RARE DISEASE
X-linked intellectual disability-craniofacioskeletal syndrome
X-linked intellectual disability-craniofacioskeletal syndrome
X-linked intellectual disability-craniofacioskeletal syndrome
Drug discovery
72
papers
On emerging therapies
Overview
X-linked intellectual disability-craniofacioskeletal syndrome is a rare hereditary disorder characterized by craniofacial and skeletal abnormalities. Females present with mild intellectual disability, microcephaly, short stature, and distinctive brain features like extra temporal lobe gyri [1][6][14]. Males exhibit severe prenatal growth restriction, cardiac/urogenital malformations, and early postnatal lethality [1][14]. Diagnosis relies on clinical assessment and genetic testing, with management focused on symptom alleviation and supportive care.
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases
Research Papers
72 drug discovery papers about X-linked intellectual disability-craniofacioskeletal syndrome. Recent publications:
72 drug discovery papers about X-linked intellectual disability-craniofacioskeletal syndrome. Recent publications:
categories:
Small molecules
small molecules
2026-08-09 | Central Thyroid Hormone Deprivation Disrupts Cortical Cilia and Oligodendrocyte Lineage in an Allan-Herndon-Dudley Syndrome Mouse Model.
Allan-Herndon-Dudley syndrome (AHDS) is an X-linked neurodevelopmental disorder caused by loss of the thyroid hormone (TH) transporter MCT8, resulting in central TH deprivation and disrupted cortical maturation, cognition, and motor control. MCT8/OATP1C1 double-knockout (dKO) mice faithfully model the human disease, recapitulating its postnatal hypomyelination, neuromotor impairment, and cortical defects. Yet, cell-type-specific pathologies underlying AHDS remain insufficiently defined. To uncover cellular perturbations by TH deprivation, we performed single-nucleus RNA sequencing on cortex and attached cerebral nuclei from P21 WT and dKO mice. Differential gene expression, trajectory, pseudotime and gene-set enrichment analyses, and NeuronChat-based cell-cell communication modeling were integrated with LC-MS/MS-based TH quantification, immunofluorescence, and RNAscope. In 48 clusters identified across cortical and striatal regions, we found increased numbers of GABAergic striatal D1 and D2 neurons in dKO mice, whereas mature oligodendrocytes were reduced. Trajectory analysis uncovered a bifurcation within the oligodendrocyte lineage, separating WT and dKO maturation paths and producing a dKO branch with gene profiles reminiscent of a stress-responsive, demyelination-prone state, despite largely preserved expression of core myelination genes. Trajectory analyses revealed shifted pseudotime states and distinct gene expression profiles in glutamatergic intratelencephalic and corticothalamic lineages of dKO mice. Differential gene expression patterns showed limited correspondence to Slc16a2 or Slco1c1 transcript levels but aligned strongly with published TH deprivation datasets, validating our findings and indicating that cellular perturbations are largely established by P21. Cell-cell communication analysis revealed a network imbalance favoring GABAergic over glutamatergic signaling, accompanied by altered neurexin-neuroligin interactions. In parallel, we identified a coordinated dysregulation of cilia-related genes, together with changes in cilia length and number. Our findings provide the first single-cell-level cortical map of AHDS brain pathology, revealing cilia defects, excitation-inhibition imbalance, differing pseudotime trajectories in glutamatergic neuronal populations and altered oligodendrocyte maturation, with actionable candidate genes such as Lama2, Litaf, and Dcc, as promising targets for future mechanistic and therapeutic exploration in AHDS. Slc16a2 and Slco1c1 transcript abundance alone did not predict cellular vulnerability, highlighting TH availability rather than transporter expression as key determinant of cell-type sensitivity and core mechanism for cortical network homeostasis.
2026-04-30 | Exaggerated NMDA Receptor-Primed Metaplasticity via SK Channel Dysregulation in Fmr1 Knockout Mice.
Fragile X syndrome (FXS), the most common monogenic neurodevelopmental disorder associated with autism and intellectual disability, results from the loss of expression of the X-linked FMR1 gene. Synaptic and circuit-level abnormalities in the brain are well documented in FXS and extensively studied in the Fmr1 KO mouse model. In CA1 hippocampal neurons, functional, molecular, and structural synaptic changes have been described, yet the canonical form of Hebbian CA1 long-term potentiation (LTP) remains intact in Fmr1 KO mice. Here we examined whether state-dependent synaptic plasticity in CA1, in which prior "priming" activity modulates subsequent synaptic plasticity, was altered in male Fmr1 KO mice. We found that NMDA receptor activation prior to LTP induction produced metaplastic inhibition of LTP, which was exaggerated in Fmr1 KO mice. This effect was mediated by the activity of small conductance calcium-activated potassium (SK) channels which was enhanced after NMDA priming and dampened dendritic excitability. Blocking SK channels during NMDA-primed LTP induction eliminated the abnormal metaplasticity in Fmr1 KO slices, implicating altered SK activity in the exaggerated LTP inhibition in Fmr1 KO mice. These finding reveal a disrupted functional coupling between NMDA receptors and SK channels in Fmr1 KO mice, altering the impact of priming on LTP expression in the CA1. Altered metaplasticity may represent a neural correlate of impaired hippocampal function in Fmr1 KO mice and potentially contribute to clinical manifestations in FXS individuals.
2026-03-06 | PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation.
Arts syndrome is a rare X-linked recessive neurodevelopmental disorder arising from pathogenic variants in PRPS1, which encodes phosphoribosyl pyrophosphate synthetase 1-an enzyme essential for de novo nucleotide biosynthesis. Affected individuals typically exhibit sensorineural hearing loss, intellectual disability, cerebellar ataxia, and recurrent infections. However, despite the severity of these clinical manifestations, therapeutic interventions remain limited, largely due to an incomplete understanding of the cellular pathophysiology underlying the disorder. In this study, we generated patient-specific induced pluripotent stem cells harboring the PRPS1 p.V42L variant and differentiated them into neural stem cells (NSCs) and neurons to elucidate disease mechanisms and explore potential therapeutic strategies. Patient-derived NSCs demonstrated significantly reduced proliferative capacity, aberrant nuclear morphology, and increased neuronal senescence, while mitochondrial integrity and function were largely preserved. Neurons differentiated from these NSCs exhibited impaired neurite outgrowth and reduced branching complexity, indicative of disrupted neurodevelopmental processes. Notably, supplementation with nicotinamide mononucleotide, a precursor of nicotinamide adenine dinucleotide (NAD＋), partially ameliorated defects in NSC proliferation, nuclear architecture, and neuronal morphology. Collectively, these findings delineate key cellular mechanisms underlying PRPS1-associated neurodevelopmental pathology and identify NAD＋ metabolic augmentation as a promising therapeutic avenue for Arts syndrome and related PRPS1-mediated disorders.
2025-11-01 | Spermine synthase in Snyder-Robinson syndrome and cancer.
