deficits at 1 year post-injury, because the severity of functional impairment at 1 year seems the best predictor of long-term significant disability up to 7 years post-TBI.