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Variants in the TUBB4A gene are associated with dystonia (DYT- TUBB4A), Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC) and spastic paraplegia. Phenotypes intermediate to these three broad phenotypes are also observed. These are rare disorders, and data from diverse populations remains limited. We report seven Indian cases with dystonia phenotype related to TUBB4A mutation. Among these seven patients, age at onset ranged from 5 to 48 years. Five patients had cranio-cervical onset of dystonia. One patient had prominent parkinsonism with dystonia. Patients responded well to botulinum toxin injected for laryngeal, cervical and jaw dystonia. The patient with parkinsonism responded well to levodopa, albeit with development of dyskinesias. Apart from the common p.Arg2Gly variant in three patients with DYT- TUBB4A , other variants included p.Arg262Pro, p.Arg39Cys and p.Asp245Asn. We report the first collection of cases with TUBB4A mutation from India. We expand the phenotype to include levodopa-responsive parkinsonism. Indian patients, consistent with global literature, harbor prominent adductor dysphonia, cervical and jaw dystonia, which responds well to botulinum treatment. • Indian patients with DYT-TUBB4A had severe adductor spasmodic dysphonia and prominent cervical involvement. • A novel Arg262Pro variant was associated with levodopa-responsive parkinsonism. • Intermediate phenotypes, with prominent dystonia and white matter involvement, showed relatively severe clinical features. [ABSTRACT FROM AUTHOR]

Very preterm infants who survive are at high risk of white matter injury (WMI). With a greater understanding of the pathogenesis of WMI, the gut microbiota has recently drawn increasing attention in this field. This review tries to clarify the possible mechanisms behind the communication of the gut bacteria and the immature brain via the gut–brain axis. The gut microbiota releases signals, such as microbial metabolites. These metabolites regulate inflammatory and immune responses characterized by microglial activation, which ultimately impact the differentiation of pre-myelinating oligodendrocytes (pre-OLs) and lead to WMI. Moreover, probiotics and prebiotics emerge as a promising therapy to improve the neurodevelopmental outcome. However, future studies are required to clarify the function of these above products and the optimal time for their administration within a larger population. Based on the existing evidence, it is still too early to recommend probiotics and prebiotics as effective treatments for WMI. [ABSTRACT FROM AUTHOR]

CNTNAP1 encodes CASPR1, involved in the paranodal junction. Thirty-three patients, with CNTNAP1 biallelic mutations have been described previously. Most of them had a very severe neurological impairment and passed away in the first months of life. We identified four patients, from two unrelated families, who survived over the neonatal period. Exome sequencing showed compound heterozygous or homozygous variants. Severe hypotonia was a constant feature. When compared to previous reports, the most important clinical differences observed in our patients were the absence of antenatal problems and, in two of them, the lack of respiratory distress. Less commonly reported characteristics such as epileptic seizures, dystonia, and impaired communication skills were also observed. MRIs revealed hypomyelination or abnormal white matter signal, cerebral or cerebellar atrophy. The present observations support a wider than initially reported clinical spectrum, including survival after the neonatal period and additional neurological features. They contribute to better delineate the phenotype–genotype correlations for CNTNAP1. In addition, we report one more family with two sibs who carry a missense variant of uncertain significance which we propose could be associated with a milder phenotype. • CNTNAP1 mutations appear as a novel aetiology for severe hypotonia in newborns and infants. • This study confirms that survival after infancy can occur in patients with CNTNAP1 pathogenic variants. • Clinical spectrum is extended with new cases of dystonia, better motor and communication skills than previously described. • Three novel missense variants are described. [ABSTRACT FROM AUTHOR]

Very preterm infants who survive are at high risk of white matter injury (WMI). With a greater understanding of the pathogenesis of WMI, the gut microbiota has recently drawn increasing attention in this field. This review tries to clarify the possible mechanisms behind the communication of the gut bacteria and the immature brain via the gut–brain axis. The gut microbiota releases signals, such as microbial metabolites. These metabolites regulate inflammatory and immune responses characterized by microglial activation, which ultimately impact the differentiation of pre-myelinating oligodendrocytes (pre-OLs) and lead to WMI. Moreover, probiotics and prebiotics emerge as a promising therapy to improve the neurodevelopmental outcome. However, future studies are required to clarify the function of these above products and the optimal time for their administration within a larger population. Based on the existing evidence, it is still too early to recommend probiotics and prebiotics as effective treatments for WMI.

WW domain‐containing oxidoreductase (WWOX) is an emerging neural gene‐regulating homeostasis of the central nervous system. Germline biallelic mutations in WWOX cause WWOX‐related epileptic encephalopathy (WOREE) syndrome and spinocerebellar ataxia and autosomal recessive 12 (SCAR12), two devastating neurodevelopmental disorders with highly heterogenous clinical outcomes, the most common being severe epileptic encephalopathy and profound global developmental delay. We recently demonstrated that neuronal ablation of murine Wwox recapitulates phenotypes of Wwox‐null mice leading to intractable epilepsy, hypomyelination, and postnatal lethality. Here, we designed and produced an adeno‐associated viral vector (AAV9) harboring murine Wwox or human WWOX cDNA and driven by the human neuronal Synapsin I promoter (AAV‐SynI‐WWOX). Testing the efficacy of AAV‐SynI‐WWOX delivery in Wwox‐null mice demonstrated that specific neuronal restoration of WWOX expression rescued brain hyperexcitability and seizures, hypoglycemia, myelination deficits, and the premature lethality and behavioral deficits of Wwox‐null mice. These findings provide a proof‐of‐concept for WWOX gene therapy as a promising approach to curing children with WOREE and SCAR12. SYNOPSIS: AAV‐mediated neuronal WWOX restoration reverses abnormal defects of Wwox null mice, providing a proof‐of‐concept for WWOX gene therapy as a promising approach for treating children with WOREE syndrome. Neuronal WWOX restoration improves the overall growth of Wwox null mice.WWOX restoration reduces neuronal hyperexcitability and neuroinflammation.Neuronal WWOX delivery increases myelination, likely by promoting differentiation of OPCs to mature oligodendrocytes.Neuronal restoration of WWOX is associated with normal behavioral and motor functions of the rescued Wwox null mice. [ABSTRACT FROM AUTHOR]

