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Research Square Sep 2023Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and...
Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SNF2H () or SNF2L () ISWI-chromatin remodeling enzyme. Pathogenic variants in and were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with or maternally inherited pathogenic variants in . This novel NDD was associated with mild to severe ID/DD, delayed or regressive speech development, and some recurrent facial dysmorphisms. Individuals carrying loss-of-function variants exhibited a mild genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using , and and double mouse knockouts revealed the importance of NURF composition and dosage for proper forebrain development. Finally, we propose that genetic alterations affecting different NURF components result in a NDD with a broad clinical spectrum.
PubMed: 37841849
DOI: 10.21203/rs.3.rs-3317938/v1 -
Neuron Feb 2023Preclinical models of neurodevelopmental disorders typically use single inbred mouse strains, which fail to capture the genetic diversity and symptom heterogeneity that...
Preclinical models of neurodevelopmental disorders typically use single inbred mouse strains, which fail to capture the genetic diversity and symptom heterogeneity that is common clinically. We tested whether modeling genetic background diversity in mouse genetic reference panels would recapitulate population and individual differences in responses to a syndromic mutation in the high-confidence autism risk gene, CHD8. We measured clinically relevant phenotypes in >1,000 mice from 33 strains, including brain and body weights and cognition, activity, anxiety, and social behaviors, using 5 behavioral assays: cued fear conditioning, open field tests in dark and bright light, direct social interaction, and social dominance. Trait disruptions mimicked those seen clinically, with robust strain and sex differences. Some strains exhibited large effect-size trait disruptions, sometimes in opposite directions, and-remarkably-others expressed resilience. Therefore, systematically introducing genetic diversity into models of neurodevelopmental disorders provides a better framework for discovering individual differences in symptom etiologies.
Topics: Humans; Mice; Female; Male; Animals; Haploinsufficiency; Brain; Phenotype; Mice, Inbred Strains; Genetics, Population; Behavior, Animal; Mice, Inbred C57BL; DNA-Binding Proteins; Transcription Factors
PubMed: 36738737
DOI: 10.1016/j.neuron.2023.01.009 -
The Journal of Nutrition Oct 2020Lysine is an essential amino acid, and inherited diseases of its metabolism therefore represent defects of lysine catabolism. Although some of these enzyme defects are... (Review)
Review
Lysine is an essential amino acid, and inherited diseases of its metabolism therefore represent defects of lysine catabolism. Although some of these enzyme defects are not well described yet, glutaric aciduria type I (GA1) and antiquitin (2-aminoadipic-6-semialdehyde dehydrogenase) deficiency represent the most well-characterized diseases. GA1 is an autosomal recessive disorder due to a deficiency of glutaryl-CoA dehydrogenase. Untreated patients exhibit early onset macrocephaly and may present a neurological deterioration with regression and movement disorder at the time of a presumably "benign" infection most often during the first year of life. This is associated with a characteristic neuroimaging pattern with frontotemporal atrophy and striatal injuries. Diagnosis relies on the identification of glutaric and 3-hydroxyglutaric acid in urine along with plasma glutarylcarnitine. Treatment consists of a low-lysine diet aiming at reducing the putatively neurotoxic glutaric and 3-hydroxyglutaric acids. Additional therapeutic measures include administration of l-carnitine associated with emergency measures at the time of intercurrent illnesses aiming at preventing brain injury. Early treated (ideally through newborn screening) patients exhibit a favorable long-term neurocognitive outcome, whereas late-treated or untreated patients may present severe neurocognitive irreversible disabilities. Antiquitin deficiency is the most common form of pyridoxine-dependent epilepsy. α-Aminoadipic acid semialdehyde (AASA) and Δ-1-piperideine-6-carboxylate (P6C) accumulate proximal to the enzymatic block. P6C forms a complex with pyridoxal phosphate (PLP), a key vitamer of pyridoxine, thereby reducing PLP bioavailability and subsequently causing epilepsy. Urinary AASA is a biomarker of antiquitin deficiency. Despite seizure control, only 25% of the pyridoxine-treated patients show normal neurodevelopment. Low-lysine diet and arginine supplementation are proposed in some patients with decrease of AASA, but the impact on neurodevelopment is unclear. In summary, GA1 and antiquitin deficiency are the 2 main human defects of lysine catabolism. Both include neurological impairment. Lysine dietary restriction is a key therapy for GA1, whereas its benefits in antiquitin deficiency appear less clear.