Spermine synthase (Sms), a key enzyme in polyamine biosynthesis, catalyzes the conversion of spermidine to spermine using decarboxylated S-adenosylmethionine (dcAdoMet) as an aminopropyl donor. Although Sms is well-characterized in eukaryotes, it is relatively rare in bacteria, where spermine in some species is probably produced by non-specific aminopropyltransferases. In humans, SMS mutations cause Snyder-Robinson syndrome (SRS), an X-linked disorder characterized by intellectual disability, osteoporosis, and neurological dysfunction due to disrupted polyamine homeostasis. Structural studies reveal that Sms functions as a dimer, with its N-terminal domain essential for enzymatic activity. Loss of Sms leads to spermine deficiency, elevated spermidine levels, and metabolic imbalances, contributing to SRS pathology. Therapeutic strategies under investigation include rebalancing spermidine/spermine ratio, polyamine biosynthesis inhibitors (e.g., DFMO), antioxidants and gene therapy using AAV vectors. Conversely, in multiple cancer types, Sms overexpression promotes tumor progression by altering polyamine metabolism, activating oncogenic pathways (e.g., AKT, mTOR), and facilitating immune evasion. Elevated Sms expression correlates with poor prognosis in colorectal, pancreatic, hepatocellular, and head and neck cancers, highlighting its potential as a therapeutic target. However, spermine's role is context-dependent, exhibiting both pro-tumorigenic and cytotoxic effects. While inhibition of Sms may suppress cancer growth, its deficiency in SRS underscores the delicate balance required in polyamine regulation. Insights from SRS and cancer studies highlight Sms as a critical enzyme in cellular homeostasis, with therapeutic implications for both degenerative and proliferative diseases. Further research is needed to elucidate its complex role and optimize targeted interventions.
2025-10-27 | Altered Dopamine Metabolism and Response to Treatment with Levodopa/Carbidopa in MCT8 Deficiency.
Allan-Herndon-Dudley syndrome (AHDS)/monocarboxylate transporter 8 (MCT8) deficiency is a rare X-linked encephalopathy caused by SLC16A2 variants, impairing thyroid hormone (TH) transport into the brain. This leads to early central nervous system (CNS) TH deficiency, affecting brain maturation. Dopaminergic circuit involvement is suggested by both pathophysiology and clinical features, reminiscent of infantile parkinsonism. This study investigates dopamine metabolism and levodopa/carbidopa response in MCT8 patients. We retrospectively and prospectively collected clinical, genetic, and neuroimaging data, performed cerebrospinal fluid (CSF) biogenic amine analyses, and conducted neurological assessments before and after the levodopa trial (10 mg/kg/day). Ten patients exhibited developmental delay, spasticity, and infantile parkinsonism. CSF analysis showed reduced homovanillic acid in 3/10 patients, with 7/10 in the lowest quartile. Levodopa improved parkinsonism and reactivity in 7/10 patients. Our findings confirm dopaminergic involvement in AHDS and show that levodopa/carbidopa effectively treats extrapyramidal symptoms. Further investigations could differentiate presynaptic and postsynaptic defects to optimize dopaminergic therapy. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
proteins
2024-11-27 | Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder.
Mutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absence of Cdkl5 negatively impacts neuronal proliferation, survival, and maturation in in vitro and in vivo models, resulting in behavioral deficits in the Cdkl5 KO mouse. While there is no targeted therapy for CDD, several studies showed that treatments enabling an increase in brain BDNF levels give rise to structural and behavioral improvements in Cdkl5 KO mice. P021, a tetra-peptide derived from the biologically active region of the human ciliary neurotrophic factor (CNTF), was found to enhance neurogenesis and synaptic plasticity by promoting an increase in BDNF expression in preclinical models of brain disorders, such as Alzheimer's disease and Down syndrome, resulting in a beneficial therapeutic effect. Considering the positive actions of P021 on brain development and cognition associated with increased BDNF expression, the present study aimed to evaluate the possible beneficial effect of treatment with P021 in an in vitro and in vivo model of CDD. We used SH-CDKL5-KO cells as an in vitro model of CDD to test the efficacy of P021 on neuronal proliferation, survival, and maturation. In addition, both young and adult Cdkl5 KO mice were used to evaluate the in vivo effects of P021, on neuroanatomical and behavioral defects. We found that P021 treatment was effective in restoring neuronal proliferation, survival, and maturation deficits, as well as alterations in the GSK3β signaling pathway, features that characterize a human neuronal model of CDKL5 deficiency. Unexpectedly, chronic in vivo P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 KO mice, resulting in limited behavioral benefit. At present, it remains to be understood whether initiating the treatment prenatally, or prolonging the duration of treatment will be necessary in order to achieve similar results in vivo in CDD mice to those obtained in vitro.
2024-08-04 | Defective thyroid hormone transport to the brain leads to astroglial alterations.
Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disorder that causes severe neurological damage, for which there is no effective treatment. AHDS is due to inactivating mutations in the thyroid hormone transporter MCT8 that impair the entry of thyroid hormones into the brain, resulting in cerebral hypothyroidism. However, the pathophysiology of AHDS is still not fully understood and this is essential to develop therapeutic strategies. Based on evidence suggesting that thyroid hormone deficit leads to alterations in astroglial cells, including gliosis, in this work, we have evaluated astroglial impairments in MCT8 deficiency by means of magnetic resonance imaging, histological, ultrastructural, and immunohistochemical techniques, and by mining available RNA sequencing outputs. Apparent diffusion coefficient (ADC) imaging values obtained from magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients (n = 11) compared to control subjects (n = 11). Astroglial alterations were confirmed by immunohistochemistry against astroglial markers in autopsy brain samples of an 11-year-old and a 30th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. These findings were validated and further explored in a mouse model of AHDS. Our findings confirm changes in all the astroglial populations of the cerebral cortex in MCT8 deficiency that impact astrocytic metabolic and mitochondrial cellular respiration functions. These impairments arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, morphology of cortical astrocytes, along with altered transcriptome, compatible with an astrogliosis-like phenotype at adult stages. We conclude that astrocytes are potential novel therapeutic targets in AHDS, and we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.
2024-03-02 | PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS.
The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS). The mechanisms by which PHF6 regulates transcription and how its mutations cause BFLS remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex in the vicinity of genes involved in central nervous system development and neurogenesis. Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors. We identify a panel of Ephrin receptors (EphRs) as direct transcriptional targets of PHF6. Mechanistically, we show that PHF6 regulation of EphR is impaired in BFLS mice and in conditional Phf6 knock-out mice. Knockdown of EphR-A phenocopies the PHF6 loss-of-function defects in altering eNSCs, and its forced expression rescues defects of BFLS mice-derived eNSCs. Our data indicate that PHF6 directly promotes Ephrin receptor expression to control eNSC behaviour in the developing brain, and that this pathway is impaired in BFLS.
2023-02-04 | CDKL5 sculpts functional callosal connectivity to promote cognitive flexibility.
