Defining the Genetic Landscape of Congenital Mirror Movements in 80 Affected Individuals.

BACKGROUND: Congenital mirror movements (CMM) is a rare neurodevelopmental disorder characterized by involuntary movements from one side of the body that mirror voluntary movements on the opposite side. To date, five genes have been associated with CMM, namely DCC, RAD51, NTN1, ARHGEF7, and DNAL4. OBJECTIVE: The aim of this study is to characterize the genetic landscape of CMM in a large group of 80 affected individuals. METHODS: We screened 80 individuals with CMM from 43 families for pathogenic variants in CMM genes. In large CMM families, we tested for presence of pathogenic variants in multiple affected and unaffected individuals. In addition, we evaluated the impact of three missense DCC variants on binding between DCC and Netrin-1 in vitro. RESULTS: Causal pathogenic/likely pathogenic variants were found in 35% of probands overall, and 70% with familial CMM. The most common causal gene was DCC, responsible for 28% of CMM probands and 80% of solved cases. RAD51, NTN1, and ARHGEF7 were rare causes of CMM, responsible for 2% each. Penetrance of CMM in DCC pathogenic variant carriers was 68% and higher in males than females (74% vs. 54%). The three tested missense variants (p.Ile164Thr; p.Asn176Ser; and p.Arg1343His) bind Netrin-1 similarly to wild type DCC. CONCLUSIONS: A genetic etiology can be identified in one third of CMM individuals, with DCC being the most common gene involved. Two thirds of CMM individuals were unsolved, highlighting that CMM is genetically heterogeneous and other CMM genes are yet to be discovered. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genetics of mirror movements identifies a multifunctional complex required for Netrin-1 guidance and lateralization of motor control.

Mirror movements (MM) disorder is characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side. We performed genetic characterization of a family with autosomal dominant MM and identified ARHGEF7, a RhoGEF, as a candidate MM gene. We found that Arhgef7 and its partner Git1 bind directly to Dcc. Dcc is the receptor for Netrin-1, an axon guidance cue that attracts commissural axons to the midline, promoting the midline crossing of axon tracts. We show that Arhgef7 and Git1 are required for Netrin-1-mediated axon guidance and act as a multifunctional effector complex. Arhgef7/Git1 activates Rac1 and Cdc42 and inhibits Arf1 downstream of Netrin-1. Furthermore, Arhgef7/Git1, via Arf1, mediates the Netrin-1-induced increase in cell surface Dcc. Mice heterozygous for Arhgef7 have defects in commissural axon trajectories and increased symmetrical paw placements during skilled walking, a MM-like phenotype. Thus, we have delineated how ARHGEF7 mutation causes MM.

Gas discrimination by simultaneous sound velocity and attenuation measurements using uncoated capacitive micromachined ultrasonic transducers.

Chemically functionalized or coated sensors are by far the most employed solution in gas sensing. However, their poor long term stability represents a concern in applications dealing with hazardous gases. Uncoated sensors are durable but their selectivity is poor or non-existent. In this study, multi-parametric discrimination is used as an alternative to selectivity for uncoated capacitive micromachined ultrasonic transducers (CMUTs). This paper shows how measuring simultaneously the attenuation coefficient and the time of flight under different nitrogen mixtures allows to identify hydrogen, carbon dioxide and methane from each other and determine their concentration along with identification of temperature and humidity drifts. Theoretical comparison and specific signal processing to deal with the issue of multiple reflections are also presented. Some potential applications are monitoring of refueling stations, vehicles and nuclear waste storage facilities.

Histologic Correlates of Molecular Group 4 Pediatric Medulloblastoma: A Retrospective Canadian Review.

INTRODUCTION: The World Health Organization currently classifies medulloblastoma (MB) into four molecular groups (WNT, SHH, Group 3 and Group 4) and four histologic subtypes (classic, desmoplastic nodular, MB with extensive nodularity, and large cell/anaplastic). "Classic" MB is the most frequent histology, but unfortunately it does not predict molecular group or patient outcome. While MB may exhibit additional histologic features outside of the traditional WHO subtypes, the clinical significance of such features, in a molecular context, is unclear. METHODS: The clinicopathologic features of 120 pediatric MB were reviewed in the context of NanoString molecular grouping. Each case was evaluated for five ancillary histologic features, including: nodularity without desmoplasia (i.e., "biphasic", B-MB), rhythmic palisades, and focal anaplasia. Molecular and histological features were statistically correlated to clinical outcome using Chi-square, log-rank, and multivariate Cox regression analysis. RESULTS: While B-MB (N = 32) and rhythmic palisades (N = 12) were enriched amongst non-WNT/SHH MB (especially Group 4), they were not statistically associated with outcome. In contrast, focal anaplasia (N = 12) was not associated with any molecular group, but did predict unfavorable outcome. CONCLUSION: These data nominate B-MB as a surrogate marker of Groups 3 and particularly 4 MB, which may earmark a clinically significant subset of cases.