Abstract Background Microglia activation is associated with the development of hypoxic–ischemic brain injury (HIBI). Neuroinflammation suppression might be a suitable therapeutic target in hypoxic oligodendrocyte injury. This study aims to determine whether clemastine can improve hypomyelination by suppressing the activated microglia and promoting the maturation of oligodendrocyte progenitor cells (OPCs) in HIBI. Methods A bilateral common carotid artery occlusion (BCCAO) rat model that received continuous intraperitoneal injection (1 mg/kg) for 14 days was employed to elaborate the neuroprotection effects of clemastine. Interleukin-1β (IL-1β), nod-like receptor protein 3 (NLRP3), histamine H1 receptor, and OPC differentiation levels in the corpus callosum were measured. Primary cultured OPCs and co-culture of microglia and OPCs were used to explore the link between microglia activation and hypomyelination. Data were evaluated by one-way ANOVA with Fisher’s protected least significant difference test. Results Clemastine treatment could reverse hypomyelination and restrain the upregulation of IL-1β and NLRP3 in the corpus callosum of BCCAO rats. Primary cultured OPCs treated with IL-1β showed failed maturation. However, clemastine could also reverse the OPC maturation arrest by activating the extracellular signal-regulated kinase (ERK) signaling pathway. Co-culture of microglia and OPCs with oxygen glucose deprivation treatment exhibited IL-1β and NLRP3 upregulation. Clemastine could downregulate NLRP3 and IL-1β and reverse hypomyelination by inhibiting the p38 signaling pathway. Conclusions Clemastine could restrain microglia activation, improve axonal hypomyelination in BCCAO rats, and thus might be a viable strategy to inhibit hypomyelination in the corpus callosum of patients with HIBI.

The myelin sheath, which is wrapped around axons, is a lipid-enriched structure produced by mature oligodendrocytes. Disruption of the myelin sheath is observed in several neurological diseases, such as multiple sclerosis. A crucial component of myelin is sphingomyelin, levels of which can be increased by ABCA8, a member of the ATP-binding cassette transporter family. ABCA8 is highly expressed in the cerebellum, specifically in oligodendroglia. However, whether ABCA8 plays a role in myelination and mechanisms that would underlie this role remain unknown. Here, we found that the absence of Abca8b, a mouse ortholog of ABCA8, led to decreased numbers of cerebellar oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes in mice. We show that in oligodendrocytes, ABCA8 interacts with chondroitin sulfate proteoglycan 4 (CSPG4), a molecule essential for OPC proliferation, migration, and myelination. In the absence of Abca8b, localization of CSPG4 to the plasma membrane was decreased, contributing to reduced cerebellar CSPG4 expression. Cerebellar CSPG4+ OPCs were also diminished, leading to decreased mature myelinating oligodendrocyte numbers and cerebellar myelination levels in Abca8b−/− mice. In addition, electron microscopy analyses showed that the number of nonmyelinated cerebellar axons was increased, whereas cerebellar myelin thickness (g-ratio), myelin sheath periodicity, and axonal diameter were all decreased, indicative of disordered myelin ultrastructure. In line with disrupted cerebellar myelination, Abca8b−/− mice showed lower cerebellar conduction velocity and disturbed locomotion. In summary, ABCA8 modulates cerebellar myelination, in part through functional regulation of the ABCA8-interacting protein CSPG4. Our findings suggest that ABCA8 disruption may contribute to the pathophysiology of myelin disorders.

Abstract Wolfram syndrome is a rare multisystem disorder caused by mutations in WFS1 or CISD2 genes leading to brain structural abnormalities and neurological symptoms. These abnormalities appear in early stages of the disease. The pathogenesis of Wolfram syndrome involves abnormalities in the endoplasmic reticulum (ER) and mitochondrial dynamics, which are common features in several other neurodegenerative disorders. Mutations in WFS1 are responsible for the majority of Wolfram syndrome cases. WFS1 encodes for an endoplasmic reticulum (ER) protein, wolframin. It is proposed that wolframin deficiency triggers the unfolded protein response (UPR) pathway resulting in an increased ER stress-mediated neuronal loss. Recent neuroimaging studies showed marked alteration in early brain development, primarily characterized by abnormal white matter myelination. Interestingly, ER stress and the UPR pathway are implicated in the pathogenesis of some inherited myelin disorders like Pelizaeus-Merzbacher disease, and Vanishing White Matter disease. In addition, exploratory gene-expression network-based analyses suggest that WFS1 expression occurs preferentially in oligodendrocytes during early brain development. Therefore, we propose that Wolfram syndrome could belong to a category of neurodevelopmental disorders characterized by ER stress-mediated myelination impairment. Further studies of myelination and oligodendrocyte function in Wolfram syndrome could provide new insights into the underlying mechanisms of the Wolfram syndrome-associated brain changes and identify potential connections between neurodevelopmental disorders and neurodegeneration.

Hypomyelinating leukodystrophies (HLDs) are a heterogeneous group of white matter diseases characterized by permanent deficiency of myelin deposition in brain. MRI is instrumental in the diagnosis and recommending genetic analysis, and is especially useful as many patients have a considerable clinical overlap, with the primary presenting complains being global developmental delay with psychomotor regression. Hypomyelination is defined as deficient myelination on two successive MR scans, taken at least 6 months apart, one of which should have been obtained after 1 year of age. Due to subtle differences in MRI features, the need for a systematic imaging approach to diagnose and classify hypomyelinating disorders is reiterated. The presented article provides an explicit review of imaging features of a myriad of primary and secondary HLDs, using state of the art genetically proven MR cases. A systematic pattern-based approach using MR features and specific clinical clues is illustrated for a quick yet optimal diagnosis of common as well as rare hypomyelinating disorders. The major MR features helping to narrow the differential diagnosis include extent of involvement like diffuse or patchy hypomyelination with selective involvement or sparing of certain white matter structures like optic radiations, median lemniscus, posterior limb of internal capsule and periventricular white matter; cerebellar atrophy; brainstem, corpus callosal or basal ganglia involvement; T2 hypointense signal of the thalami; and presence of calcifications. The authors also discuss the genetic and pathophysiologic basis of HLDs and recent methods to quantify myelin in vivo using advanced neuroradiology tools. The proposed algorithmic approach provides an improved understanding of these rare yet important disorders, enhancing diagnostic precision and improving patient outcomes. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 5., (© 2024 International Society for Magnetic Resonance in Medicine.)