Functional and structural connectivity alterations in short- and long-range projections have been reported across neurodevelopmental disorders (NDD). Interhemispheric callosal projection neurons (CPN) represent one of the major long-range projections in the brain, which are particularly important for higher-order cognitive function and flexibility. However, whether a causal relationship exists between interhemispheric connectivity alterations and cognitive deficits in NDD remains elusive. Here, we focused on CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental disorder caused by mutations in the X-linked Cyclin-dependent kinase-like 5 (CDKL5) gene. We found an increase in homotopic interhemispheric connectivity and functional hyperconnectivity across higher cognitive areas in adult male and female CDKL5-deficient mice by resting-state functional MRI (rs-fMRI) analysis. This was accompanied by an increase in the number of callosal synaptic inputs but decrease in local synaptic connectivity in the cingulate cortex of juvenile CDKL5-deficient mice, suggesting an impairment in excitatory synapse development and a differential role of CDKL5 across excitatory neuron subtypes. These deficits were associated with significant cognitive impairments in CDKL5 KO mice. Selective deletion of CDKL5 in the largest subtype of CPN likewise resulted in an increase of functional callosal inputs, without however significantly altering intracortical cingulate networks. Notably, such callosal-specific changes were sufficient to cause cognitive deficits. Finally, when CDKL5 was selectively re-expressed only in this CPN subtype, in otherwise CDKL5-deficient mice, it was sufficient to prevent the cognitive impairments of CDKL5 mutants. Together, these results reveal a novel role of CDKL5 by demonstrating that it is both necessary and sufficient for proper CPN connectivity and cognitive function and flexibility, and further validates a causal relationship between CPN dysfunction and cognitive impairment in a model of NDD.
2016-03-14 | Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1.
Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly caused by mutations in the X-linked MECP2 gene associated with severe intellectual disability, movement disorders, and autistic-like behaviors. Its pathogenesis remains mostly not understood and no effective therapy is available. High circulating levels of oxidative stress markers in patients and the occurrence of oxidative brain damage in MeCP2-deficient mouse models suggest the involvement of oxidative stress in RTT pathogenesis. However, the molecular mechanism and the origin of the oxidative stress have not been elucidated. Here we demonstrate that a redox imbalance arises from aberrant mitochondrial functionality in the brain of MeCP2-308 heterozygous female mice, a condition that more closely recapitulates that of RTT patients. The marked increase in the rate of hydrogen peroxide generation in the brain of RTT mice seems mainly produced by the dysfunctional complex II of the mitochondrial respiratory chain. In addition, both membrane potential generation and mitochondrial ATP synthesis are decreased in RTT mouse brains when succinate, the complex II respiratory substrate, is used as an energy source. Respiratory chain impairment is brain area specific, owing to a decrease in either cAMP-dependent phosphorylation or protein levels of specific complex subunits. Further, we investigated whether the treatment of RTT mice with the bacterial protein CNF1, previously reported to ameliorate the neurobehavioral phenotype and brain bioenergetic markers in an RTT mouse model, exerts specific effects on brain mitochondrial function and consequently on hydrogen peroxide production. In RTT brains treated with CNF1, we observed the reactivation of respiratory chain complexes, the rescue of mitochondrial functionality, and the prevention of brain hydrogen peroxide overproduction. These results provide definitive evidence of mitochondrial reactive oxygen species overproduction in RTT mouse brain and highlight CNF1 efficacy in counteracting RTT-related mitochondrial defects.
gene therapies
2026-04-05 | Viral vector-mediated SLC9A6 gene replacement reduces cerebellar motor and molecular abnormalities in the shaker rat model of Christianson syndrome.
Christianson syndrome is an x-linked recessive neurodevelopmental and neurodegenerative condition caused by mutations to the SLC9A6 gene encoding NHE6, a sodium-hydrogen exchanger critical for regulating endosomal pH. Using an adeno-associated viral (AAV) vector targeting Purkinje cells (PHP.eB-L7-Slc9a6-GFP), we recently performed functional complementation studies to demonstrate that mutation to the rat Slc9a6 gene causes a Christianson syndrome-relevant cerebellar phenotype in the shaker rat. We carried out a longitudinal study evaluating the impact of gene replacement targeting Purkinje cells on ataxia and tremor in the shaker rat. Further, in a smaller follow-up study, we tested administration of AAV9-CAG-hSLC9A6 to determine whether key molecular and motor findings could be replicated with a more clinically relevant viral construct. In both experimental cohorts, we performed molecular studies to evaluate expression of NHE6 and key cerebellar markers. Administration of either of PHP.eB-L7-Slc9a6-GFP or AAV9-CAG-hSLC9A6 AAV vectors led to significant improvement in both the molecular and motor phenotypes. The abundance of each disease-relevant cerebellar proteins was strongly correlated to motor ataxia, but less so to tremor. Further, while ataxia and tremor were initially strongly correlated early in the disease progression, this relationship weakened over time. These findings impact future SLC9A6-targeted gene therapy efforts for Christianson syndrome and support gene replacement as a potentially viable therapeutic strategy. Common markers associated with cerebellar degeneration are much more strongly tied to ataxia than to tremor, indicating that ataxia may be more tied related to degenerative processes than tremor.
2026-03-16 | OTUD5-related rare X-linked multiple congenital anomalies and neurodevelopmental syndrome: clinical findings and review of the literature.
The OTUD5 gene (OMIM #300713), located on Xp11.23, encodes the ovarian tumor deubiquitinase 5, a deubiquitinase enzyme with critical functions in chromatin remodeling, transcriptional regulation, neuroectodermal differentiation, and innate immune signaling. Hemizygous pathogenic variants in OTUD5 are associated with X-linked multiple congenital anomalies–neurodevelopmental syndrome (MCAND, OMIM #301056), a rare multisystem disorder characterized by developmental delay, intellectual disability, craniofacial dysmorphism, and variable involvement of the cardiac, skeletal, and genitourinary systems. Although fewer than 30 cases have been reported worldwide, the clinical spectrum appears to be highly heterogeneous, ranging from early infantile lethality to survival into adulthood.We report a male patient, born prematurely at 32 weeks, who presented with global developmental delay, neonatal seizures, truncal hypotonia, and multiple dysmorphic features. Facial dysmorphism, microcephaly, overlapping fingers, hypospadias, bilateral cryptorchidism, congenital heart defects, bilateral sensorineural hearing loss, and structural brain abnormalities were observed. Despite supportive management, the patient died at 1.5 years of age due to pneumonia complicated by sepsis.Genetic testing through whole-exome sequencing identified a hemizygous missense variant in OTUD5, NM_001136157.2:c.1195 C > T (NP_001129629.1:p.Arg399Trp). Segregation analysis confirmed maternal carrier status and heterozygosity in one female sibling. Our findings indicate that bilateral sensorineural hearing loss and cranial anomalies may constitute variable or previously underrecognized features of MCAND; however, validation in additional, systematically evaluated cases is necessary before these manifestations can be regarded as part of the established phenotypic spectrum. Furthermore, the patient’s fatal course due to infectious complications underscores the role of OTUD5 in innate immunity and suggests a possible predisposition to immune deficiency. This case emphasizes the importance of early genetic testing in patients with complex congenital anomalies and supports close monitoring for infections as part of comprehensive clinical management.
2026-02-18 | NONO-Related Syndromic X-Linked Developmental Disability 34: Further Clinical and Molecular Delineation in a Prenatal Cohort.
