Background: Mucopolysaccharidoses (MPS) are a group of rare genetic lysosomal storage disorders with a wide spectrum of clinical severities. Chronic pain is frequent but difficult to assess. The aim of this study was to evaluate the detection and management of pain in pediatric MPS patients. Methods:Pain-related data were retrospectively collected from the medical records of pediatric MPS patients from five French centers for inborn metabolic disorders. A national online survey was also conducted about the feelingsof patients and/or their families and of healthcare professionals about the detection and management of pain in pediatricMPS patients. Results: The medical records of 48 patients with all subtypes of MPS were analyzed. Painwas frequent and recurrent in MPS patients (pain was reported in 94% of the patients), but it was undoubtedly difficult to assess. We observed important differences between (1) medical records demonstrating frequent assessment and treatment of pain, (2) feelings of patients or their families (53 questionnaires) reporting frequent pain, and (3) feelings of healthcare professionals (21 questionnaires) who were quite satisfied with their own practices, suggesting that the majority of patients were unpainful. We recommend a more systematic evaluation of pain, particularly for outpatients, with the use of adapted tools, notably in children with disabilities,and with a multidimensional approach to pain assessment and management. Caregiver training is also needed,and close collaboration with pain centers is encouraged. Conclusion: A routine pain assessment protocol for MPS patients is required that covers the entire spectrum of pain and canbe adapted for every type of patient, including those with neurocognitive and motor impairments.

Data on clinical manifestations of neurofibromatosis-Noonan syndrome (NF-NS) remain heterogeneous, with limited validated descriptions. This study aims to better define the clinical and molecular features of NF-NS and compare them with existing literature. Secondary objectives include evaluating inter-rater diagnostic agreement among experienced clinicians and assessing the utility of deep-learning algorithms (Face2Gene® [F2G]). Additionally, we assess the prevalence of congenital heart malformations (CHM) in NF-NS compared to ‘classic’ neurofibromatosis type 1 (NF1). A 9-year, prospective, monocentric study was conducted, involving patients with NF1 pathogenic variants (PVs) and Noonan syndrome-like facial phenotype (NSLFP). Twenty-six patients were enrolled. NSLFP was categorized as ‘suggestive’ in 69

Résumé L’amyotrophie spinale infantile (SMA pour spinal muscular atrophy) liée au gène SMN1 est une maladie neuromusculaire d’origine génétique, de transmission autosomique récessive, touchant environ 120 nouveau-nés par an en France. Elle se décline en cinq types cliniques, le type le plus courant entraînant le décès de l’enfant avant l’âge de 18 mois en l’absence de traitement. Trois thérapies innovantes se sont révélées efficaces, particulièrement si elles sont administrées avant l’apparition des symptômes. Ainsi, plusieurs pays ont déjà instauré le dépistage néonatal (DNN) de la SMA. En France, le programme de DNN actuel concerne treize maladies et utilise des tests biochimiques. Le DNN de la SMA serait le premier à utiliser un test génétique en première intention. Le projet préfigurateur DEPISMA a pour objectif de démontrer la faisabilité de ce dépistage dans deux grandes régions françaises, les régions Grand-Est et Nouvelle-Aquitaine, en prévision d’un déploiement national. Au 10 septembre 2024, 117769 nouveau-nés ont été testés, soit un taux d’exhaustivité de 94 %. Onze patients atteints de SMA ont été dépistés, dont huit ont bénéficié d’une thérapie génique. Ces résultats, associés à l’avis favorable de la Haute Autorité de santé (HAS), devraient ouvrir la voie à la mise en œuvre d’un programme national de dépistage, prévu à partir de juin 2025.

BACKGROUND:High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD).METHODS:This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28).RESULTS:A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.CONCLUSION:Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.

ABSTRACT High-impact pathogenic variants in more than 1,000 protein-coding genes cause Mendelian forms of neurodevelopmental disorders (NDD), including the newly reported AGO2 gene. This study describes the molecular and clinical characterization of 28 probands with NDD harboring heterozygous AGO1 coding variants. De novo status was always confirmed when parents were available (26/28). A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Some variants were recurrently identified in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linkers domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behavior and additional behavioral manifestations. Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to AGO2 phenotype.