The enzyme ubiquitin-like modifier activating enzyme 5 (UBA5) plays an important role in activating ubiquitin-fold modifier 1 (UFM1) and its associated cascade. UFM1 is widely expressed and known to facilitate the post-translational modification of proteins. Variants in UBA5 and UFM1 are involved in neurodevelopmental disorders with early-onset epileptic encephalopathy as a frequently seen disease manifestation. Using whole exome sequencing, we detected a homozygous UBA5 variant (c.895C > T p. [Pro299Ser]) in a patient with severe global developmental delay and epilepsy, the latter from the age of 4 years. Magnetic resonance imaging showed hypomyelination with atrophy and T2 hyperintensity of the thalamus. Histology of the sural nerve showed axonal neuropathy with decreased myelin. Functional analyses confirmed the effect of the Pro299Ser variant on UBA5 protein function, showing 58% residual protein activity. Our findings indicate that the epilepsy currently associated with UBA5 variants may present later in life than previously thought, and that radiological signs include hypomyelination and thalamic involvement. The data also reinforce recently reported associations between UBA5 variants and peripheral neuropathy. [ABSTRACT FROM AUTHOR]

RNA polymerase (Pol) III synthesizes abundant short noncoding RNAs that have essential functions in protein synthesis, secretion, and other processes. Despite the ubiquitous functions of these RNAs, mutations in Pol III subunits cause Pol III-related leukodystrophy, an early-onset neurodegenerative disease. The basis of this neural sensitivity and the mechanisms of disease pathogenesis are unknown. Here we show that mice expressing pathogenic mutations in the largest Pol III subunit, Polr3a, specifically in Olig2- expressing cells, have impaired growth and developmental delay, deficits in cognitive, sensory, and fine sensorimotor function, and hypomyelination in multiple regions of the cerebrum and spinal cord. These phenotypes reflect a subset of clinical features seen in patients. In contrast, the gross motor defects and cerebellar hypomyelination that are common features of severely affected patients are absent in the mice, suggesting a relatively mild form of the disease in this conditional model. Our results show that disease pathogenesis in the mice involves defects that reduce both the number of mature myelinating oligodendrocytes and the ability of these cells to produce a myelin sheath of normal thickness. The findings suggest unique sensitivities of oligodendrogenesis and myelination to perturbations of Pol III transcription. [ABSTRACT FROM AUTHOR]

Severe loss of TBCE function has been related to two well-known dysmorphic syndromes, while TBCE hypomorphic variants have been linked to neurodegenerative conditions due to perturbed microtubule dynamics and homeostasis, with signs of central and peripheral nervous system involvement. We report on an Italian female originating from Southern Italy who presented early-onset regression and neurodegeneration, with neurological features of tetraparesis and signs of peripheral nervous system involvement. Her brain MRI revealed white matter involvement. Analyzing all known hypomyelination leukodystrophies related genes, two mutations in TBCE (NM_001079515) were detected: the missense variant c.464 T > A; p. (Ile155Asn) and the frameshift variant c.924del; p. (Leu309Ter), in compound heterozygosity, already reported in the literature in patients coming from the same geographical area. The clinical phenotype of the proposita was more severe and with an earlier onset than the majority of the patients reported so far. Next Generation Sequencing is becoming increasingly necessary to assess unusual phenotypes, with the opportunity to establish prognosis and disease mechanisms, and facilitating differential diagnosis. [ABSTRACT FROM AUTHOR]

Background: Platelet‐derived growth factor (PDGF) signaling, through the ligand PDGF‐A and its receptor PDGFRA, is important for the growth and maintenance of oligodendrocyte progenitor cells (OPCs) in the central nervous system (CNS). PDGFRA signaling is downregulated prior to OPC differentiation into mature myelinating oligodendrocytes. By contrast, PDGFRA is often genetically amplified or mutated in many types of gliomas, including diffuse midline glioma (DMG) where OPCs are considered the most likely cell‐of‐origin. The cellular and molecular changes that occur in OPCs in response to unregulated PDGFRA expression, however, are not known. Methods: Here, we created a conditional knock‐in (KI) mouse that overexpresses wild type (WT) human PDGFRA (hPDGFRA) in prenatal Olig2‐expressing progenitors, and examined in vivo cellular and molecular consequences. Results: The KI mice exhibited stunted growth, ataxia, and a severe loss of myelination in the brain and spinal cord. When combined with the loss of p53, a tumor suppressor gene whose activity is decreased in DMG, the KI mice failed to develop tumors but still exhibited hypomyelination. RNA‐sequencing analysis revealed decreased myelination gene signatures, indicating a defect in oligodendroglial development. Mice overexpressing PDGFRA in prenatal GFAP‐expressing progenitors, which give rise to a broader lineage of cells than Olig2‐progenitors, also developed myelination defects. Conclusion: Our results suggest that embryonic overexpression of hPDGFRA in Olig2‐ or GFAP‐progenitors is deleterious to OPC development and leads to CNS hypomyelination. [ABSTRACT FROM AUTHOR]

WWOX-related epileptic encephalopathy (WOREE) syndrome caused by human germline bi-allelic mutations in WWOX is a neurodevelopmental disorder characterized by intractable epilepsy, severe developmental delay, ataxia and premature death at the age of 2-4 years. The underlying mechanisms of WWOX actions are poorly understood. In the current study, we show that specific neuronal deletion of murine Wwox produces phenotypes typical of the Wwox-null mutation leading to brain hyperexcitability, intractable epilepsy, ataxia and postnatal lethality. A significant decrease in transcript levels of genes involved in myelination was observed in mouse cortex and hippocampus. Wwox-mutant mice exhibited reduced maturation of oligodendrocytes, reduced myelinated axons and impaired axonal conductivity. Brain hyperexcitability and hypomyelination were also revealed in human brain organoids with a WWOX deletion. These findings provide cellular and molecular evidence for myelination defects and hyperexcitability in the WOREE syndrome linked to neuronal function of WWOX. [ABSTRACT FROM AUTHOR]

PYCR2 pathogenic variants lead to an autosomal recessive hypomyelinating leukodystrophy 10 (HLD10), characterized by global developmental delay, microcephaly, facial dysmorphism, movement disorder, and hypomyelination. This study identified the first two unrelated Thai patients with HLD10. Patient 1 harbored the novel compound heterozygous variants, c.257T>G (p.Val86Gly) and c.400G>A (p.Val134Met), whereas patient 2 possessed the homozygous variant, c.400G>A (p.Val134Met), in PYCR2. Haplotype analysis revealed that the two families' members shared a 2.3 Mb region covering the c.400G>A variant, indicating a common ancestry. The variant was estimated to age 1450 years ago. Since the c.400G>A was detected in three out of four mutant alleles and with a common ancestry, this variant might be common in Thai patients. We also reviewed the phenotype and genotype of all 35 previously reported PYCR2 patients and found that majorities of cases were homozygous with a consanguineous family history, except patient 1 and another reported case who were compound heterozygous. All patients had microcephaly and developmental delay. Hypotonia and peripheral spasticity were common. Hypomyelination or delayed myelination was a typical radiographic feature. Here, we report the first two Thai patients with HLD10 with the novel PYCR2 variants expanding the genotypic spectrum and suggest that the c.400G>A might be a common mutation in Thai patients. [ABSTRACT FROM AUTHOR]

Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating disorder of the central nervous system (CNS) linked to mutations in the proteolipid protein-1 (PLP1) gene. Although there are multiple animal models of PMD, few of them fully mimic the human disease. Here, we report three spontaneous cases of male neonatal rhesus macaques with the clinical symptoms of hypomyelinating disease, including intention tremors, progressively worsening motor dysfunction, and nystagmus. These animals demonstrated a paucity of CNS myelination accompanied by reactive astrogliosis, and a lack of PLP1 expression throughout white matter. Genetic analysis revealed that these animals were related to one another and that their parents carried a rare, hemizygous missense variant in exon 5 of the PLP1 gene. These animals therefore represent the first reported non-human primate model of PMD, providing a novel and valuable opportunity for preclinical studies that aim to promote myelination in pediatric hypomyelinating diseases.