To characterize the prenatal sonographic features across different trimesters and genomic spectrum of NONO-related X-linked intellectual developmental disorder. We analyzed two fetuses presenting with corpus callosum agenesis and rare cardiac anomalies using genome sequencing and exome sequencing. A systematic literature review was conducted to provide a comprehensive analysis of genotype-phenotype correlations. Two novel cases were reported in this study: one with a de novo 61.7 kb deletion affecting both NONO and ITGB1BP2, and another with a de novo c.1093 C > T(p.Arg365Ter), a recurrent variant reported in the literature. A total of 23 cases with NONO defects and prenatal phenotypes were identified, encompassing 19 distinct variant types. Large deletions and splicing variants accounted for approximately 32% (6/19). Among all cases, 78% (18/23) exhibited typical or concurrent brain abnormalities, such as corpus callosum agenesis, cardiac defects including left ventricular noncompaction (LVNC), or short long bones in the second trimester. Notably, 4% (1/23) of cases were reported with isolated intrauterine growth restriction (IUGR), primarily identified in the third trimester. Genome sequencing facilitates thorough identification of the genetic causes of NONO-related syndrome. The recurrent variant p.Arg365Ter has been reported to cause variable cardiac abnormalities in different patients, suggesting that other genetic or non-genetic factors may contribute to the cardiac manifestations in NONO-related syndromes.
2025-12-11 | Concomitant Mosaic Turner Syndrome and Congenital Adrenal Hyperplasia in 1 of 3 Patients of USP9X Variant-Associated Autism Spectrum Disorder.
X-linked intellectual developmental disorder 99 (XLID99) is a rare neurodevelopmental disorder associated with mutations in the USP9X gene. This study reports on 3 patients diagnosed with autism spectrum disorder (ASD), highlighting novel genetic findings. Among the 3 patients, two male siblings exhibited a novel USP9X gene missense variant, while the third, a female, presented a unique deletion of the USP9X gene alongside adrenal insufficiency and mosaic Turner syndrome. This variant has not been reported in public databases and may influence ASD development. This report documents the first instance of a triple diagnosis of XLID99, Turner syndrome, and congenital adrenal hyperplasia. Findings underline the significance of genetic evaluation in ASD for identifying rare and complex diagnoses.
2025-11-15 | A rare variant of USP9X associated with female-restricted X-linked syndromic intellectual disability.
USP9X gene variations have been associated with the rare syndrome female-restricted X-linked syndromic intellectual disability (MRXS99F). Loss-of-function mutations in USP9X gene is primarily characterized by development delay, speech and motor disorders, special facial features and multiple congenital malformations. We reported a newborn who presented with special facial features and developmental delay. We performed whole-genome sequencing and identified a rare novel heterozygous USP9X variant, c.4071-4077delCTTTACT (p.Thr1359Trpfs*19). To date, only seven USP9X variants in infants have been reported. Affected individuals typically exhibit a spectrum of congenital anomalies, including craniofacial dysmorphisms (such as hypertelorism, flat nasal bridge, and cleft palate), skeletal abnormalities (such as limb shortening, scoliosis, and rib anomalies), and neurological deficits (including severe intellectual disability, epilepsy, and motor delay). The radio logical tests revealed structural anomalies, such as corpus callosum agenesis and congenital hip dysplasia. This study expands the genotypic and clinical phenotypic spectrum of USP9X-related MRXS99F and reinforces the utility of whole-genome sequencing in early diagnosis and genetic counseling.
oligonucleotides
2025-05-19 | MECP2 duplication syndrome: Recent advances in pathophysiology and therapeutic perspectives.
MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder caused by duplication or extra copies of MECP2 gene. It primarily affects males and is characterized by intellectual disability, hypotonia, epilepsy, recurrent infections, and autistic features. Methyl-CpG binding protein 2 (MeCP2) encoded by MECP2 is a crucial epigenetic regulator of brain function. Expression levels are strictly regulated during brain development and maturation, and altered levels lead to severe neurodevelopmental disorders; excessive levels are associated with MDS, while insufficient levels cause Rett syndrome. This review provides a comprehensive overview of the recent advances in the pathophysiology and therapeutic perspectives of MDS, focusing on its pathophysiology, clinical features, disease models, and therapeutic strategies. Advances in studies using animal and patient-derived induced pluripotent stem cells (iPSCs)-derived neuronal models have provided insights into the molecular and cellular abnormalities associated with MDS and have facilitated therapeutic development. Among the emerging treatments, antisense oligonucleotide (ASO) therapy has gained significant attention as a promising approach for selectively suppressing MeCP2 overexpression. Preclinical studies using MDS mouse models and iPSCs-derived neurons have demonstrated that ASO treatment can partially restore neuronal abnormalities and clinical trials are currently underway.
2024-12-19 | Structural variant allelic heterogeneity in MECP2 duplication syndrome provides insight into clinical severity and variability of disease expression.
MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated. To study the role of the genomic rearrangement structures on an individual's clinical phenotypic variability, we employed a comprehensive genomics, transcriptomics, and deep phenotyping analysis approach on 137 individuals affected by MRXSL. Genomic structural information was correlated with transcriptomic and quantitative phenotypic analysis using Human Phenotype Ontology (HPO) semantic similarity scores. Duplication sizes in the cohort ranging from 64.6 kb to 16.5 Mb were classified into four categories comprising of tandem duplications (48%), terminal duplications (22%), inverted triplications (20%), and other CGRs (10%). Most of the terminal duplication structures consist of translocations (65%) followed by recombinant chromosomes (23%). Notably, 65% of de novo events occurred in the Terminal duplication group in contrast with 17% observed in Tandem duplications. RNA-seq data from lymphoblastoid cell lines indicated that the MECP2 transcript quantity in MECP2 triplications is statistically different from all duplications, but not between other classes of genomic structures. We also observed a significant (p < 0.05) correlation (Pearson R = 0.6, Spearman p = 0.63) between the log-transformed MECP2 RNA levels and MECP2 protein levels, demonstrating that genomic aberrations spanning MECP2 lead to altered MECP2 RNA and MECP2 protein levels. Genotype-phenotype analyses indicated a gradual worsening of phenotypic features, including overall survival, developmental levels, microcephaly, epilepsy, and genitourinary/eye abnormalities in the following order: Tandem duplications, Other complex duplications, Terminal duplications/Translocations, and Triplications encompassing MECP2. In aggregate, this combined analysis uncovers an interplay between MECP2 dosage, genomic rearrangement structure and phenotypic traits. Whereas the level of MECP2 is a key determinant of the phenotype, the DNA rearrangement structure can contribute to clinical severity and disease expression variability. Employing this type of analytical approach will advance our understanding of the impact of genomic rearrangements on genomic disorders and may help guide more targeted therapeutic approaches.
2021-07-12 | Antisense oligonucleotide therapy in a humanized mouse model of MECP2 duplication syndrome.
Many intellectual disability disorders are due to copy number variations, and, to date, there have been no treatment options tested for this class of diseases. MECP2 duplication syndrome (MDS) is one of the most common genomic rearrangements in males and results from duplications spanning the methyl-CpG binding protein 2 (MECP2) gene locus. We previously showed that antisense oligonucleotide (ASO) therapy can reduce MeCP2 protein amount in an MDS mouse model and reverse its disease features. This MDS mouse model, however, carried one transgenic human allele and one mouse allele, with the latter being protected from human-specific MECP2-ASO targeting. Because MeCP2 is a dosage-sensitive protein, the ASO must be titrated such that the amount of MeCP2 is not reduced too far, which would cause Rett syndrome. Therefore, we generated an "MECP2 humanized" MDS model that carries two human MECP2 alleles and no mouse endogenous allele. Intracerebroventricular injection of the MECP2-ASO efficiently down-regulated MeCP2 expression throughout the brain in these mice. Moreover, MECP2-ASO mitigated several behavioral deficits and restored expression of selected MeCP2-regulated genes in a dose-dependent manner without any toxicity. Central nervous system administration of MECP2-ASO is therefore well tolerated and beneficial in this mouse model and provides a translatable approach that could be feasible for treating MDS.
small molecules
2026-08-09 | Central Thyroid Hormone Deprivation Disrupts Cortical Cilia and Oligodendrocyte Lineage in an Allan-Herndon-Dudley Syndrome Mouse Model.