High-flow lesions diagnosed in the prenatal period are represented mainly by rapidly involuting congenital hemangioma of the soft tissues1, hepatic hemangioma2 or vein of Galen aneurysmal malformation (VGAM)3. We report here the prenatal diagnosis of two cases of cerebral and extracerebral high-flow lesions, which led to identification of familial capillary malformation-arteriovenous malformation (CM-AVM) syndrome, related to RASA1 mutation. The first patient was referred at 32 weeks due to unexplained polyhydramnios and fetal cardiomegaly. A neurosonogram showed an enlargement of the circle of Willis with major lateral venous drainage (Figure 1a), suggestive of a high-flow lesion, and more specifically of a pial arteriovenous (AV) fistula. The maternal medical history included termination of pregnancy for VGAM associated with severe parenchymal ischemic lesions. Both medical history and prenatal imaging data prompted careful parental dermatological examination in order to consider a diagnosis of familial CM-AVM syndrome. Indeed, physical maternal examination showed small multifocal CMs, compatible with the diagnosis of CM-AVM syndrome (Figure 1b). The diagnosis was confirmed on genetic testing (pathogenic RASA1 nonsense mutation c.3028C > T; p.Arg1010*) of maternal blood. After birth, the diagnosis of a pial AV fistula was confirmed on postnatal imaging workup (Figure 1c) and the infant required multiple embolization procedures. The second patient was referred at 31 weeks due to unexplained polyhydramnios. Ultrasound demonstrated unilateral hypertrophy of the left arm associated with spots of increased vascularization of the soft tissue (Figure 2a), suggestive of AV fistulas, as is found in Parkes Weber syndrome. Maternal history included surgical excision of a nasal AVM. Similar to our first presented case, both familial medical history and prenatal imaging findings led us to perform a maternal dermatological examination, which showed small multifocal CMs (Figure 2b), which were also found on physical examination of her mother. In keeping with the family tree (Figure 2c), the diagnosis of familial CM-AVM syndrome was suggested and confirmed on genetic testing (pathogenic RASA1 nonsense mutation c.2035C > T; p.Arg679*) of maternal blood. Physical examination at birth (Figure 2d) confirmed the prenatal diagnosis of Parkes Weber syndrome. Follow-up at 15 months was uneventful. CM-AVM syndrome is an autosomal disorder related to RASA1 mutation. Multiple CMs are the cardinal feature and are present in all affected patients4. High-flow lesions are present in approximately 30% of affected individuals, involving either soft tissue (dermis, hypodermis and muscle) or the central nervous system (CNS)4. Regarding soft tissue involvement, multiple AV microfistulas involving one enlarged limb associated with a port-wine stain, i.e. Parkes Weber syndrome, has also been reported in CM-AVM syndrome5. High-flow lesions involving the CNS included pial AV fistula and VGAM, which are, per se, rare entities5, 6. In our first case, prenatal imaging findings suggestive of a pial AV fistula, previous pregnancy affected by fetal VGAM and the presence of multiple CMs in the mother, were highly suggestive of underlying CM-AVM syndrome. The presence of a pial AV fistula, which is rarely detected prenatally, could also suggest hereditary hemorrhagic telangiectasia7. However, VGAM has not been described in such a syndrome, contrary to what has been described in CM-AVM. Regarding the second case, global enlargement of the left arm associated with diffuse focal spots of hypervascularization in the soft tissue were suggestive of Parkes Weber syndrome rather than congenital hemangiomas, which tend to be well circumscribed lesions1. Both familial history and prenatal findings, as well as multiple maternal CMs, were highly suggestive of CM-AVM syndrome. Prenatal diagnosis of a cerebral high-flow lesion or soft-tissue AV fistula is rare and should prompt systematic careful parental dermatological examination, as well as familial history assessment, in order to consider a diagnosis of familial CM-AVM syndrome. This is of importance as the parents or affected members of the family are at potential risk of cerebral hemorrhage due to unknown cerebral AVM4.

DNA microarrays are commonly used in pangenomic approach for investigation of syndromic intellectual deficiencies. Routine utilization leads to the characterization of CNV (Copy Number Variant), whose interpretation is sometimes difficult. Gene dosage anomalies are identified in about 12 to 18 % of cases with syndromic intellectual deficiency. Most of these deletions or duplications are not recognized on standard karyotype. The most common terminal deletions are 1p36 monosomy and 22q13 deletion.

Les prédispositions génétiques sont présentes chez 10 % des enfants atteints de cancer. Leur identification est un « pré-requis » pour améliorer la prise en charge de ces patients. Les points d’appel d’une telle prédisposition doivent être répertoriés précisément. Décrire dans une série non sélectionnée d’enfants traités pour cancer, les situations qui justifiaient et qui ont conduit à une prise en charge oncogénétique. Faire une proposition d’amélioration organisationnelle au sein d’un centre spécialisé : repérage des situations à risque et consultation d’oncogénétique. Ce travail a inclus les enfants atteints d’un cancer entre 2011 et 2012 dans le centre spécialisé d’oncologie pédiatrique du CHU de Bordeaux. Les critères d’orientation d’un risque de prédisposition génétique, étaient : âge inférieur à un an, multifocalité des lésions, type de cancer, tumeur secondaire, histoire familiale de cancer et points d’appels cliniques. Deux cent vingt-trois enfants atteints d’un cancer ont été pris en charge entre 2011 et 2012. Soixante-seize patients (33,9 %) présentaient au moins un critère d’orientation de prédisposition génétique. Les 2 critères d’orientation majoritaires étaient l’âge inférieur à un an (34,2 %) et une histoire familiale de cancer (48,7 %). Au total, 65,8 % des patients ne présentaient qu’un critère d’orientation. Seulement 23 patients (30 %) ont été pris en charge en oncogénétique. Il s’agissait surtout des patients avec une atteinte multifocale ou plusieurs critères d’orientation. Une large proportion (33,9 %) de patients nécessiterait une consultation d’oncogénétique. Seule une minorité en a bénéficié. Il s’agissait des patients présentant des critères visibles pour le clinicien. Une fiche de recueil de données faciliterait le dépistage de ces patients à risque. Cancer genetic predispositions were reported to occur in about 10% of children with cancer. Identifying such a genetic background is an “important requirement” to improve children's and family management. Clinical key points leading to identify patients with cancer genetic predispositions should be identified. Firstly, to describe, in an unselected cohort of children with cancer, the clinical data requiring and conducting to an oncogenetic work-up. Second, to further refine the strategy in a pediatric hematology-oncology unit: screening at-risk-patients, oncogenetic work-up and counseling. This study was conducted on all children diagnosed with cancer between 2011 and 2012, in a specialized centre of Pediatric Hematology and Oncology. The chosen guiding criteria for cancer predisposition included age under one year at diagnosis, multifocal lesions, type of cancer, secondary malignancy, family history of cancer and a suggestive anomaly at clinical examination points. Two hundred and twenty-three children with a cancer were treated between 2011 and 2012. There were 76 patients (33.9%) with at least one guiding criterion for genetic cancer susceptibility. The guiding criteria most frequently encountered were age under one year at diagnosis (34.2%) and a family history of cancer (48.7%). In total, 65.8% of our cohort presented one risk factor. Finally, only 23 patients (30%) with guiding criteria were addressed for oncogenetic consultation. They were mainly patients with multifocal disease or multiple guiding criteria. A large proportion of children treated for cancer required an oncogenetic consultation. However, a minority of patients with visible criteria for clinicians benefited from it. A systematic data collection file could be useful to improve identification of patients at risk.