Abstract Background Platelet‐derived growth factor (PDGF) signaling, through the ligand PDGF‐A and its receptor PDGFRA, is important for the growth and maintenance of oligodendrocyte progenitor cells (OPCs) in the central nervous system (CNS). PDGFRA signaling is downregulated prior to OPC differentiation into mature myelinating oligodendrocytes. By contrast, PDGFRA is often genetically amplified or mutated in many types of gliomas, including diffuse midline glioma (DMG) where OPCs are considered the most likely cell‐of‐origin. The cellular and molecular changes that occur in OPCs in response to unregulated PDGFRA expression, however, are not known. Methods Here, we created a conditional knock‐in (KI) mouse that overexpresses wild type (WT) human PDGFRA (hPDGFRA) in prenatal Olig2‐expressing progenitors, and examined in vivo cellular and molecular consequences. Results The KI mice exhibited stunted growth, ataxia, and a severe loss of myelination in the brain and spinal cord. When combined with the loss of p53, a tumor suppressor gene whose activity is decreased in DMG, the KI mice failed to develop tumors but still exhibited hypomyelination. RNA‐sequencing analysis revealed decreased myelination gene signatures, indicating a defect in oligodendroglial development. Mice overexpressing PDGFRA in prenatal GFAP‐expressing progenitors, which give rise to a broader lineage of cells than Olig2‐progenitors, also developed myelination defects. Conclusion Our results suggest that embryonic overexpression of hPDGFRA in Olig2‐ or GFAP‐progenitors is deleterious to OPC development and leads to CNS hypomyelination.

Recessive mutations in the POLR3A gene cause POLR3-HLD (the second-most-common form of childhood-onset hypomyelinating leukodystrophy), a neurodegenerative disorder featuring deficient cerebral myelin formation. To date, more than 140 POLR3A (NM_007055.3) missense mutations are related to the pathogenesis of POLR3-related leukodystrophy and spastic ataxia. Herein, in a cohort of five families from Sicily (Italy), we detected two cases of patients affected by POLR3-related leukodystrophy, one due to a compound heterozygous mutation in the POLR3A gene, including a previously undescribed missense mutation (c.328A > G (p.Lys110Glu)). Our study used an in-house NGS gene panel comprising 41 known leukodystrophy genes. Successively, we used a predictive test supporting the missense mutation as causative of disease, thus this mutation can be considered “Likely Pathogenic” and could be as a new pathogenetic mutation of the POLR3A gene causing a severe form of POLR3-HLD.

Hypomyelination and congenital cataract (HCC) is characterized by congenital cataract, progressive neurologic impairment, and diffuse myelin deficiency. This autosomal recessive disorder is caused by homozygous variant in the FAM126A gene. Five consanguineous Tunisian patients, belonging to three unrelated families, underwent routine blood tests, electroneuromyography, and magnetic resonance imaging of the brain. The direct sequencing of FAM126A exons was performed for the patients and their relatives. We summarized the 30 previously published HCC cases. All of our patients were carriers of a previously reported c.414 + 1G > T (IVS5 + 1G > T) variant, but the clinical spectrum was variable. Despite the absence of a phenotype–genotype correlation in HCC disease, screening of this splice site variant should be performed in family members at risk. [ABSTRACT FROM AUTHOR]

Novel mutations in myelin and myelin-associated genes have provided important information on oligodendrocytes and myelin and the effects of their disruption on the normal developmental process of myelination of the central nervous system (CNS). We report here a mutation in the folliculin-interacting protein 2 (FNIP2) gene in the Weimaraner dog that results in hypomyelination of the brain and a tract-specific myelin defect in the spinal cord. This myelination disruption results in a notable tremor syndrome from which affected dogs recover with time. In the peripheral tracts of the lateral and ventral columns of the spinal cord, there is a lack of mature oligodendrocytes. A genome-wide association study of DNA from three groups of dogs mapped the gene to canine chromosome 15. Sequencing of all the genes in the candidate region identified a frameshift mutation in the FNIP2 gene that segregated with the phenotype. While the functional role of FNIP2 is not known, our data would suggest that production of truncated protein results in a delay or failure of maturation of a subpopulation of oligodendrocytes.

Background: Shaking puppy syndrome is commonly attributed to abnormal myelination of the central nervous system. Hypothesis/Objectives: To report the long‐term clinical course and the imaging characteristics of hypomyelinating leukodystrophy in German Shepherd dogs. Animals and Methods: Three related litters with 11 affected dogs. Results: The 11 affected dogs experienced coarse, side‐to‐side tremors of the head and trunk, which interfered with normal goal‐oriented movements and disappeared at rest. Signs were noticed shortly after birth. Nine dogs were euthanized, 3 dogs underwent pathological examination, and 2 littermates were raised by their breeder. Tremors improved gradually until 6 to 7 months of age. Adult dogs walked with severe residual pelvic limb ataxia. One dog developed epilepsy with tonic‐clonic seizures at 15 months of age. Conventional magnetic resonance imaging (MRI) disclosed homogenous hyperintense signal of the entire subcortical white matter in 3 affected 7‐week‐old dogs and a hypointense signal in a presumably unaffected littermate. Subcortical white matter appeared isointense to gray matter at 15 and 27 weeks of age on repeated MRI. Abnormal white matter signal with failure to display normal gray‐white matter contrast persisted into adulthood. Cerebellar arbor vitae was not visible at any time point. Clinical signs, MRI findings, and pathological examinations were indicative of a hypomyelinating leukodystrophy. All parents of the affected litters shared a common ancestor and relatedness of the puppies suggested an autosomal recessive mode of inheritance. Conclusion: We describe a novel hypomyelinating leukodystrophy in German Shepherd dogs with a suspected inherited origin. [ABSTRACT FROM AUTHOR]

Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is a non-catalytic component of the multi-tRNA synthetase complex that catalyzes the ligation of amino acids to their correct tRNAs. Bi-allelic truncating variants in the AIMP1 gene have been associated with hypomyelinating leukodystrophy-3 (HLD3; MIM 260600), which is characterized by hypomyelination, microcephaly, seizures and decreased life expectancy. Although peripheral nerve involvement has been assumed for HLD3, no compelling evidence is available to date. The case was a first-born Filipino male. He showed profound developmental delay, failure to thrive, and spasticity in his limbs. At three months of age he developed refractory epilepsy. Serial magnetic resonance imaging (MRIs) showed profound myelination delay and progressive cerebral atrophy. He showed abnormal nerve conduction studies. Genetic testing revealed a homozygous pathogenic variant in the AIMP1 gene (NM_004757.3: c.115C > T: p.Gln39*). The parents were heterozygous for the same variant. Here, we report a patient with a homozygous nonsense AIMP1 variant showing peripheral neuropathy as well as HLD3. Our case suggests that AIMP1 plays a pivotal role in the peripheral nerve as well as the central nervous system. [ABSTRACT FROM AUTHOR]

Background and purpose: Little is known about hypomyelinating leukodystrophies (HLDs) in adults. The aim of this study was to investigate HLD occurrence, clinical features, and etiology among undefined leukoencephalopathies in adulthood. Methods: We recruited the patients with cerebral hypomyelinating magnetic resonance imaging pattern (mild T2 hyperintensity with normal or near‐normal T1 signal) from our cohort of 62 adult index cases with undefined leukoencephalopathies, reviewed their clinical features, and used a leukoencephalopathy‐targeted next generation sequencing panel. Results: We identified 25/62 patients (~40%) with hypomyelination. Cardinal manifestations were spastic gait and varying degree of cognitive impairment. Etiology was determined in 44% (definite, 10/25; likely, 1/25). Specifically, we found pathogenic variants in the POLR3A (n = 2), POLR1C (n = 1), RARS1 (n = 1), and TUBB4A (n = 1) genes, which are typically associated with severe early‐onset HLDs, and in the GJA1 gene (n = 1), which is associated with oculodentodigital dysplasia. Duplication of a large chromosome X region encompassing PLP1 and a pathogenic GJC2 variant were found in two patients, both females, with early‐onset HLDs persisting into adulthood. Finally, we found likely pathogenic variants in PEX3 (n = 1) and PEX13 (n = 1) and potentially relevant variants of unknown significance in TBCD (n = 1), which are genes associated with severe, early‐onset diseases with central hypomyelination/dysmyelination. Conclusions: A hypomyelinating pattern characterizes a relevant number of undefined leukoencephalopathies in adulthood. A comprehensive genetic screening allows definite diagnosis in about half of patients, and demonstrates the involvement of many disease‐causing genes, including genes associated with severe early‐onset HLDs, and genes causing peroxisome biogenesis disorders. [ABSTRACT FROM AUTHOR]

[Display omitted] • Endocrine signals play a crucial role in myelin development and diseases. • Several EDCs can interfere with myelination during development. • Several EDCs exert deleterious effects on myelin in the mature nervous system. • Some endocrine modulators could be therapeutic options in demyelinating conditions. • The underlying mechanisms of EDCs impacts on myelin are still poorly understood. In the central and peripheral nervous systems, myelin is essential for efficient conduction of action potentials. During development, oligodendrocytes and Schwann cells differentiate and ensure axon myelination, and disruption of these processes can contribute to neurodevelopmental disorders. In adults, demyelination can lead to important disabilities, and recovery capacities by remyelination often decrease with disease progression. Among environmental chemical pollutants, endocrine disrupting chemicals (EDCs) are of major concern for human health and are notably suspected to participate in neurodevelopmental and neurodegenerative diseases. In this review, we have combined the current knowledge on EDCs impacts on myelin including several persistent organic pollutants, bisphenol A, triclosan, heavy metals, pesticides, and nicotine. Besides, we presented several other endocrine modulators, including pharmaceuticals and the phytoestrogen genistein, some of which are candidates for treating demyelinating conditions but could also be deleterious as contaminants. The direct impacts of EDCs on myelinating cells were considered as well as their indirect consequences on myelin, particularly on immune mechanisms associated with demyelinating conditions. More studies are needed to describe the effects of these compounds and to further understand the underlying mechanisms in relation to the potential for endocrine disruption. [ABSTRACT FROM AUTHOR]

Objective: Kinesin family member 5A (KIF5A) is a molecular motor protein responsible for intracellular transport, specifically in neurons. While abnormalities in the KIF5A gene have been reported in the onset of various neurological diseases, there are no studies demonstrating an association between this gene and West syndrome. Methods: In the case presented here, epileptic spasms appeared at 7 months; electroencephalogram (EEG) investigation confirmed hypsarrhythmia, resulting in a diagnosis of West syndrome. The patient exhibited peculiar facies, hypotonia, failure to thrive, and severe global developmental delay. Results: Cranial magnetic resonance imaging (MRI) revealed severe delayed myelination. 123I‐iomazenil SPECT image at 7 months demonstrated decreased accumulation in bilateral areas, including the primary somatosensory and motor cortices, and the primary and association visual areas compared to an age‐matched control. Whole exome sequencing analysis demonstrated a novel de novo heterozygous missense variant in KIF5A, (NM_004984.4:c.710A>T: p. Glu237Val). Significance: It was concluded that the KIF5A variant impaired the transport of GABAA receptors to the cell membrane surface, thus leading to an imbalance of these receptors between regions of the cerebrum and resulting in the onset of epilepsy. [ABSTRACT FROM AUTHOR]

Leukodystrophies are a class of rare inherited central nervous system (CNS) disorders that affect the white matter of the brain, typically leading to progressive neurodegeneration and early death. Hypomyelinating leukodystrophies are characterized by the abnormal formation of the myelin sheath during development. POLR3-related or 4H (hypomyelination, hypodontia, and hypogonadotropic hypogonadism) leukodystrophy is one of the most common types of hypomyelinating leukodystrophy for which no curative treatment or disease-modifying therapy is available. This review aims to describe potential therapies that could be further studied for effectiveness in pre-clinical studies, for an eventual translation to the clinic to treat the neurological manifestations associated with POLR3-related leukodystrophy. Here, we discuss the therapeutic approaches that have shown promise in other leukodystrophies, as well as other genetic diseases, and consider their use in treating POLR3-related leukodystrophy. More specifically, we explore the approaches of using stem cell transplantation, gene replacement therapy, and gene editing as potential treatment options, and discuss their possible benefits and limitations as future therapeutic directions.