Allan-Herndon-Dudley syndrome (AHDS) is an X-linked neurodevelopmental disorder caused by loss of the thyroid hormone (TH) transporter MCT8, resulting in central TH deprivation and disrupted cortical maturation, cognition, and motor control. MCT8/OATP1C1 double-knockout (dKO) mice faithfully model the human disease, recapitulating its postnatal hypomyelination, neuromotor impairment, and cortical defects. Yet, cell-type-specific pathologies underlying AHDS remain insufficiently defined. To uncover cellular perturbations by TH deprivation, we performed single-nucleus RNA sequencing on cortex and attached cerebral nuclei from P21 WT and dKO mice. Differential gene expression, trajectory, pseudotime and gene-set enrichment analyses, and NeuronChat-based cell-cell communication modeling were integrated with LC-MS/MS-based TH quantification, immunofluorescence, and RNAscope. In 48 clusters identified across cortical and striatal regions, we found increased numbers of GABAergic striatal D1 and D2 neurons in dKO mice, whereas mature oligodendrocytes were reduced. Trajectory analysis uncovered a bifurcation within the oligodendrocyte lineage, separating WT and dKO maturation paths and producing a dKO branch with gene profiles reminiscent of a stress-responsive, demyelination-prone state, despite largely preserved expression of core myelination genes. Trajectory analyses revealed shifted pseudotime states and distinct gene expression profiles in glutamatergic intratelencephalic and corticothalamic lineages of dKO mice. Differential gene expression patterns showed limited correspondence to Slc16a2 or Slco1c1 transcript levels but aligned strongly with published TH deprivation datasets, validating our findings and indicating that cellular perturbations are largely established by P21. Cell-cell communication analysis revealed a network imbalance favoring GABAergic over glutamatergic signaling, accompanied by altered neurexin-neuroligin interactions. In parallel, we identified a coordinated dysregulation of cilia-related genes, together with changes in cilia length and number. Our findings provide the first single-cell-level cortical map of AHDS brain pathology, revealing cilia defects, excitation-inhibition imbalance, differing pseudotime trajectories in glutamatergic neuronal populations and altered oligodendrocyte maturation, with actionable candidate genes such as Lama2, Litaf, and Dcc, as promising targets for future mechanistic and therapeutic exploration in AHDS. Slc16a2 and Slco1c1 transcript abundance alone did not predict cellular vulnerability, highlighting TH availability rather than transporter expression as key determinant of cell-type sensitivity and core mechanism for cortical network homeostasis.
2026-04-30 | Exaggerated NMDA Receptor-Primed Metaplasticity via SK Channel Dysregulation in Fmr1 Knockout Mice.
Fragile X syndrome (FXS), the most common monogenic neurodevelopmental disorder associated with autism and intellectual disability, results from the loss of expression of the X-linked FMR1 gene. Synaptic and circuit-level abnormalities in the brain are well documented in FXS and extensively studied in the Fmr1 KO mouse model. In CA1 hippocampal neurons, functional, molecular, and structural synaptic changes have been described, yet the canonical form of Hebbian CA1 long-term potentiation (LTP) remains intact in Fmr1 KO mice. Here we examined whether state-dependent synaptic plasticity in CA1, in which prior "priming" activity modulates subsequent synaptic plasticity, was altered in male Fmr1 KO mice. We found that NMDA receptor activation prior to LTP induction produced metaplastic inhibition of LTP, which was exaggerated in Fmr1 KO mice. This effect was mediated by the activity of small conductance calcium-activated potassium (SK) channels which was enhanced after NMDA priming and dampened dendritic excitability. Blocking SK channels during NMDA-primed LTP induction eliminated the abnormal metaplasticity in Fmr1 KO slices, implicating altered SK activity in the exaggerated LTP inhibition in Fmr1 KO mice. These finding reveal a disrupted functional coupling between NMDA receptors and SK channels in Fmr1 KO mice, altering the impact of priming on LTP expression in the CA1. Altered metaplasticity may represent a neural correlate of impaired hippocampal function in Fmr1 KO mice and potentially contribute to clinical manifestations in FXS individuals.
2026-03-06 | PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation.
Arts syndrome is a rare X-linked recessive neurodevelopmental disorder arising from pathogenic variants in PRPS1, which encodes phosphoribosyl pyrophosphate synthetase 1-an enzyme essential for de novo nucleotide biosynthesis. Affected individuals typically exhibit sensorineural hearing loss, intellectual disability, cerebellar ataxia, and recurrent infections. However, despite the severity of these clinical manifestations, therapeutic interventions remain limited, largely due to an incomplete understanding of the cellular pathophysiology underlying the disorder. In this study, we generated patient-specific induced pluripotent stem cells harboring the PRPS1 p.V42L variant and differentiated them into neural stem cells (NSCs) and neurons to elucidate disease mechanisms and explore potential therapeutic strategies. Patient-derived NSCs demonstrated significantly reduced proliferative capacity, aberrant nuclear morphology, and increased neuronal senescence, while mitochondrial integrity and function were largely preserved. Neurons differentiated from these NSCs exhibited impaired neurite outgrowth and reduced branching complexity, indicative of disrupted neurodevelopmental processes. Notably, supplementation with nicotinamide mononucleotide, a precursor of nicotinamide adenine dinucleotide (NAD＋), partially ameliorated defects in NSC proliferation, nuclear architecture, and neuronal morphology. Collectively, these findings delineate key cellular mechanisms underlying PRPS1-associated neurodevelopmental pathology and identify NAD＋ metabolic augmentation as a promising therapeutic avenue for Arts syndrome and related PRPS1-mediated disorders.
2025-11-01 | Spermine synthase in Snyder-Robinson syndrome and cancer.