Inhaled Solvent Abuse Mimicking Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

Exposure to n-hexane or toluene-containing solvents such as glue or gasoline can produce clinical symptoms and neurophysiological findings that can mimic chronic inflammatory demyelinating polyneuropathy. The authors present a case of a boy with severe sensorimotor polyneuropathy with demyelinating features. Cerebrospinal fluid testing and magnetic resonance imaging spine did not show findings typical of chronic inflammatory demyelinating polyneuropathy. His lack of response to immunosuppressive therapy prompted a nerve biopsy which was instrumental in confirming a diagnosis of chronic organic solvent exposure, subsequently confirmed on history. This case highlights the importance of additional testing to ensure diagnostic certainty which allows appropriate treatment and/or disease management to be tailored appropriately including in this instance, the involvement of mental health counseling and avoidance of immunosuppressant medication.

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor.

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.

Fatal Second Impact Syndrome in Rowan Stringer, A 17-Year-Old Rugby Player.

Second impact syndrome (SIS) is associated with malignant brain swelling and usually occurs in young athletes with one or more prior, recent concussions. SIS is rare and some dispute its existence. We report a case of SIS in Rowan Stringer, age 17, a rugby player who sustained a fatal brain injury despite prompt medical therapy including decompression surgery. The cause of the massive brain swelling was initially unknown. An inquest revealed Rowan's text messages to friends describing symptoms from two prior, recent rugby brain injuries, likely concussions, within 5 days of the fatal blow and confirming the diagnosis of SIS.

Neu-Laxova syndrome presenting prenatally with increased nuchal translucency and cystic hygroma: The utility of exome sequencing in deciphering the diagnosis.

Neu-Laxova syndrome (NLS) is a lethal autosomal recessive microcephaly syndrome associated with intrauterine growth restriction (IUGR) and multiple congenital anomalies. Clinical features include central nervous system malformations, joint contractures, ichthyosis, edema, and dysmorphic facial features. Biallelic pathogenic variants in either the PHGDH or PSAT1 genes have been shown to cause NLS. Using exome sequencing, we aimed to identify the underlying genetic diagnosis in three fetuses (from one family) with prenatal skin edema, severe IUGR, micrognathia, renal anomalies, and arthrogryposis and identified a homozygous c.1A>C (p.Met1?, NM_006623.3) variant in the PHGDH gene. Loss of the translation start codon is a novel genetic mechanism for the development of NLS. Prenatal diagnosis of NLS is challenging and few reports describe the fetal pathology. Fetal neuropathologic examination revealed: delayed brain development, congenital agenesis of the corticospinal tracts, and hypoplasia of the hippocampus, cerebellum and brainstem. Each pregnancy also showed increased nuchal translucency (NT) or cystic hygroma. While NLS is rare, it may be a cause of recurrent increased NT/cystic hygroma. This finding provides further support that cystic hygroma has many different genetic causes and that exome sequencing may shed light on the underlying genetic diagnoses in this group of prenatal patients.

Self-antigen MASH2 combined with the AS15 immunostimulant induces tumor protection in colorectal cancer mouse models.

Human achaete scute homolog 2 (HASH2) and its murine ortholog MASH2 are potential targets for colorectal cancer immunotherapy. We assessed immunogenicity and antitumor potential of recombinant MASH2 protein combined with AS15 immunostimulant (recMASH2+AS15) in CB6F1 and Apc+/Min-FCCC mice. CB6F1 mice received 4 injections of recMASH2+AS15 or AS15 alone before challenge with TC1-MASH2 tumor cells (Tumor Challenge). Apc+/Min-FCCC mice received 9 injections of recMASH2+AS15 or vehicle (phosphate buffer saline [PBS] or AS15 alone), before (two independent Prophylactic Studies) or after (Immunotherapy) colon adenomas were detectable by colonoscopy. CB6F1 mice immunized with recMASH2+AS15 had a significantly smaller mean tumor size and improved survival rate compared to controls (104 mm2 vs. 197 mm2 [p = 0.009] and 67% vs. 7% [p = 0.001], respectively). In Prophylactic Study 1, the mean number of colon adenomas was significantly lower in Apc+/Min-FCCC mice receiving recMASH2+AS15 compared to PBS (1.8 [95% confidence interval 1.0-3.3] vs. 5.2 [3.7-7.4], p = 0.003). Fewer microadenomas were observed in recMASH2+AS15 groups compared to PBS in both Prophylactic Studies (Study 1: mean 0.4 [0.2-1.0] vs. 1.5 [0.9-2.4], p = 0.009; Study 2: 0.4 [0.2-0.6] vs. 1.1 [0.8-1.5], p = 0.001). In the Immunotherapy Study, fewer colon adenomas tended to be observed in recMASH2+AS15-treated mice (4.1 [2.9-6.0]) compared to controls (AS15 4.7 [3.3-6.6]; PBS 4.9 [3.5-6.9]; no significant difference). recMASH2+AS15 induced MASH2-specific antibody and CD4+ responses in both mouse models. recMASH2+AS15 partially protected mice against MASH2-expressing tumors and reduced spontaneous colorectal adenomas in Apc+/Min-FCCC mice, indicating that MASH2/HASH2 antigens are targets for colorectal cancer immunotherapy.

