Lateral Meningocele Research Articles

Antisense oligonucleotides targeting a NOTCH3 mutation in male mice ameliorate the cortical osteopenia of lateral meningocele syndrome.

Lateral Meningocele Syndrome (LMS) is a monogenic disorder associated with NOTCH3 pathogenic variants that result in the stabilization of NOTCH3 and a gain-of-function. A mouse model (Notch3em1Ecan) harboring a 6691-TAATGA mutation in the Notch3 locus that results in a functional outcome analogous to LMS exhibits cancellous and cortical bone osteopenia. We tested Notch3 antisense oligonucleotides (ASOs) specific to the Notch36691-TAATGA mutation for their effects on Notch3 downregulation and on the osteopenia of Notch3em1Ecan mice. Twenty-four mouse Notch3 mutant ASOs were designed and tested for toxic effects in vivo, and 12 safe ASOs were tested for their impact on the downregulation of Notch36691-TAATGA and Notch3 mRNA in osteoblast cultures from Notch3em1Ecan mice. Three ASOs downregulated Notch3 mutant transcripts specifically and were tested in vivo for their effects on the bone microarchitecture of Notch3em1Ecan mice. All three ASOs were well tolerated. One of these ASOs had more consistent effects in vivo and was studied in detail. The Notch3 mutant ASO downregulated Notch3 mutant transcripts in osteoblasts and bone marrow stromal cells and had no effect on other Notch receptors. The subcutaneous administration of Notch3 mutant ASO at 50mg/Kg decreased Notch36691-TAATGA mRNA in bone without apparent toxicity; microcomputed tomography demonstrated that the ASO ameliorated the cortical osteopenia of Notch3em1Ecan mice but not the cancellous bone osteopenia. In conclusion, a Notch3 ASO that downregulates Notch3 mutant expression specifically ameliorates the cortical osteopenia in Notch3em1Ecan mice. ASOs may become useful strategies in the management of monogenic disorders affecting the skeleton.

Hdac1 and Hdac2 positively regulate Notch1 gain-of-function pathogenic signaling in committed osteoblasts of male mice.

Skeletal development requires precise extrinsic and intrinsic signals to regulate processes that form and maintain bone and cartilage. Notch1 is a highly conserved signaling receptor that regulates cell fate decisions by controlling the duration of transcriptional bursts. Epigenetic molecular events reversibly modify DNA and histone tails by influencing the spatial organization of chromatin and can fine-tune the outcome of a Notch1 transcriptional response. Histone deacetylase 1 and 2 (HDAC1 and HDAC2) are chromatin modifying enzymes that mediate osteoblast differentiation. While an HDAC1-Notch interaction has been studied in vitro and in Drosophila, its role in mammalian skeletal development and disorders is unclear. Osteosclerosis is a bone disorder with an abnormal increase in the number of osteoblasts and excessive bone formation. Here, we tested whether Hdac1/2 contribute to the pathogenesis of osteosclerosis in a murine model of the disease owing to conditionally cre-activated expression of the Notch1 intracellular domain in immature osteoblasts. Importantly, selective homozygous deletions of Hdac1/2 in osteoblasts partially alleviate osteosclerotic phenotypes (Col2.3kb-Cre; TGRosaN1ICD/+ ; Hdac1flox/flox ; Hdac2flox/flox ) with a 40% decrease in bone volume and a 22% decrease in trabecular thickness in 4 weeks old when compared to male mice with heterozygous deletions of Hdac1/2 (Col2.3 kb-Cre; TGRosaN1ICD/+ ; Hdac1flox/+ ; Hdac2flox/+ ). Osteoblast-specific deletion of Hdac1/2 in male and female mice results in no overt bone phenotype in the absence of the Notch1 gain-of-function (GOF) allele. These results provide evidence that Hdac1/2 contribute to Notch1 pathogenic signaling in the mammalian skeleton. Our study on epigenetic regulation of Notch1 GOF-induced osteosclerosis may facilitate further mechanistic studies of skeletal birth defects caused by Notch-related GOF mutations in human patients, such as Adams-Oliver disease, congenital heart disease, and lateral meningocele syndrome.