Spermine synthase (Sms), a key enzyme in polyamine biosynthesis, catalyzes the conversion of spermidine to spermine using decarboxylated S-adenosylmethionine (dcAdoMet) as an aminopropyl donor. Although Sms is well-characterized in eukaryotes, it is relatively rare in bacteria, where spermine in some species is probably produced by non-specific aminopropyltransferases. In humans, SMS mutations cause Snyder-Robinson syndrome (SRS), an X-linked disorder characterized by intellectual disability, osteoporosis, and neurological dysfunction due to disrupted polyamine homeostasis. Structural studies reveal that Sms functions as a dimer, with its N-terminal domain essential for enzymatic activity. Loss of Sms leads to spermine deficiency, elevated spermidine levels, and metabolic imbalances, contributing to SRS pathology. Therapeutic strategies under investigation include rebalancing spermidine/spermine ratio, polyamine biosynthesis inhibitors (e.g., DFMO), antioxidants and gene therapy using AAV vectors. Conversely, in multiple cancer types, Sms overexpression promotes tumor progression by altering polyamine metabolism, activating oncogenic pathways (e.g., AKT, mTOR), and facilitating immune evasion. Elevated Sms expression correlates with poor prognosis in colorectal, pancreatic, hepatocellular, and head and neck cancers, highlighting its potential as a therapeutic target. However, spermine's role is context-dependent, exhibiting both pro-tumorigenic and cytotoxic effects. While inhibition of Sms may suppress cancer growth, its deficiency in SRS underscores the delicate balance required in polyamine regulation. Insights from SRS and cancer studies highlight Sms as a critical enzyme in cellular homeostasis, with therapeutic implications for both degenerative and proliferative diseases. Further research is needed to elucidate its complex role and optimize targeted interventions.
2025-10-27 | Altered Dopamine Metabolism and Response to Treatment with Levodopa/Carbidopa in MCT8 Deficiency.
Allan-Herndon-Dudley syndrome (AHDS)/monocarboxylate transporter 8 (MCT8) deficiency is a rare X-linked encephalopathy caused by SLC16A2 variants, impairing thyroid hormone (TH) transport into the brain. This leads to early central nervous system (CNS) TH deficiency, affecting brain maturation. Dopaminergic circuit involvement is suggested by both pathophysiology and clinical features, reminiscent of infantile parkinsonism. This study investigates dopamine metabolism and levodopa/carbidopa response in MCT8 patients. We retrospectively and prospectively collected clinical, genetic, and neuroimaging data, performed cerebrospinal fluid (CSF) biogenic amine analyses, and conducted neurological assessments before and after the levodopa trial (10 mg/kg/day). Ten patients exhibited developmental delay, spasticity, and infantile parkinsonism. CSF analysis showed reduced homovanillic acid in 3/10 patients, with 7/10 in the lowest quartile. Levodopa improved parkinsonism and reactivity in 7/10 patients. Our findings confirm dopaminergic involvement in AHDS and show that levodopa/carbidopa effectively treats extrapyramidal symptoms. Further investigations could differentiate presynaptic and postsynaptic defects to optimize dopaminergic therapy. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
proteins
2024-11-27 | Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder.
Mutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absence of Cdkl5 negatively impacts neuronal proliferation, survival, and maturation in in vitro and in vivo models, resulting in behavioral deficits in the Cdkl5 KO mouse. While there is no targeted therapy for CDD, several studies showed that treatments enabling an increase in brain BDNF levels give rise to structural and behavioral improvements in Cdkl5 KO mice. P021, a tetra-peptide derived from the biologically active region of the human ciliary neurotrophic factor (CNTF), was found to enhance neurogenesis and synaptic plasticity by promoting an increase in BDNF expression in preclinical models of brain disorders, such as Alzheimer's disease and Down syndrome, resulting in a beneficial therapeutic effect. Considering the positive actions of P021 on brain development and cognition associated with increased BDNF expression, the present study aimed to evaluate the possible beneficial effect of treatment with P021 in an in vitro and in vivo model of CDD. We used SH-CDKL5-KO cells as an in vitro model of CDD to test the efficacy of P021 on neuronal proliferation, survival, and maturation. In addition, both young and adult Cdkl5 KO mice were used to evaluate the in vivo effects of P021, on neuroanatomical and behavioral defects. We found that P021 treatment was effective in restoring neuronal proliferation, survival, and maturation deficits, as well as alterations in the GSK3β signaling pathway, features that characterize a human neuronal model of CDKL5 deficiency. Unexpectedly, chronic in vivo P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 KO mice, resulting in limited behavioral benefit. At present, it remains to be understood whether initiating the treatment prenatally, or prolonging the duration of treatment will be necessary in order to achieve similar results in vivo in CDD mice to those obtained in vitro.
2024-08-04 | Defective thyroid hormone transport to the brain leads to astroglial alterations.
Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disorder that causes severe neurological damage, for which there is no effective treatment. AHDS is due to inactivating mutations in the thyroid hormone transporter MCT8 that impair the entry of thyroid hormones into the brain, resulting in cerebral hypothyroidism. However, the pathophysiology of AHDS is still not fully understood and this is essential to develop therapeutic strategies. Based on evidence suggesting that thyroid hormone deficit leads to alterations in astroglial cells, including gliosis, in this work, we have evaluated astroglial impairments in MCT8 deficiency by means of magnetic resonance imaging, histological, ultrastructural, and immunohistochemical techniques, and by mining available RNA sequencing outputs. Apparent diffusion coefficient (ADC) imaging values obtained from magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients (n = 11) compared to control subjects (n = 11). Astroglial alterations were confirmed by immunohistochemistry against astroglial markers in autopsy brain samples of an 11-year-old and a 30th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. These findings were validated and further explored in a mouse model of AHDS. Our findings confirm changes in all the astroglial populations of the cerebral cortex in MCT8 deficiency that impact astrocytic metabolic and mitochondrial cellular respiration functions. These impairments arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, morphology of cortical astrocytes, along with altered transcriptome, compatible with an astrogliosis-like phenotype at adult stages. We conclude that astrocytes are potential novel therapeutic targets in AHDS, and we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.
2024-03-02 | PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS.
The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS). The mechanisms by which PHF6 regulates transcription and how its mutations cause BFLS remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex in the vicinity of genes involved in central nervous system development and neurogenesis. Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors. We identify a panel of Ephrin receptors (EphRs) as direct transcriptional targets of PHF6. Mechanistically, we show that PHF6 regulation of EphR is impaired in BFLS mice and in conditional Phf6 knock-out mice. Knockdown of EphR-A phenocopies the PHF6 loss-of-function defects in altering eNSCs, and its forced expression rescues defects of BFLS mice-derived eNSCs. Our data indicate that PHF6 directly promotes Ephrin receptor expression to control eNSC behaviour in the developing brain, and that this pathway is impaired in BFLS.
2023-02-04 | CDKL5 sculpts functional callosal connectivity to promote cognitive flexibility.
Functional and structural connectivity alterations in short- and long-range projections have been reported across neurodevelopmental disorders (NDD). Interhemispheric callosal projection neurons (CPN) represent one of the major long-range projections in the brain, which are particularly important for higher-order cognitive function and flexibility. However, whether a causal relationship exists between interhemispheric connectivity alterations and cognitive deficits in NDD remains elusive. Here, we focused on CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental disorder caused by mutations in the X-linked Cyclin-dependent kinase-like 5 (CDKL5) gene. We found an increase in homotopic interhemispheric connectivity and functional hyperconnectivity across higher cognitive areas in adult male and female CDKL5-deficient mice by resting-state functional MRI (rs-fMRI) analysis. This was accompanied by an increase in the number of callosal synaptic inputs but decrease in local synaptic connectivity in the cingulate cortex of juvenile CDKL5-deficient mice, suggesting an impairment in excitatory synapse development and a differential role of CDKL5 across excitatory neuron subtypes. These deficits were associated with significant cognitive impairments in CDKL5 KO mice. Selective deletion of CDKL5 in the largest subtype of CPN likewise resulted in an increase of functional callosal inputs, without however significantly altering intracortical cingulate networks. Notably, such callosal-specific changes were sufficient to cause cognitive deficits. Finally, when CDKL5 was selectively re-expressed only in this CPN subtype, in otherwise CDKL5-deficient mice, it was sufficient to prevent the cognitive impairments of CDKL5 mutants. Together, these results reveal a novel role of CDKL5 by demonstrating that it is both necessary and sufficient for proper CPN connectivity and cognitive function and flexibility, and further validates a causal relationship between CPN dysfunction and cognitive impairment in a model of NDD.