Leukodystrophies are a class of rare inherited central nervous system (CNS) disorders that affect the white matter of the brain, typically leading to progressive neurodegeneration and early death. Hypomyelinating leukodystrophies are characterized by the abnormal formation of the myelin sheath during development. POLR3-related or 4H (hypomyelination, hypodontia, and hypogonadotropic hypogonadism) leukodystrophy is one of the most common types of hypomyelinating leukodystrophy for which no curative treatment or disease-modifying therapy is available. This review aims to describe potential therapies that could be further studied for effectiveness in pre-clinical studies, for an eventual translation to the clinic to treat the neurological manifestations associated with POLR3-related leukodystrophy. Here, we discuss the therapeutic approaches that have shown promise in other leukodystrophies, as well as other genetic diseases, and consider their use in treating POLR3-related leukodystrophy. More specifically, we explore the approaches of using stem cell transplantation, gene replacement therapy, and gene editing as potential treatment options, and discuss their possible benefits and limitations as future therapeutic directions. [ABSTRACT FROM AUTHOR]

Mutations in TUBB4A result in a spectrum of leukodystrophy including Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC), a rare hypomyelinating leukodystrophy, often associated with a recurring variant p.Asp249Asn (D249N). We have developed a novel knock-in mouse model harboring heterozygous (Tubb4aD249N/+) and the homozygous (Tubb4aD249N/D249N) mutation that recapitulate the progressive motor dysfunction with tremor, dystonia and ataxia seen in H-ABC. Tubb4aD249N/D249N mice have myelination deficits along with dramatic decrease in mature oligodendrocytes and their progenitor cells. Additionally, a significant loss occurs in the cerebellar granular neurons and striatal neurons in Tubb4aD249N/D249N mice. In vitro studies show decreased survival and dysfunction in microtubule dynamics in neurons from Tubb4aD249N/D249N mice. Thus Tubb4aD249N/D249N mice demonstrate the complex cellular physiology of H-ABC, likely due to independent effects on oligodendrocytes, striatal neurons, and cerebellar granule cells in the context of altered microtubule dynamics, with profound neurodevelopmental deficits.

Neonatal sepsis is associated with cognitive deficit in the later life. Axonal myelination plays a pivotal role in neurotransmission and formation of learning and memory. This study aimed to explore if systemic lipopolysaccharide (LPS) injection would induce hypomyelination in the prefrontal cortex and hippocampus in developing septic neonatal rats. Sprague–Dawley rats (1-day old) were injected with LPS (1 mg/kg) intraperitoneally. By electron microscopy, axonal hypomyelination was evident in the subcortical white matter and hippocampus. The expression of myelin proteins including CNPase, MBP, PLP and MAG was downregulated in both areas of the brain at 7, 14 and 28 days after LPS injection. The frequency of MBP and PLP-positive oligodendrocyte was significantly reduced using in situ hybridization in the cerebral cortex and hippocampus at the corresponding time points after LPS injection, whereas the expression of NG2 and PDGFRα was noticeably increased. In tandem with this was reduction of Olig1 and Olig2 expressions which are involved in differentiation/maturation of OPCs. Expression of NFL, NFM, and NFH was significantly downregulated, indicating that axon development was disrupted after LPS injection. Morris Water Maze behavioral test, Open field test, Rotarod test, and Pole test were used to evaluate neurological behaviors of 28 days rats. The rats in the LPS group showed the impairment of motor coordination, balance, memory, and learning ability and represented bradykinesia and anxiety-like behavior. The present results suggest that following systemic LPS injection, differentiation/maturation of OPCs was affected which may be attributed to the inhibition of transcription factors Olig1 and Olig2 expression resulting in impairment to axonal development. It is suggested that this would ultimately lead to axonal hypomyelination in the prefrontal cortex and hippocampus, which may be associated with neurological deficits in later life. [ABSTRACT FROM AUTHOR]

• Stress-related psychiatric disorders are associated with myelin aberrations in brain. • There is a link between chronic stress in rodents and alterations of CNS myelination. • The mechanisms of impaired OPC differentiation under chronic stress are unknown yet. The myelination of axons, which is performed in brain tissues by specialized glial cells (oligodendrocytes) is crucial for correct formation of the complicated neural circuitry necessary for normal cognition, sensation, and motor function. Myelin-related anomalies are seen in many neurodegenerative diseases and in psychiatric disorders, including major depressive disorder and post-traumatic stress disorder. Chronic stress involving chronic stress early in life is believed to be a major etiological factor of neuropsychiatric disorders. Although molecular and cellular mechanisms underlying stress-induced psychopathologies are actively investigated, there is still little data about the role that is played in the development of these pathologies by myelin and oligodendrocyte impairments caused by chronic stress. In this article, after brief review of published data on myelin abnormalities in stress-related psychiatric disorders, we focus on recent cellular and molecular discoveries in various rodent models including models of chronic unpredictable stress, social isolation stress, chronic social defeat stress, and chronic immobilization stress. We also attempt to compile and analyze currently scarce data on myelin-related impairments resulting from early postnatal stress. [ABSTRACT FROM AUTHOR]

Background: Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5. Global developmental delay occurs at an early age with slow progression to dystonia, parkinsonism, and dementia due to progressive iron accumulation in the brain.Methods: We present 17 new cases and reviewed 106 reported cases of neurodegeneration with brain iron accumulation type 5. Detailed information related to developmental history and key time to event measures was collected.Results: Within this cohort, there were 19 males. Most individuals were molecularly diagnosed by whole-exome testing. Overall 10 novel variants were identified across 11 subjects. All individuals were affected by developmental delay, most prominently in verbal skills. Most individuals experienced a decline in motor and cognitive skills. Although most individuals were affected by seizures, the spectrum ranged from provoked seizures to intractable epilepsy. The imaging findings varied as well, often evolving over time. The classic iron accumulation in the globus pallidus and substantia nigra was noted in half of our cohort and was associated with older age of image acquisition, whereas myelination abnormalities were associated with younger age.Conclusions: WDR45 mutations lead to a progressive and evolving disorder whose diagnosis is often delayed. Developmental delay and seizures predominate in early childhood, followed by a progressive decline of neurological function. There is variable expressivity in the clinical phenotypes of individuals with WDR45 mutations, suggesting that this gene should be considered in the diagnostic evaluation of children with myelination abnormalities, iron deposition, developmental delay, and epilepsy depending on the age at evaluation. [ABSTRACT FROM AUTHOR]