Induction of a NOTCH3 Lehman syndrome mutation in osteocytes causes osteopenia in male C57BL/6J mice.

Lateral Meningocele or Lehman Syndrome (LMS) is associated with NOTCH3 mutations causing deletions of the PEST domain and a gain-of-NOTCH3 function. We demonstrated that Notch3em1Ecan mice harboring Notch3 mutations analogous to those found in LMS are osteopenic because of enhanced bone resorption. To determine the contribution of specific cell lineages to the phenotype, we created a conditional-by-inversion (Notch3COIN) model termed Notch3em2Ecan in which Cre recombination generates a Notch3INV allele expressing a NOTCH3 mutant lacking the PEST domain. Germ line Notch3COIN inversion caused osteopenia and phenocopied the Notch3em1Ecan mutant, validating the model. To induce the mutation in osteocytes, smooth muscle and endothelial cells, Notch3COIN mice were bred with mice expressing Cre from the Dmp1, Sm22a and Cdh5 promoters, respectively, creating experimental mice harboring Notch3INV alleles in Cre-expressing cells and control littermates harboring Notch3COIN alleles. Notch3COIN inversion in osteocytes led to femoral and vertebral cancellous bone osteopenia, whereas Notch3COIN inversion in mural Sm22a or endothelial Cdh5-expressing cells did not result in a skeletal phenotype. In conclusion, introduction of the LMS mutation in osteocytes but not in vascular cells causes osteopenia and phenocopies Notch3em1Ecan global mutant mice.

Use of antisense oligonucleotides to target Notch3 in skeletal cells.

Notch receptors are determinants of cell fate and function, and play an important role in the regulation of bone development and skeletal remodeling. Lateral Meningocele Syndrome (LMS) is a monogenic disorder associated with NOTCH3 pathogenic variants that result in the stabilization of NOTCH3 and a gain-of-function. LMS presents with neurological developmental abnormalities and bone loss. We created a mouse model (Notch3em1Ecan) harboring a 6691TAATGA mutation in the Notch3 locus, and heterozygous Notch3em1Ecan mice exhibit cancellous and cortical bone osteopenia. In the present work, we explored whether Notch3 antisense oligonucleotides (ASO) downregulate Notch3 and have the potential to ameliorate the osteopenia of Notch3em1Ecan mice. Notch3 ASOs decreased the expression of Notch3 wild type and Notch36691-TAATGA mutant mRNA expressed by Notch3em1Ecan mice in osteoblast cultures without evidence of cellular toxicity. The effect was specific since ASOs did not downregulate Notch1, Notch2 or Notch4. The expression of Notch3 wild type and Notch36691-TAATGA mutant transcripts also was decreased in bone marrow stromal cells and osteocytes following exposure to Notch3 ASOs. In vivo, the subcutaneous administration of Notch3 ASOs at 25 to 50 mg/Kg decreased Notch3 mRNA in the liver, heart and bone. Microcomputed tomography demonstrated that the administration of Notch3 ASOs ameliorates the cortical osteopenia of Notch3em1Ecan mice, and ASOs decreased femoral cortical porosity and increased cortical thickness and bone volume. However, the administration of Notch3 ASOs did not ameliorate the cancellous bone osteopenia of Notchem1Ecan mice. In conclusion, Notch3 ASOs downregulate Notch3 expression in skeletal cells and their systemic administration ameliorates cortical osteopenia in Notch3em1Ecan mice; as such ASOs may become useful strategies in the management of skeletal diseases affected by Notch gain-of-function.

Management of lateral meningocele syndrome in a child without neurological symptoms and literature review.

Lateral meningocele syndrome (LMS) is a rare genetic connective tissue disorder which is associated with meningocele-related neurologic dysfunction. Several patients with LMS have been reported. But, guidelines for screening and treatment of LMS have not been established. We review the current knowledge of LMS in the article. Then, we describe a boy for whom a genomic analysis which allowed us to make a diagnosis of LMS and to begin monitoring of his condition for possible neurological complications. It would be difficult to make a diagnosis of LMS on the basis of clinical manifestations alone. The natural history of dural ectasia in patients with LMS needs to be better defined to establish surgical indications. Based upon the current literature, ventriculoperitoneal shunting (V-Ps) has been recommended as the first-line surgical treatment option for patients with symptomatic thoracolumbar meningoceles.