OBJECTIVE:Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in the SACS gene. SACS encodes sacsin, a protein whose function remains unknown, despite the description of numerous protein domains and the recent focus on its potential role in the regulation of mitochondrial physiology. This study aimed to identify new mutations in a large population of ataxic patients and to functionally analyze their cellular effects in the mitochondrial compartment.METHODS:A total of 321 index patients with spastic ataxia selected from the SPATAX network were analyzed by direct sequencing of the SACS gene, and 156 patients from the ATAXIC project presenting with congenital ataxia were investigated either by targeted or whole exome sequencing. For functional analyses, primary cultures of fibroblasts were obtained from 11 patients carrying either mono- or biallelic variants, including 1 case harboring a large deletion encompassing the entire SACS gene.RESULTS:We identified biallelic SACS variants in 33 patients from SPATAX, and in 5 nonprogressive ataxia patients from ATAXIC. Moreover, a drastic and recurrent alteration of the mitochondrial network was observed in 10 of the 11 patients tested.INTERPRETATION:Our results permit extension of the clinical and mutational spectrum of ARSACS patients. Moreover, we suggest that the observed mitochondrial network anomalies could be used as a trait biomarker for the diagnosis of ARSACS when SACS molecular results are difficult to interpret (ie, missense variants and heterozygous truncating variant). Based on our findings, we propose new diagnostic definitions for ARSACS using clinical, genetic, and cellular criteria.

Array comparative genomic hybridization (array CGH) has proven its utility in uncovering cryptic rearrangements in patients with X‐linked intellectual disability. In 2009, Giorda et al. identified inherited and de novo recurrent Xp11.23p11.22 microduplications in two males and six females from a wide cohort of patients presenting with syndromic intellectual disability. To date, 14 females and 5 males with an overlapping microduplication have been reported in the literature. To further characterize this emerging syndrome, we collected clinical and microarray data from 17 new patients, 10 females, and 7 males. The Xp11.23p11.2 microduplications detected by array CGH ranged in size from 331 Kb to 8.9 Mb. Five patients harbored 4.5 Mb recurrent duplications mediated by non‐allelic homologous recombination between segmental duplications and 12 harbored atypical duplications. The chromosomal rearrangement occurred de novo in eight patients and was inherited in six affected males from three families. Patients shared several common major characteristics including moderate to severe intellectual disability, early onset of puberty, language impairment, and age related epileptic syndromes such as West syndrome and focal epilepsy with activation during sleep evolving in some patients to continuous spikes‐and‐waves during slow sleep. Atypical microduplications allowed us to identify minimal critical regions that might be responsible for specific clinical findings of the syndrome and to suggest possible candidate genes: FTSJ1 and SHROOM4 for intellectual disability along with PQBP1 and SLC35A2 for epilepsy. Xp11.23p11.22 microduplication is a recently‐recognized syndrome associated with intellectual disability, epilepsy, and early onset of puberty in females. In this study, we propose several genes that could contribute to the phenotype. © 2014 Wiley Periodicals, Inc.

The original article to which this Erratum refers was published in Human Mutation 34(1):97–102 (DOI 10.1002/humu.22222). Due to a technical error, the human genes and proteins discussed in this article (PDE4D and PDE4D, respectively) were mistakenly coded as animal (mouse) genes and proteins (Pde4d and Pde4d, respectively). This has since been corrected, and the corrected article has been published online (http://onlinelibrary.wiley.com/doi/10.1002/humu.22222/abstract). Results and conclusions are unchanged. The Publisher regrets this error.