Hypomyelinating Leukodystrophies (HLDs) are a genetically heterogeneous, clinically overlapping group of disorders with the unifying MR imaging appearance of myelin deficit in the brain. In fact, it is the MRI phenotype that typically raises the diagnostic suspicion in this single largest group of undiagnosed leukodystrophies and guides gene testing for confirmation. This article reviews the neurobiology of myelination, focussing on the complex interplay of molecular genetic pathways and presents a practical clinico-radiological diagnostic algorithm based on the neuroimaging patterns of the common hypomyelinating disorders. The authors also address the current controversies about the definition and use of the term 'hypomyelination'. • Hypomyelination is a commonly encountered MR imaging phenotype in Paediatric Neurology practice. • Many clinically and genetically diverse group of disorders share the hypomyelination phenotype on imaging. It is imperative to differentiate primary delayed myelination and demyelination from this entity. • Clinical clues, pattern recognition and recognition of other associated imaging findings can help narrow these differential diagnoses and guide the diagnostic process. • Our understanding of normal myelination and disorders affecting it is still evolving. This leads to semantic confusions and diagnostic conundrums around hypomyelinating disorders. Accurate description of imaging features and reverse phenotyping after genetic diagnosis are possible practical solutions. [ABSTRACT FROM AUTHOR]

4H leukodystrophy, also known as Pol III‐related leukodystrophy, is a rare autosomal recessive neurodegenerative disorder characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. It is caused by biallelic mutations in POLR3A, POL3RB, or POLR1C. So far, only two patients have been described with homozygosity for the common c.1568T>A (p.Val523Glu) POLR3B mutation, both of them showing a remarkably mild clinical course. Here, we report another patient with homozygosity for the same mutation, but with a more severe phenotype including ataxia, developmental delay, and intellectual disability. This information is of importance for clinicians to provide comprehensive counseling to patients with 4H leukodystrophy and their families. [ABSTRACT FROM AUTHOR]

• Differentiation of oligodendroglial-lineage was largely suppressed in embryo. • Decrease of population expansion of oligodendroglial-lineage was mild in embryo. • Oligodendroglial-lineage cells mostly died after birth. • The neonatal brains were severely hypomyelinated. • Aberrant overgrowth of blood vessels appeared, and the neuronal axons degenerated. The platelet-derived growth factor receptor-α (PDGFRα) principally mediates growth factor signals in oligodendroglial progenitors and is involved in oligodendrogenesis and myelinogenesis in the developing spinal cord. However, the role of PDGFRα in the developing forebrain remains relatively unknown. We established a conditional knockout mouse for the Pdgfra gene (N-PRα-KO) using a Nestin promoter/enhancer-driven Cre recombinase and examined forebrain development. The expression of PDGFRα was efficiently suppressed in the Olig2+ cells in N-PRα-KO mice. In these mice, Olig2+ cells were slightly decreased during embryonic periods. The decrease was particularly striking during the postnatal period. The commitment of Pdgfra -inactivated Olig2+ cells to Sox10+ oligodendroglial-lineage was largely suppressed. Surviving Olig2+ cells and Sox10+ cells were distributed widely in the N-PRα-KO mouse brain, similarly to those in control mice until the early neonatal period. After that, these cells were drastically depleted in the forebrain during the second postnatal week. The brains of N-PRα-KO mice were severely hypomyelinated, and these mice died on approximately P17 with motor disturbances. Disturbed axonal fibers and extensively aberrant vascular formations appeared in the postnatal N-PRα-KO mouse brains. After the defective PDGFRα signal in the forebrain, these phenotypes were clearly different from those in the spinal cord that showed defective populations expansion and migration of oligodendroglial lineage and premature myelination, as previously described. In contrast, areas of severe hypomyelination were common to both anatomical sites. PDGFRα was critically involved in the myelination of the forebrain and may differently regulate oligodendroglial lineage between the forebrain and spinal cord. [ABSTRACT FROM AUTHOR]

Neuroinflammation is thought to play a pivotal role in the pathogenesis of periventricular white matter (PWM) damage (PWMD) induced by neonatal sepsis. Because the complement cascade is implicated in inflammatory response, this study was carried out to determine whether C3a is involved in PWMD, and, if so, whether it would induce axonal hypomyelination. Furthermore, we explored if C3a would act through its C3a receptor (C3aR) and thence inhibit maturation of oligodendrocyte precursor cells (OPCs) via the WNT/β‐catenin signal pathway. Sprague Dawley (SD) rats aged 1 day were intraperitoneally injected with lipopolysaccharide (LPS) (1 mg/kg). C3a was upregulated in activated microglia and astrocytes in the PWM up to 7 days after LPS injection. Concomitantly, enhanced C3aR expression was observed in NG2+ oligodendrocytes (OLs). Myelin proteins including CNPase, PLP, MBP and MAG were significantly reduced in the PWM of 28‐day septic rats. The number of PLP+ and MBP+ cells was markedly decreased. By electron microscopy, myelin sheath thickness was thinner and the average g‐ratios were higher. This was coupled with an increase in number of NG2+ cells and decreased number of CC1+ cells. Olig1, Olig2 and SOX10 protein expression was significantly reduced in the PWM after LPS injection. Very strikingly, C3aRa administration for the first 7 days could reverse the above‐mentioned pathological alterations in the PWM of septic rats. When incubated with C3a, expression of MBP, CNPase, PLP, MAG, Olig1, Olig2, SOX10 and CC1 in primary cultured OPCs was significantly downregulated as opposed to increased NG2. Moreover, WNT/β‐catenin signaling pathway was found to be implicated in inhibition of OPCs maturation and differentiation induced by C3a in vitro. As a corollary, it is speculated that C3a in the PWM of septic rats is closely associated with the disorder of OPCs differentiation and maturation through WNT/β‐catenin signaling pathway, which would contribute ultimately to axonal hypomyelination. [ABSTRACT FROM AUTHOR]

Biallelic variants in POLR3A cause 4H leukodystrophy, characterized by hypomyelination in combination with cerebellar and pyramidal signs and variable non-neurological manifestations. Basal ganglia are spared in 4H leukodystrophy, and dystonia is not prominent. Three patients with variants in POLR3A, an atypical presentation with dystonia, and MR involvement of putamen and caudate nucleus (striatum) and red nucleus have previously been reported. Genetic, clinical findings and 18 MRI scans from nine patients with homozygous or compound heterozygous POLR3A variants and predominant striatal changes were retrospectively reviewed in order to characterize the striatal variant of POLR3A-associated disease. Prominent extrapyramidal involvement was the predominant clinical sign in all patients. The three youngest children were severely affected with muscle hypotonia, impaired head control, and choreic movements. Presentation of the six older patients was milder. Two brothers diagnosed with juvenile parkinsonism were homozygous for the c.1771-6C > G variant in POLR3A; the other seven either carried c.1771-6C > G (n = 1) or c.1771-7C > G (n = 7) together with another variant (missense, synonymous, or intronic). Striatal T2-hyperintensity and atrophy together with involvement of the superior cerebellar peduncles were characteristic. Additional MRI findings were involvement of dentate nuclei, hila, or peridentate white matter (3, 6, and 4/9), inferior cerebellar peduncles (6/9), red nuclei (2/9), and abnormal myelination of pyramidal and visual tracts (6/9) but no frank hypomyelination. Clinical and MRI findings in patients with a striatal variant of POLR3A-related disease are distinct from 4H leukodystrophy and associated with one of two intronic variants, c.1771-6C > G or c.1771-7C > G, in combination with another POLR3A variant. [ABSTRACT FROM AUTHOR]