Topics: 2-Aminoadipic Acid; Aldehyde Dehydrogenase; Amino Acid Metabolism, Inborn Errors; Arginine; Brain; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Carnitine; Epilepsy; Glutarates; Glutaryl-CoA Dehydrogenase; Humans; Lysine; Metabolic Diseases; Pyridoxal Phosphate; Pyridoxine
PubMed: 33000154
DOI: 10.1093/jn/nxaa112 -
Genes Dec 2022Macrocephaly frequently occurs in single-gene disorders affecting the PI3K-AKT-MTOR pathway; however, epigenetic mutations, mosaicism, and copy number variations (CNVs)... (Review)
Review
Macrocephaly frequently occurs in single-gene disorders affecting the PI3K-AKT-MTOR pathway; however, epigenetic mutations, mosaicism, and copy number variations (CNVs) are emerging relevant causative factors, revealing a higher genetic heterogeneity than previously expected. The aim of this study was to investigate the role of rare CNVs in patients with macrocephaly and review genomic loci and known genes. We retrieved from the DECIPHER database <500 kb CNVs reported on patients with macrocephaly; in four cases, a candidate gene for macrocephaly could be pinpointed: a known microcephaly gene-, and three genes based on their functional roles-, , and . From the literature review, 28 pathogenic CNV genomic loci and over 300 known genes linked to macrocephaly were gathered. Among the genomic regions, 17 CNV loci (~61%) exhibited mirror phenotypes, that is, deletions and duplications having opposite effects on head size. Identifying structural variants affecting head size can be a preeminent source of information about pathways underlying brain development. In this study, we reviewed these genes and recurrent CNV loci associated with macrocephaly, as well as suggested novel potential candidate genes deserving further studies to endorse their involvement with this phenotype.
Topics: Humans; DNA Copy Number Variations; Phosphatidylinositol 3-Kinases; Genome; Genomics; Megalencephaly
PubMed: 36553552
DOI: 10.3390/genes13122285 -
Cell Discovery Mar 2023Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that affects social interaction and behavior. Mutations in the gene encoding chromodomain...
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that affects social interaction and behavior. Mutations in the gene encoding chromodomain helicase DNA-binding protein 8 (CHD8) lead to autism symptoms and macrocephaly by a haploinsufficiency mechanism. However, studies of small animal models showed inconsistent findings about the mechanisms for CHD8 deficiency-mediated autism symptoms and macrocephaly. Using the nonhuman primate as a model system, we found that CRISPR/Cas9-mediated CHD8 mutations in the embryos of cynomolgus monkeys led to increased gliogenesis to cause macrocephaly in cynomolgus monkeys. Disrupting CHD8 in the fetal monkey brain prior to gliogenesis increased the number of glial cells in newborn monkeys. Moreover, knocking down CHD8 via CRISPR/Cas9 in organotypic monkey brain slices from newborn monkeys also enhanced the proliferation of glial cells. Our findings suggest that gliogenesis is critical for brain size in primates and that abnormal gliogenesis may contribute to ASD.
PubMed: 36878905
DOI: 10.1038/s41421-023-00525-3 -
Revue Medicale de Liege Jan 2022Macrocephaly is a frequent reason for seeking advice in a pediatric neurology consultation. It is a non-specific neurological sign that can be isolated, be the sign of a...
Macrocephaly is a frequent reason for seeking advice in a pediatric neurology consultation. It is a non-specific neurological sign that can be isolated, be the sign of a serious acquired pathology or be part of a syndromic picture. Clinical history, physical examination and imaging are key elements of the diagnostic strategy. Signs of intracranial hypertension require an emergency work-up. Genetics, exome in particular, has enabled the characterization of various syndromes associating macrocephaly and neurodevelopmental delay. In this article, we propose an update of practices based on clinical signs.
Topics: Child; Humans; Megalencephaly
PubMed: 35029342
DOI: No ID Found -
Child's Nervous System : ChNS :... Oct 2021The knowledge of the development and the anatomy of the posterior cranial fossa (PCF) is crucial to define the occurrence and the prognosis of diseases where the surface... (Review)
Review
BACKGROUND
The knowledge of the development and the anatomy of the posterior cranial fossa (PCF) is crucial to define the occurrence and the prognosis of diseases where the surface and/or the volume of PCF is reduced, as several forms of craniosynostosis or Chiari type I malformation (CIM). To understand the functional and morphological changes resulting from such a hypoplasia is mandatory for their correct management. The purpose of this article is to review the pertinent literature to provide an update on this topic.
METHODS
The related and most recent literature addressing the issue of the changes in hypoplasic PCF has been reviewed with particular interest in the studies focusing on the PCF characteristics in craniosynostosis, CIM, and achondroplasia.
