Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish.

In the human genome, about 750 genes contain one intron excised by the minor spliceosome. This spliceosome comprises its own set of snRNAs, among which U4atac. Its noncoding gene, RNU4ATAC, has been found mutated in Taybi-Linder (TALS/microcephalic osteodysplastic primordial dwarfism type 1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes. These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy, and immunodeficiency. Here, we report bi-allelic RNU4ATAC mutations in five patients presenting with traits suggestive of the Joubert syndrome (JBTS), a well-characterized ciliopathy. These patients also present with traits typical of TALS/RFMN/LWS, thus widening the clinical spectrum of RNU4ATAC-associated disorders and indicating ciliary dysfunction as a mechanism downstream of minor splicing defects. Intriguingly, all five patients carry the n.16G>A mutation, in the Stem II domain, either at the homozygous or compound heterozygous state. A gene ontology term enrichment analysis on minor intron-containing genes reveals that the cilium assembly process is over-represented, with no less than 86 cilium-related genes containing at least one minor intron, among which there are 23 ciliopathy-related genes. The link between RNU4ATAC mutations and ciliopathy traits is supported by alterations of primary cilium function in TALS and JBTS-like patient fibroblasts, as well as by u4atac zebrafish model, which exhibits ciliopathy-related phenotypes and ciliary defects. These phenotypes could be rescued by WT but not by pathogenic variants-carrying human U4atac. Altogether, our data indicate that alteration of cilium biogenesis is part of the physiopathological mechanisms of TALS/RFMN/LWS, secondarily to defects of minor intron splicing.

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.

Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B.

BACKGROUND: Malformations of cortical development (MCDs) have been reported in a subset of patients with pathogenic heterozygous variants in GRIN1 or GRIN2B, genes which encode for subunits of the N-methyl-D-aspartate receptor (NMDAR). The aim of this study was to further define the phenotypic spectrum of NMDAR-related MCDs. METHODS: We report the clinical, radiological and molecular features of 7 new patients and review data on 18 previously reported individuals with NMDAR-related MCDs. Neuropathological findings for two individuals with heterozygous variants in GRIN1 are presented. We report the clinical and neuropathological features of one additional individual with homozygous pathogenic variants in GRIN1. RESULTS: Heterozygous variants in GRIN1 and GRIN2B were associated with overlapping severe clinical and imaging features, including global developmental delay, epilepsy, diffuse dysgyria, dysmorphic basal ganglia and hippocampi. Neuropathological examination in two fetuses with heterozygous GRIN1 variants suggests that proliferation as well as radial and tangential neuronal migration are impaired. In addition, we show that neuronal migration is also impaired by homozygous GRIN1 variants in an individual with microcephaly with simplified gyral pattern. CONCLUSION: These findings expand our understanding of the clinical and imaging features of the 'NMDARopathy' spectrum and contribute to our understanding of the likely underlying pathogenic mechanisms leading to MCD in these patients.

Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and requires long-term hepatic follow-up.

Liver disease, occurring during pediatric or adult age, is often of undetermined cause. Some cases are probably related to undiagnosed inherited metabolic disorders. Hepatic disorders associated with fructose-1,6-bisphosphatase deficiency, a gluconeogenesis defect, are not reported in the literature. These symptoms are mainly described during acute crises, and many reports do not mention them because hypoglycemia and hyperlactatemia are more frequently in the forefront. Herein, the liver manifestations of 18 patients affected with fructose-1,6-bisphosphatase deficiency are described and the corresponding literature is reviewed. Interestingly, all 18 patients had liver abnormalities either during follow-up (hepatomegaly [n = 8/18], elevation of transaminases [n = 6/15], bright liver [n = 7/11]) or during acute crises (hepatomegaly [n = 10/17], elevation of transaminases [n = 13/16], acute liver failure [n = 6/14], bright liver [n = 4/14]). Initial reports described cases of liver steatosis, when liver biopsy was necessary to confirm the diagnosis by an enzymatic study. There is no clear pathophysiological basis for this fatty liver disease but we postulate that endoplasmic reticulum stress and de novo lipogenesis activation could be key factors, as observed in FBP1 knockout mice. Liver steatosis may expose patients to severe long-term liver complications. As hypoglycemia becomes less frequent with age, most adult patients are no longer monitored by hepatologist. Signs of fructose-1,6-bisphosphatase deficiency may be subtle and can be missed in childhood. We suggest that fructose-1,6-bisphosphatase deficiency should be considered as an etiology of hepatic steatosis, and a liver monitoring protocol should be set up for these patients, during lifelong follow-up.

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.

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.

Central Nervous System Involvement of Hemophagocytic Lymphohistiocytosis: When 18F-FDG PET/CT Solves a Complex Diagnostic Investigation.

ABSTRACT: Hemophagocytic lymphohistiocytosis is rare life-threatening syndrome, hereditary or acquired, mainly affecting children. Hemophagocytic lymphohistiocytosis is an immune deficiency characterized by severe inflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages. The usual biological and clinical data may associate polyadenopathy, hepatosplenomegaly, fever, multivisceral damages, and cytopenias with potential multiorgan dysfunction and death. We report the case of a 4-year-old girl, hospitalized for recurrent cerebellar symptoms (ataxia) associated later with fever and pancytopenia. 18F-FDG PET/CT revealed a node pathological uptake, which was biopsied and confirmed a diagnosis of hemophagocytic lymphohistiocytosis.