Sudden bilateral lower limb paralysis with dural ectasia in Neurofibromatosis type 1

Abstract Introduction: Neurofibromatosis type 1 (NF-1) is an autosomal dominant disorder characterized by pigmented lesions (café-au-lait macules, skinfold freckling, and Lisch nodules), and dermal neurofibromas. In some subjects, NF-1 presents with complications such as brain tumors, skeletal abnormalities, peripheral nerve tumors, and behavioral abnormalities. Patient concerns: We report the case of a 30-year-old man who presented with sudden bilateral lower limb paralysis and acute-onset lower back pain following a fall while rising from a seated position. He denied a history of back pain or muscle weakness before the index event. On examination, the patella and Achilles tendon reflexes were absent bilaterally. The patient presented with a power grade of 0 in all lower limb muscle groups and normal muscle bulk. Diagnosis: Bilateral lower limb paralysis was associated with sensory loss in the T11 dermatome. X-ray, computed tomography, and magnetic resonance imaging (MRI) showed vertebral canal enlargement (dural ectasia) at multiple levels suggestive of a lateral meningocele associated with neurofibromatosis. After repeated MRI studies, herniation of nerve root sleeves was noted, with marked compression of the traversing nerve roots. Notably, there was no evidence of cord compression on either the computed tomography or MRI. The cerebrospinal fluid studies were unremarkable. Interventions: No particular intervention was performed to address specific NF symptoms. In the hospital, the patient received analgesics and antibiotics (gentamicin and cefuroxime) for a urinary tract infection, lactulose for constipation and enoxaparin as anticoagulant prophylaxis. Outcomes: The patient experienced a clinical decline unrelated to his initial symptoms and succumbed to sepsis 6 weeks after admission. The cause of death was not directly linked with NF-1. Conclusion: We report a case of NF-1 with dural ectasia presenting with sudden bilateral lower limb paralysis and lower back pain following mild trauma. Although 70% of dural ectasia cases are associated with NF-1, there are few reports of NF-1 patients with dural ectasia and associated orthopedic complications. Here, we note that dystrophic changes in NF-1 may lead to rapidly aggravating neurological symptoms even after trivial trauma.

Imaging Diagnosis of Lateral Meningocele Syndrome

Lateral meningocele syndrome, also known as Lehman syndrome, is an exceptionally uncommon genetic disorder, which is characterized by specific facial features and multisystem involvement, including skeletal, cardiac, and urogenital anomalies, akin to other connective tissue disorders, but it is set apart by the unique occurrence of multiple lateral meningoceles. Knowledge of the distinctive imaging features can strongly suggest the diagnosis in patients with complex clinical presentations to assist in the guidance of appropriate and timely clinical management.

The Skeleton of Lateral Meningocele Syndrome

Notch (Notch1 through 4) are transmembrane receptors that determine cell differentiation and function, and are activated following interactions with ligands of the Jagged and Delta-like families. Notch has been established as a signaling pathway that plays a critical role in the differentiation and function of cells of the osteoblast and osteoclast lineages as well as in skeletal development and bone remodeling. Pathogenic variants of Notch receptors and their ligands are associated with a variety of genetic disorders presenting with significant craniofacial and skeletal manifestations. Lateral Meningocele Syndrome (LMS) is a rare genetic disorder characterized by neurological manifestations, meningoceles, skeletal developmental abnormalities and bone loss. LMS is associated with NOTCH3 gain-of-function pathogenic variants. Experimental mouse models of LMS revealed that the bone loss is secondary to increased osteoclastogenesis due to enhanced expression of receptor activator of nuclear factor kappa B ligand by cells of the osteoblast lineage. There are no effective therapies for LMS. Antisense oligonucleotides targeting Notch3 and antibodies that prevent the activation of NOTCH3 are being tested in preclinical models of the disease. In conclusion, LMS is a serious genetic disorder associated with NOTCH3 pathogenic variants. Novel experimental models have offered insight on mechanisms responsible and ways to correct the disease.

Precise detection of a murine germline mutation of the Notch3 gene associated with kyphosis and developmental disorders.