Severe TUBB4A-Related Hypomyelination With Atrophy of the Basal Ganglia and Cerebellum: Novel Neuropathological Findings.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hypomyelinating leukodystrophy characterized by infantile or childhood onset of motor developmental delay, progressive rigidity and spasticity, with hypomyelination and progressive atrophy of the basal ganglia and cerebellum due to a genetic mutation of the TUBB4A gene. It has only been recognized since 2002 and the full spectrum of the disorder is still being delineated. Here, we review a case report of a severely affected girl with a thorough neuropathological evaluation demonstrating novel clinical and pathological findings. Clinically, our patient demonstrated visual dysfunction and hypodontia in addition to the typical phenotype. Morphologically, more severe and widespread changes in the white matter were observed, including to the optic tracts; in gray structures such as the caudate nucleus, thalamus, globus pallidus, and substantia nigra; as well as an area of focal cortical dysplasia. Overall this case offers further insight into the broad range of clinical and neuropathological findings that may be associated with H-ABC and related TUBB4A gene mutations.

Infantile Myofibromatosis With Intracranial Extradural Involvement and PDGFRB Mutation: A Case Report and Review of the Literature.

Infantile myofibroma is a rare benign mesenchymal tumor that presents as solitary or multiple lesions (myofibromatosis) in the skin, soft tissue, bone, or internal organs. It most commonly affects the head and neck of infants and young children, but it can also affect adults. Intracranial involvement is reported to be extremely rare, and its clinical picture has been poorly characterized. Recently, it has been demonstrated that germline and somatic mutations in the platelet-derived growth factor receptor beta (PDGFRB) are associated with familial infantile myofibromatosis. We report a case of infantile myofibromatosis with predominant posterior fossa extradural involvement in a 14-year-old adolescent girl with a confirmed mutation in the PDGFRB gene.

Yunis-Varón syndrome caused by biallelic VAC14 mutations.

Yunis-Varón syndrome (YVS) is an autosomal recessive disorder comprising skeletal anomalies, dysmorphism, global developmental delay and intracytoplasmic vacuolation in brain and other tissues. All hitherto-reported pathogenic variants affect FIG4, a lipid phosphatase involved in phosphatidylinositol (3,5)-bisphosphate [PtdIns(3,5)P2] metabolism. FIG4 interacts with PIKfyve, a lipid kinase, via the adapter protein VAC14; all subunits of the resulting complex are essential for PtdIns(3,5)P2 synthesis in the endolysosomal membrane compartment. Here, we present the case of a female neonate with clinical features of YVS and normal FIG4 sequencing; exome sequencing identified biallelic rare coding variants in VAC14. Cultured patient fibroblasts exhibited a YVS-like vacuolation phenotype ameliorated in a dose-dependent fashion by ML-SA1, a pharmacological activator of the lysosomal PtdIns(3,5)P2 effector TRPML1. The patient developed a diffuse leukoencephalopathy with loss of the normal N-acetylaspartate spectrographic peak and presence of a large abnormal peak consistent with myoinositol. We report that VAC14 is a second gene for Yunis-Varón syndrome.

Novel Roles for Staufen1 in Embryonal and Alveolar Rhabdomyosarcoma via c-myc-dependent and -independent events.

Rhabdomyosarcoma is the most common soft tissue sarcoma in children and young adults. Rhabdomyosarcomas are skeletal muscle-like tumours that typically arise in muscle beds, and express key myogenic regulatory factors. However, their developmental program remains blocked in the proliferative phase with cells unable to exit the cell cycle to fuse into myotubes. Recently, we uncovered a key role for the RNA-binding protein Staufen1 during myogenic differentiation through the regulation of c-myc translation. Given the known implication of c-myc in rhabdomyosarcoma, we hypothesized in the current work that Staufen1 controls rhabdomyosarcoma tumorigenesis. Here, we report for the first time the novel role of Staufen1 in cancer, specifically in rhabdomyosarcoma. We demonstrate that Staufen1 is markedly upregulated in human rhabdomyosarcoma tumours and cell lines as compared to normal skeletal muscle. Moreover, we show that Staufen1 promotes the tumorigenesis of embryonal and alveolar rhabdomyosarcoma subtypes both in cell culture and in animal models. Finally, our data demonstrate that Staufen1 has differential roles in embryonal versus alveolar rhabdomyosarcoma through the control of proliferative and apoptotic pathways, respectively. Together, these results provide the first evidence for Staufen1's direct implication in cancer biology. Accordingly, Staufen1 thus represents a novel target for the development of future therapeutic strategies for rhabdomyosarcoma.