2016-03-14 | Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1.
Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly caused by mutations in the X-linked MECP2 gene associated with severe intellectual disability, movement disorders, and autistic-like behaviors. Its pathogenesis remains mostly not understood and no effective therapy is available. High circulating levels of oxidative stress markers in patients and the occurrence of oxidative brain damage in MeCP2-deficient mouse models suggest the involvement of oxidative stress in RTT pathogenesis. However, the molecular mechanism and the origin of the oxidative stress have not been elucidated. Here we demonstrate that a redox imbalance arises from aberrant mitochondrial functionality in the brain of MeCP2-308 heterozygous female mice, a condition that more closely recapitulates that of RTT patients. The marked increase in the rate of hydrogen peroxide generation in the brain of RTT mice seems mainly produced by the dysfunctional complex II of the mitochondrial respiratory chain. In addition, both membrane potential generation and mitochondrial ATP synthesis are decreased in RTT mouse brains when succinate, the complex II respiratory substrate, is used as an energy source. Respiratory chain impairment is brain area specific, owing to a decrease in either cAMP-dependent phosphorylation or protein levels of specific complex subunits. Further, we investigated whether the treatment of RTT mice with the bacterial protein CNF1, previously reported to ameliorate the neurobehavioral phenotype and brain bioenergetic markers in an RTT mouse model, exerts specific effects on brain mitochondrial function and consequently on hydrogen peroxide production. In RTT brains treated with CNF1, we observed the reactivation of respiratory chain complexes, the rescue of mitochondrial functionality, and the prevention of brain hydrogen peroxide overproduction. These results provide definitive evidence of mitochondrial reactive oxygen species overproduction in RTT mouse brain and highlight CNF1 efficacy in counteracting RTT-related mitochondrial defects.
gene therapies
2026-04-05 | Viral vector-mediated SLC9A6 gene replacement reduces cerebellar motor and molecular abnormalities in the shaker rat model of Christianson syndrome.
Christianson syndrome is an x-linked recessive neurodevelopmental and neurodegenerative condition caused by mutations to the SLC9A6 gene encoding NHE6, a sodium-hydrogen exchanger critical for regulating endosomal pH. Using an adeno-associated viral (AAV) vector targeting Purkinje cells (PHP.eB-L7-Slc9a6-GFP), we recently performed functional complementation studies to demonstrate that mutation to the rat Slc9a6 gene causes a Christianson syndrome-relevant cerebellar phenotype in the shaker rat. We carried out a longitudinal study evaluating the impact of gene replacement targeting Purkinje cells on ataxia and tremor in the shaker rat. Further, in a smaller follow-up study, we tested administration of AAV9-CAG-hSLC9A6 to determine whether key molecular and motor findings could be replicated with a more clinically relevant viral construct. In both experimental cohorts, we performed molecular studies to evaluate expression of NHE6 and key cerebellar markers. Administration of either of PHP.eB-L7-Slc9a6-GFP or AAV9-CAG-hSLC9A6 AAV vectors led to significant improvement in both the molecular and motor phenotypes. The abundance of each disease-relevant cerebellar proteins was strongly correlated to motor ataxia, but less so to tremor. Further, while ataxia and tremor were initially strongly correlated early in the disease progression, this relationship weakened over time. These findings impact future SLC9A6-targeted gene therapy efforts for Christianson syndrome and support gene replacement as a potentially viable therapeutic strategy. Common markers associated with cerebellar degeneration are much more strongly tied to ataxia than to tremor, indicating that ataxia may be more tied related to degenerative processes than tremor.
2026-03-16 | OTUD5-related rare X-linked multiple congenital anomalies and neurodevelopmental syndrome: clinical findings and review of the literature.
The OTUD5 gene (OMIM #300713), located on Xp11.23, encodes the ovarian tumor deubiquitinase 5, a deubiquitinase enzyme with critical functions in chromatin remodeling, transcriptional regulation, neuroectodermal differentiation, and innate immune signaling. Hemizygous pathogenic variants in OTUD5 are associated with X-linked multiple congenital anomalies–neurodevelopmental syndrome (MCAND, OMIM #301056), a rare multisystem disorder characterized by developmental delay, intellectual disability, craniofacial dysmorphism, and variable involvement of the cardiac, skeletal, and genitourinary systems. Although fewer than 30 cases have been reported worldwide, the clinical spectrum appears to be highly heterogeneous, ranging from early infantile lethality to survival into adulthood.We report a male patient, born prematurely at 32 weeks, who presented with global developmental delay, neonatal seizures, truncal hypotonia, and multiple dysmorphic features. Facial dysmorphism, microcephaly, overlapping fingers, hypospadias, bilateral cryptorchidism, congenital heart defects, bilateral sensorineural hearing loss, and structural brain abnormalities were observed. Despite supportive management, the patient died at 1.5 years of age due to pneumonia complicated by sepsis.Genetic testing through whole-exome sequencing identified a hemizygous missense variant in OTUD5, NM_001136157.2:c.1195 C > T (NP_001129629.1:p.Arg399Trp). Segregation analysis confirmed maternal carrier status and heterozygosity in one female sibling. Our findings indicate that bilateral sensorineural hearing loss and cranial anomalies may constitute variable or previously underrecognized features of MCAND; however, validation in additional, systematically evaluated cases is necessary before these manifestations can be regarded as part of the established phenotypic spectrum. Furthermore, the patient’s fatal course due to infectious complications underscores the role of OTUD5 in innate immunity and suggests a possible predisposition to immune deficiency. This case emphasizes the importance of early genetic testing in patients with complex congenital anomalies and supports close monitoring for infections as part of comprehensive clinical management.
2026-02-18 | NONO-Related Syndromic X-Linked Developmental Disability 34: Further Clinical and Molecular Delineation in a Prenatal Cohort.
To characterize the prenatal sonographic features across different trimesters and genomic spectrum of NONO-related X-linked intellectual developmental disorder. We analyzed two fetuses presenting with corpus callosum agenesis and rare cardiac anomalies using genome sequencing and exome sequencing. A systematic literature review was conducted to provide a comprehensive analysis of genotype-phenotype correlations. Two novel cases were reported in this study: one with a de novo 61.7 kb deletion affecting both NONO and ITGB1BP2, and another with a de novo c.1093 C > T(p.Arg365Ter), a recurrent variant reported in the literature. A total of 23 cases with NONO defects and prenatal phenotypes were identified, encompassing 19 distinct variant types. Large deletions and splicing variants accounted for approximately 32% (6/19). Among all cases, 78% (18/23) exhibited typical or concurrent brain abnormalities, such as corpus callosum agenesis, cardiac defects including left ventricular noncompaction (LVNC), or short long bones in the second trimester. Notably, 4% (1/23) of cases were reported with isolated intrauterine growth restriction (IUGR), primarily identified in the third trimester. Genome sequencing facilitates thorough identification of the genetic causes of NONO-related syndrome. The recurrent variant p.Arg365Ter has been reported to cause variable cardiac abnormalities in different patients, suggesting that other genetic or non-genetic factors may contribute to the cardiac manifestations in NONO-related syndromes.