Objective:Humpback (hpbk) mice harbor a pathogenic mutation in the Notch3 gene and can serve as a beneficial animal model for investigating human myopathy, kyphosis, and developmental disorders, including lateral meningocele syndrome. Detection of the point mutation in hpbk mice is important for maintaining strains and scrutinizing genetic rescues, especially considering that homozygous mice are infertile and indistinguishable from their littermates at a young age. This study aimed for the development of a novel, precise, and time-saving genotyping method to identify the mutation in hpbk mice.Materials and Methods:In order to study the hpbk mouse line, we describe how we applied several tools, including quantitative polymerase chain reaction (qPCR), multiplex tetra-primer amplification-refractory mutation system (ARMS-PCR) and Sanger sequencing, toward the recognition of heterozygous and homozygous mice.Results:The Notch3 mutation was clearly identified using qPCR and ARMS assays, but the latter was a more precise and cost-effective approach. The lengths of the ARMS-PCR amplicons are 210 bp and 164 bp for the wild-type and hpbk alleles, respectively. Moreover, the genotyping results for each mouse were corroborated by Sanger DNA sequencing.Conclusion:Our newly developed PCR-based ARMS system affords a swift and precise way to genotype the hpbk mice. ARMS-PCR does not rely on any advanced equipment and is useful as a genotyping method for other model organisms that harbor a pathogenic variant.

A lateral meningocele in a 48 years lady revealed by a CSF fistula

Background: Lateral meningocele is defined by the presence of protrusions of the arachnoid and the dura matter extending laterally through inter- or intravertebral foramina. It is an extremely rare condition; to the best of our knowledge, only a few cases are reported in the literature and most of them in childhood.
 Case presentation: Authors reported a case of a 48 years old lady who consulted for a lombo-sacral mass right-sided with a CSF fistula. The Spinal MRI objectified a meningocele lateralized in the right side associated with multiples malformations. The patient underwent surgery and the meningocele was closed after excision of the associated subcutaneous lipoma. The long term outcome was favourable and the follow up was assured by clinical examination monthly in the first year.
 Conclusion: Lateral meningocele is very rarely reported, it is usually associated with multiples malformations. Surgical treatment is a good option for treatment for avoiding complications. The prognostic depends on the preoperative status and the associated malformations.

Expansion of the phenotype of lateral meningocele syndrome

Lateral meningocele syndrome (LMS) is due to specific pathogenic variants in the last exon of NOTCH3 gene. Besides the lateral meningoceles, this condition presents with dysmorphic features, short stature, congenital heart defects, and feeding difficulties. Here, we report a girl with neurosensorial hearing loss, severe gastroesophageal reflux disease, congenital heart defects, multiple renal cysts, kyphosis and left‐convex scoliosis, dysmorphic features, and mild developmental delay. Exome sequencing detected the previously unreported de novo loss‐of‐function variant in exon 33 of NOTCH3 p.(Lys2137fs). Following the identification of the gene defect, MRI of the brain and spine revealed temporal encephaloceles, inner ears anomalies, multiple spinal lateral meningoceles, and intra‐ and extra‐dural arachnoid spinal cysts. This case illustrates the power of reverse phenotyping to establish clinical diagnosis and expands the spectrum of clinical manifestations related to LMS to include inner ear abnormalities and multi‐cystic kidney disease.

Notch Pathway and Inherited Diseases: Challenge and Promise.

The evolutionary highly conserved Notch pathway governs many cellular core processes including cell fate decisions. Although it is characterized by a simple molecular design, Notch signaling, which first developed in metazoans, represents one of the most important pathways that govern embryonic development. Consequently, a broad variety of independent inherited diseases linked to defective Notch signaling has now been identified, including Alagille, Adams-Oliver, and Hajdu-Cheney syndromes, CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), early-onset arteriopathy with cavitating leukodystrophy, lateral meningocele syndrome, and infantile myofibromatosis. In this review, we give a brief overview on molecular pathology and clinical findings in congenital diseases linked to the Notch pathway. Moreover, we discuss future developments in basic science and clinical practice that may emerge from recent progress in our understanding of the role of Notch in health and disease.