RESULTS AND CONCLUSIONS
In craniosynostoses, namely, the syndromic ones, PCF shows different degrees of hypoplasia, according to the different pattern and timing of early suture fusion. Several factors concur to PCF hypoplasia and contribute to the resulting problems (CIM, hydrocephalus), as the fusion of the major and minor sutures of the lambdoid arch, the involvement of the basal synchondroses, and the occlusion of the jugular foramina. The combination of these factors explains the variety of the clinical and radiological phenotypes. In primary CIM, the matter is complicated by the evidence that, in spite of impaired PCF 2D measurements and theories on the mesodermal defect, the PCF volumetry is often comparable to healthy subjects. CIM is revealed by the overcrowding of the foramen magnum that is the result of a cranio-cerebral disproportion (altered PCF brain volume/PCF total volume). Sometimes, this disproportion is evident and can be demonstrated (basilar invagination, real PCF hypoplasia); sometimes, it is not. Some recent genetic observations would suggest that CIM is the result of an excessive growth of the neural tissue rather than a reduced growth of PCF bones. Finally, in achondroplasia, both macrocephaly and reduced 2D and 3D values of PCF occur. Some aspects of this disease remain partially obscure, as the rare incidence of hydrocephalus and syringomyelia and the common occurrence of asymptomatic upper cervical spinal cord damage. On the other hand, the low rate of CIM could be explained on the basis of the reduced area of the foramen magnum, which would prevent the hindbrain herniation.
Topics: Arnold-Chiari Malformation; Cranial Fossa, Posterior; Craniosynostoses; Humans; Hydrocephalus; Magnetic Resonance Imaging; Syringomyelia
PubMed: 34169386
DOI: 10.1007/s00381-021-05193-w -
Frontiers in Pediatrics 2021Vascular birthmarks are common in neonates (prevalence: 20-30%) and mostly incidental findings sometimes with spontaneous regression (salmon patch and nevus simplex).... (Review)
Review
Vascular birthmarks are common in neonates (prevalence: 20-30%) and mostly incidental findings sometimes with spontaneous regression (salmon patch and nevus simplex). Capillary malformations are found in about 1% and infantile hemangiomas are found in 4% of mature newborns. Vascular malformations are classified according to their most prominent vessel type. The term "capillary malformation" (port wine stain) includes a wide range of vascular lesions with different characteristics; they may be isolated or part of specific syndromic conditions. Part of the infantile hemangiomas and of the vascular malformations may require treatment for functional or cosmetic reasons, and in rare cases, investigations are also necessary as they represent a clue for the diagnosis of complex vascular malformation or tumors associated with extracutaneous abnormalities. Complex vascular malformations are mostly mosaicism due to early somatic mutations. Genetic advances have led to identify the main pathogenic pathways involved in this disease group. Diffuse capillary malformation with overgrowth, Klippel-Trenaunay syndrome, CLAPO syndrome, CLOVES syndrome, and megalencephaly-capillary malformation belong to the PIK3CA-related overgrowth. Capillary malformation-arteriovenous malformation underlies a fast-flow vascular malformation, sometimes manifesting as Parkes-Weber syndrome. Recognition of these different types of capillary vascular stains is sometimes difficult; however, associated findings may orient the clinicians while genetic testing may confirm the diagnosis. Lymphatic malformation frequently manifests as large masses that compress and/or infiltrate the surrounding tissues, representing a neonatal emergency when airways are involved. Infantile hemangiomas may cause functional and/or permanent esthetical damage, depending on their localization (such as periorbital area, lip, nose); large (more than 5 cm) infantile hemangiomas with a segmental distribution can be associated with obstruction or malformations of the underneath organs with complications: PHACE syndrome, LUMBAR/SACRAL syndrome, and beard infantile hemangioma. In our review, we discuss controversies regarding the international classification and emerging concepts in the field of vascular anomalies. Finally, we discuss potential developments of new, non-invasive diagnostic techniques and repurposing of target therapies from oncology. Complex and/or life-threatening vascular tumors and malformations are extremely rare events and they represent a considerable therapeutic challenge. Early recognition of clinical signs suggestive for a specific disease may improve therapeutic outcomes and avoid severe complications.
PubMed: 34692608
DOI: 10.3389/fped.2021.730393 -
Nature Communications Aug 2022Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that negatively regulate mTOR...
Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that negatively regulate mTOR complex 1 (mTORC1) signaling. Current treatment strategies focus on mTOR inhibition with rapamycin and its derivatives. While effective at improving some aspects of TSC, chronic rapamycin inhibits both mTORC1 and mTORC2 and is associated with systemic side-effects. It is currently unknown which mTOR complex is most relevant for TSC-related brain phenotypes. Here we used genetic strategies to selectively reduce neuronal mTORC1 or mTORC2 activity in mouse models of TSC. We find that reduction of the mTORC1 component Raptor, but not the mTORC2 component Rictor, rebalanced mTOR signaling in Tsc1 knock-out neurons. Raptor reduction was sufficient to improve several TSC-related phenotypes including neuronal hypertrophy, macrocephaly, impaired myelination, network hyperactivity, and premature mortality. Raptor downregulation represents a promising potential therapeutic intervention for the neurological manifestations of TSC.
Topics: Animals; Disease Models, Animal; Down-Regulation; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Neurons; Regulatory-Associated Protein of mTOR; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis
PubMed: 35945201
DOI: 10.1038/s41467-022-31961-6