2025-12-11 | Concomitant Mosaic Turner Syndrome and Congenital Adrenal Hyperplasia in 1 of 3 Patients of USP9X Variant-Associated Autism Spectrum Disorder.
X-linked intellectual developmental disorder 99 (XLID99) is a rare neurodevelopmental disorder associated with mutations in the USP9X gene. This study reports on 3 patients diagnosed with autism spectrum disorder (ASD), highlighting novel genetic findings. Among the 3 patients, two male siblings exhibited a novel USP9X gene missense variant, while the third, a female, presented a unique deletion of the USP9X gene alongside adrenal insufficiency and mosaic Turner syndrome. This variant has not been reported in public databases and may influence ASD development. This report documents the first instance of a triple diagnosis of XLID99, Turner syndrome, and congenital adrenal hyperplasia. Findings underline the significance of genetic evaluation in ASD for identifying rare and complex diagnoses.
2025-11-15 | A rare variant of USP9X associated with female-restricted X-linked syndromic intellectual disability.
USP9X gene variations have been associated with the rare syndrome female-restricted X-linked syndromic intellectual disability (MRXS99F). Loss-of-function mutations in USP9X gene is primarily characterized by development delay, speech and motor disorders, special facial features and multiple congenital malformations. We reported a newborn who presented with special facial features and developmental delay. We performed whole-genome sequencing and identified a rare novel heterozygous USP9X variant, c.4071-4077delCTTTACT (p.Thr1359Trpfs*19). To date, only seven USP9X variants in infants have been reported. Affected individuals typically exhibit a spectrum of congenital anomalies, including craniofacial dysmorphisms (such as hypertelorism, flat nasal bridge, and cleft palate), skeletal abnormalities (such as limb shortening, scoliosis, and rib anomalies), and neurological deficits (including severe intellectual disability, epilepsy, and motor delay). The radio logical tests revealed structural anomalies, such as corpus callosum agenesis and congenital hip dysplasia. This study expands the genotypic and clinical phenotypic spectrum of USP9X-related MRXS99F and reinforces the utility of whole-genome sequencing in early diagnosis and genetic counseling.
oligonucleotides
2025-05-19 | MECP2 duplication syndrome: Recent advances in pathophysiology and therapeutic perspectives.
MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder caused by duplication or extra copies of MECP2 gene. It primarily affects males and is characterized by intellectual disability, hypotonia, epilepsy, recurrent infections, and autistic features. Methyl-CpG binding protein 2 (MeCP2) encoded by MECP2 is a crucial epigenetic regulator of brain function. Expression levels are strictly regulated during brain development and maturation, and altered levels lead to severe neurodevelopmental disorders; excessive levels are associated with MDS, while insufficient levels cause Rett syndrome. This review provides a comprehensive overview of the recent advances in the pathophysiology and therapeutic perspectives of MDS, focusing on its pathophysiology, clinical features, disease models, and therapeutic strategies. Advances in studies using animal and patient-derived induced pluripotent stem cells (iPSCs)-derived neuronal models have provided insights into the molecular and cellular abnormalities associated with MDS and have facilitated therapeutic development. Among the emerging treatments, antisense oligonucleotide (ASO) therapy has gained significant attention as a promising approach for selectively suppressing MeCP2 overexpression. Preclinical studies using MDS mouse models and iPSCs-derived neurons have demonstrated that ASO treatment can partially restore neuronal abnormalities and clinical trials are currently underway.
2024-12-19 | Structural variant allelic heterogeneity in MECP2 duplication syndrome provides insight into clinical severity and variability of disease expression.
MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated. To study the role of the genomic rearrangement structures on an individual's clinical phenotypic variability, we employed a comprehensive genomics, transcriptomics, and deep phenotyping analysis approach on 137 individuals affected by MRXSL. Genomic structural information was correlated with transcriptomic and quantitative phenotypic analysis using Human Phenotype Ontology (HPO) semantic similarity scores. Duplication sizes in the cohort ranging from 64.6 kb to 16.5 Mb were classified into four categories comprising of tandem duplications (48%), terminal duplications (22%), inverted triplications (20%), and other CGRs (10%). Most of the terminal duplication structures consist of translocations (65%) followed by recombinant chromosomes (23%). Notably, 65% of de novo events occurred in the Terminal duplication group in contrast with 17% observed in Tandem duplications. RNA-seq data from lymphoblastoid cell lines indicated that the MECP2 transcript quantity in MECP2 triplications is statistically different from all duplications, but not between other classes of genomic structures. We also observed a significant (p < 0.05) correlation (Pearson R = 0.6, Spearman p = 0.63) between the log-transformed MECP2 RNA levels and MECP2 protein levels, demonstrating that genomic aberrations spanning MECP2 lead to altered MECP2 RNA and MECP2 protein levels. Genotype-phenotype analyses indicated a gradual worsening of phenotypic features, including overall survival, developmental levels, microcephaly, epilepsy, and genitourinary/eye abnormalities in the following order: Tandem duplications, Other complex duplications, Terminal duplications/Translocations, and Triplications encompassing MECP2. In aggregate, this combined analysis uncovers an interplay between MECP2 dosage, genomic rearrangement structure and phenotypic traits. Whereas the level of MECP2 is a key determinant of the phenotype, the DNA rearrangement structure can contribute to clinical severity and disease expression variability. Employing this type of analytical approach will advance our understanding of the impact of genomic rearrangements on genomic disorders and may help guide more targeted therapeutic approaches.
2021-07-12 | Antisense oligonucleotide therapy in a humanized mouse model of MECP2 duplication syndrome.
Many intellectual disability disorders are due to copy number variations, and, to date, there have been no treatment options tested for this class of diseases. MECP2 duplication syndrome (MDS) is one of the most common genomic rearrangements in males and results from duplications spanning the methyl-CpG binding protein 2 (MECP2) gene locus. We previously showed that antisense oligonucleotide (ASO) therapy can reduce MeCP2 protein amount in an MDS mouse model and reverse its disease features. This MDS mouse model, however, carried one transgenic human allele and one mouse allele, with the latter being protected from human-specific MECP2-ASO targeting. Because MeCP2 is a dosage-sensitive protein, the ASO must be titrated such that the amount of MeCP2 is not reduced too far, which would cause Rett syndrome. Therefore, we generated an "MECP2 humanized" MDS model that carries two human MECP2 alleles and no mouse endogenous allele. Intracerebroventricular injection of the MECP2-ASO efficiently down-regulated MeCP2 expression throughout the brain in these mice. Moreover, MECP2-ASO mitigated several behavioral deficits and restored expression of selected MeCP2-regulated genes in a dose-dependent manner without any toxicity. Central nervous system administration of MECP2-ASO is therefore well tolerated and beneficial in this mouse model and provides a translatable approach that could be feasible for treating MDS.
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