Severe Neonatal Presentation of Mitochondrial Citrate Carrier (SLC25A1) Deficiency.

Mutations of the mitochondrial citrate carrier (CIC) SLC25A1 cause combined D-2- and L-2-hydroxyglutaric aciduria (DL-2HGA; OMIM #615182), a neurometabolic disorder characterized by developmental delay, hypotonia, and seizures. Here, we describe the female child of consanguineous parents who presented neonatally with lactic acidosis, periventricular frontal lobe cysts, facial dysmorphism, recurrent apneic episodes, and deficient complex IV (cytochrome c oxidase) activity in skeletal muscle. Exome sequencing revealed a homozygous SLC25A1 missense mutation [NM_005984.4: c.593G>A; p.(Arg198His)] of a ubiquitously conserved arginine residue putatively situated within the substrate-binding site I of CIC. Retrospective review of the patient's organic acids confirmed the D- and L-2-hydroxyglutaric aciduria typical of DL-2HGA to be present, although this was not appreciated on initial presentation. Cultured patient skin fibroblasts showed reduced survival in culture, diminished mitochondrial spare respiratory capacity, increased glycolytic flux, and normal mitochondrial bulk, inner membrane potential, and network morphology. Neither cell survival nor cellular respiratory parameters were improved by citrate supplementation, although oral citrate supplementation did coincide with amelioration of lactic acidosis and apneic attacks in the patient. This is the fifth clinical report of CIC deficiency to date. The clinical features in our patient suggest that this disorder, which can potentially be recognized either by molecular means or based on its characteristic organic aciduria, should be considered in the differential diagnosis of pyruvate dehydrogenase deficiency and respiratory chain disorders. One-Sentence Summary A novel homozygous missense substitution in SLC25A1 was identified in a neonate presenting with lactic acidosis, intracerebral cysts, and an apparent mitochondrial complex IV defect in muscle.

Fetal segmental spinal dysgenesis and unusual segmental agenesis of the anterior spinal artery.

Segmental spinal dysgenesis (SSD) is a rare congenital spinal abnormality characterized by segmental dysgenesis or agenesis of the thoracolumbar or lumbar spine, congenital kyphosis, and abnormal configuration of the underlying spinal cord. A unique feature of SSD is that the vertebrae are present above and below the defect, and there is often a lower cord segment in the caudal spinal canal. We report a fetal MRI case of SSD with postmortem and neuropathological correlations. Our report confirms already published findings including the presence of a neurenteric cyst but is the first to document anterior spinal artery segmental agenesis in SSD.

Primary cutaneous adenoid cystic carcinoma with brain metastases: case report and literature review.

Primary cutaneous adenoid cystic carcinoma (ACC) is a rare skin tumor that is unlikely to metastasize. We present a case of primary cutaneous ACC in a 67-year-old male with axillary lymph node, pulmonary and brain metastases. To the best of our knowledge, this is the first reported case of cutaneous ACC with distant metastases to the brain.

Bone marrow-derived macrophages and the CNS: An update on the use of experimental chimeric mouse models and bone marrow transplantation in neurological disorders.

The central nervous system (CNS) is a very unique system with multiple features that differentiate it from systemic tissues. One of the most captivating aspects of its distinctive nature is the presence of the blood brain barrier (BBB), which seals it from the periphery. Therefore, to preserve tissue homeostasis, the CNS has to rely heavily on resident cells such as microglia. These pivotal cells of the mononuclear lineage have important and dichotomous roles according to various neurological disorders. However, certain insults can overwhelm microglia as well as compromising the integrity of the BBB, thus allowing the infiltration of bone marrow-derived macrophages (BMDMs). The use of myeloablation and bone marrow transplantation allowed the generation of chimeric mice to study resident microglia and infiltrated BMDM separately. This breakthrough completely revolutionized the way we captured these 2 types of mononuclear phagocytic cells. We now realize that microglia and BMDM exhibit distinct features and appear to perform different tasks. Since these cells are central in several pathologies, it is crucial to use chimeric mice to analyze their functions and mechanisms to possibly harness them for therapeutic purpose. This review will shed light on the advent of this methodology and how it allowed deciphering the ontology of microglia and its maintenance during adulthood. We will also compare the different strategies used to perform myeloablation. Finally, we will discuss the landmark studies that used chimeric mice to characterize the roles of microglia and BMDM in several neurological disorders. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.