An antibody to Notch3 reverses the skeletal phenotype of lateral meningocele syndrome in male mice.

Lateral meningocele syndrome (LMS), a genetic disorder characterized by meningoceles and skeletal abnormalities, is associated with NOTCH3 mutations. We created a mouse model of LMS (Notch3tm1.1Ecan ) by introducing a tandem termination codon in the Notch3 locus upstream of the proline (P), glutamic acid (E), serine (S) and threonine (T) domain. Microcomputed tomography demonstrated that Notch3tm1.1Ecan mice exhibit osteopenia. The cancellous bone osteopenia was no longer observed after the intraperitoneal administration of antibodies directed to the negative regulatory region (NRR) of Notch3. The anti-Notch3 NRR antibody suppressed the expression of Hes1, Hey1, and Hey2 (Notch target genes), and decreased Tnfsf11 (receptor activator of NF Kappa B ligand) messenger RNA in Notch3tm1.1Ecan osteoblast (OB) cultures. Bone marrow-derived macrophages (BMMs) from Notch3tm1.1Ecan mutants exhibited enhanced osteoclastogenesis in culture, and this was increased in cocultures with Notch3tm1.1Ecan OB. Osteoclastogenesis was suppressed by anti-Notch3 NRR antibodies in Notch3tm1.1Ecan OB/BMM cocultures. In conclusion, the cancellous bone osteopenia of Notch3tm1.1Ecan mutants is reversed by anti-Notch3 NRR antibodies.

The lateral meningocele syndrome mutation causes marked osteopenia in mice

Lateral meningocele syndrome (LMS) is a rare genetic disorder characterized by neurological complications and osteoporosis. LMS is associated with mutations in exon 33 of NOTCH3 leading to a truncated protein lacking sequences for NOTCH3 degradation and presumably causing NOTCH3 gain of function. To create a mouse model reproducing human LMS-associated mutations, we utilized CRISPR/Cas9 to introduce a tandem termination codon at bases 6691-6696 (ACCAAG→TAATGA) and verified this mutation (Notch3tm1.1Ecan ) by DNA sequencing of F1 mice. One-month-old male and female heterozygous Notch3tm1.1Ecan mice had cancellous and cortical bone osteopenia but exhibited no obvious neurological alterations, and histopathology of multiple organs revealed no abnormalities. Microcomputed tomography of these mutants revealed a 35-60% decrease in cancellous bone volume associated with a reduction in trabecular number and decreased connectivity. During maturation, cancellous and cortical bones were restored in female but not in male mice, which exhibited cancellous bone osteopenia at 4 months. Cancellous bone histomorphometry revealed increased osteoblast and osteocyte numbers and a modest increase in osteoclast surface and bone formation rate. Notch3tm1.1Ecan calvarial osteoblasts had increased proliferation and increased bone γ-carboxyglutamate protein (Bglap) and TNF superfamily member 11 (Tnfsf11) mRNA levels and lower Tnfrsf11b levels. Tnfsf11 mRNA was increased in osteocyte-rich femora from Notch3tm1.1Ecan mice. Cultures of bone marrow-derived macrophages from Notch3tm1.1Ecan mice revealed increased osteoclast formation, particularly in cocultures with osteoblasts from Notch3tm1.1Ecan mice. In conclusion, the Notch3tm1.1Ecan mutation causes osteopenia despite an increase in osteoblast proliferation and function and is associated with enhanced Tnfsf11 expression in osteoblasts and osteocytes.

De novo appearance of multiple chemical sensitivity syndrome in a patient affected with lateral meningocele syndrome: unlucky coincidence?

Although the coexistence of rare pathologies in the same patient is considered an exceptional event, the possibility to contend with a condition such like this may occur in clinical practice. In these cases, a multidisciplinary approach is required in order to find the most appropriate therapeutic strategy. Here we describe the clinical case of a 61 years old female affected with a rare genetic pathology known as lateral meningocele syndrome (LMS) who developed a pathological condition that could be framed in the context of a multiple chemical sensitivity syndrome (MCSS) characterized by intolerance to several drugs, foods as well as environmental and chemical agents.

The developmental biology of genetic Notch disorders.

Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome. Furthermore, structure-abrogating mutations in NOTCH3 result in CADASIL. Here, we discuss these human congenital disorders in the context of known roles for Notch signaling during development. Drawing on recent analyses by the exome aggregation consortium (EXAC) and on recent studies of Notch signaling in model organisms, we further highlight additional Notch receptors or ligands that are likely to be involved in human genetic diseases.

Symptomatic Multiple Level Lateral Meningoceles with Intraspinal Meningocele: A Case Study and Its Surgical Management

Lateral meningocele is rare disorder of unknown etiology that represents herniation of leptomeninges through enlarged neural foramina. Most patients are asymptomatic and do not need treatment. A symptomatic case with neurologic deficit requires well-planned surgical approach. We report a case of 9-year-old boy who presented with mid backache and progressive asymmetric paraparesis with urinary incontinence. The patient did not appear to have any neurologic disorder. Magnetic resonance imaging (MRI) of spine revealed bilateral multiple thoracic and lumbar paraspinal cerebrospinal fluid (CSF) intensity cystic lesions projecting from the neural foramen and extending laterally suggesting multiple bilateral meningoceles. He was surgically treated, meningocele repair was done, and thecoperitoneal shunt was inserted. Postoperatively he improved symptomatically. Bilateral multiple lateral meningoceles are very rare entity and those who are surgically treated are few. We emphasize our innovative surgical approach to this case.

Lateral Meningomyelocele in a Neonate: A Case Report

Lateral presentation of meningocele and meningomyelocele is extremely rare. Most of the lateral meningocele described are associated with other syndromes. Isolated lateral meningomyelocele cases are rarer still. We herein report a neonate with isolated lateral gluteal meningomyelocele.

Lehman Syndrome: A New Syndrome for Pierre Robin Sequence

Lehman syndrome, or lateral meningocele syndrome, is characterized by facial dysmorphism, multiple lateral meningoceles, and skeletal abnormalities. Only nine cases have been described. We present a case of a 2-year-old boy presenting with micrognathia, glossoptosis, and hypertelorism as well as associated severe obstructive sleep apnea. He was submitted to bilateral mandibular distraction with external nonresorbable devices to correct Pierre Robin sequence (PRS). Later, multiple lateral meningoceles were identified, and a diagnosis of Lehman syndrome was made. Lehman syndrome must be considered in syndromic infants with PRS. Distraction osteogenesis is a safe procedure that is effective as a first choice in the treatment of patients with Lehman syndrome presenting with micrognathia.

Computed tomography (CT) findings in 88 neurofibromatosis 1 (NF1) patients: Prevalence rates and correlations of thoracic findings

PurposeTo evaluate the prevalence rates and the correlations of thoracic computed tomography (CT) findings of neurofibromatosis 1 (NF1) in 88 patients. Materials and methodsChest CT images of 88 NF1 patients were independently reviewed by three observers, and the CT findings were evaluated. If abnormal findings were present, their number, size, and distribution were recorded. The prevalence rate of each CT finding was calculated, and the correlations between CT findings were analyzed. ResultsOf the 88 cases, 13 were positive for cysts, 16 for emphysema, 8 for nodules, 8 for GGNs (ground glass nodules), 13 for mediastinal masses, 20 for scoliosis, 44 for subcutaneous nodules, and 34 for skin nodules. Cysts showed upper and peripheral dominant distributions. Regarding 13 mediastinal masses, 2 were diagnosed as malignant peripheral nerve sheath tumors (MPNSTs), 1 was diagnosed as primary lung cancer, 2 were diagnosed as lateral meningocele, 3 were diagnosed as neurofibromas, and the remaining 7 were considered neurofibromas. There was a significant correlation between the prevalence of subcutaneous nodules and that of skin nodules. Significant positive correlations were also seen between size and number, size and rate of central distribution, and number and rate of central distribution of cysts. ConclusionVarious CT findings were found in NF-1 patients, and the prevalence rates of subcutaneous and skin nodules were higher than other findings. Though the prevalence rates of subcutaneous nodules and skin nodules were significantly correlated, the other CT findings in NF-1 occurred independently. The number, size, and distribution of the cysts showed significant positive correlations with each other.