Oligodendrocyte (OL) and myelin development are crucial for network integration and are associated with higher brain functions. Accumulating evidence has demonstrated structural and functional impairment of OLs and myelin in serious mental illnesses. However, whether these deficits contribute to the brain dysfunction or pathogenesis of such diseases still lacks direct evidence. In this study, we conditionally deleted Olig2 in oligodendroglial lineage cells (Olig2 cKO) and screened the behavioral changes in adult mice. We found that Olig2 ablation impaired myelin development, which further resulted in severe hypomyelination in the anterior cingulate cortex. Strikingly, Olig2 cKO mice exhibited an anxious phenotype, aberrant responses to stress, and cognitive deficits. Moreover, Olig2 cKO mice showed increased vulnerability to social avoidance under the mild stress of social isolation. Together, these results indicate that developmental deficits in OL and myelin lead to cognitive impairment and increase the risk of phenotypes reminiscent of mental illnesses. [ABSTRACT FROM AUTHOR]

Background: Microglia activation is associated with the development of hypoxic-ischemic brain injury (HIBI). Neuroinflammation suppression might be a suitable therapeutic target in hypoxic oligodendrocyte injury. This study aims to determine whether clemastine can improve hypomyelination by suppressing the activated microglia and promoting the maturation of oligodendrocyte progenitor cells (OPCs) in HIBI.Methods: A bilateral common carotid artery occlusion (BCCAO) rat model that received continuous intraperitoneal injection (1 mg/kg) for 14 days was employed to elaborate the neuroprotection effects of clemastine. Interleukin-1β (IL-1β), nod-like receptor protein 3 (NLRP3), histamine H1 receptor, and OPC differentiation levels in the corpus callosum were measured. Primary cultured OPCs and co-culture of microglia and OPCs were used to explore the link between microglia activation and hypomyelination. Data were evaluated by one-way ANOVA with Fisher's protected least significant difference test.Results: Clemastine treatment could reverse hypomyelination and restrain the upregulation of IL-1β and NLRP3 in the corpus callosum of BCCAO rats. Primary cultured OPCs treated with IL-1β showed failed maturation. However, clemastine could also reverse the OPC maturation arrest by activating the extracellular signal-regulated kinase (ERK) signaling pathway. Co-culture of microglia and OPCs with oxygen glucose deprivation treatment exhibited IL-1β and NLRP3 upregulation. Clemastine could downregulate NLRP3 and IL-1β and reverse hypomyelination by inhibiting the p38 signaling pathway.Conclusions: Clemastine could restrain microglia activation, improve axonal hypomyelination in BCCAO rats, and thus might be a viable strategy to inhibit hypomyelination in the corpus callosum of patients with HIBI. [ABSTRACT FROM AUTHOR]

Background and purpose: Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi‐allelic mutations in NKX6‐2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. Methods: Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6‐2 mutations in a multicentre setting is described. Then, all reported NKX6‐2 mutations and those identified in this study were combined and an in‐depth analysis of NKX6‐2‐related disease spectrum was provided. Results: Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6‐2 were identified, evidencing a high NKX6‐2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6‐2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. Conclusions: NKX6‐2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6‐2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels. [ABSTRACT FROM AUTHOR]

• VEGF + bFGF nanofiber membrane (NFM) treatment inhibited neuronal apoptosis and neuronal loss. • VEGF + bFGF NFM treatment attenuated microglial activation and blocked the launch of NLRP3/caspase-1/IL-1β pathway. • VEGF + bFGF NFM treatment prevented disruption to the pre/postsynaptic membranes and loss of myelin sheath. • Oligodendrogenesis, neurogenesis and PI3K/AKT/mTOR pathway were involved in the treatment of VEGF + bFGF NFM against CCH-induced neuronal injury and hypomyelination. Currently, there are no effective therapeutic targets for the treatment of chronic cerebral hypoperfusion(CCH)-induced cerebral ischemic injury. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are discovered as the inducers of neurogenesis and angiogenesis. We previously made a nanofiber membrane (NFM), maintaining a long-term release of VEGF and bFGF up to 35 days, which might make VEGF and bFGF NFM as the potential protective agents against cerebral ischemic insult. In this study, the effects of VEGF and bFGF delivered by NFM into brain were investigated as well as their underlying mechanismsin a rat model of CCH. VEGF + bFGF NFM application increased the expressions of tight junction proteins, maintained BBB integrity, and alleviated vasogenic cerebral edema. Furthermore, VEGF + bFGF NFM sticking enhanced angiogenesis and elevated CBF. Besides, VEGF + bFGF NFM treatment inhibited neuronal apoptosis and decreased neuronal loss. Moreover, roofing of VEGF + bFGF NFM attenuated microglial activation and blocked the launch of NLRP3/caspase-1/IL-1β pathway. In addition, VEGF + bFGF NFM administration prevented disruption to the pre/postsynaptic membranes and loss of myelin sheath, relieving synaptic injury and demyelination. Oligodendrogenesis, neurogenesis and PI3K/AKT/mTOR pathway were involved in the treatment of VEGF + bFGF NFM against CCH-induced neuronal injury and hypomyelination. These findings supported that VEGF + bFGF NFM application constitutes a neuroprotective strategy for the treatment of CCH, which may be worth further clinical translational research as a novel neuroprotective approach, benifiting indirect surgical revascularization. [ABSTRACT FROM AUTHOR]

Abstract Recessive mutations in the ubiquitously expressed POLR3A gene cause one of the most frequent forms of childhood-onset hypomyelinating leukodystrophy (HLD): POLR3-HLD. POLR3A encodes the largest subunit of RNA Polymerase III (Pol III), which is responsible for the transcription of transfer RNAs (tRNAs) and a large array of other small non-coding RNAs. In order to study the central nervous system pathophysiology of the disease, we introduced the French Canadian founder Polr3a mutation c.2015G > A (p.G672E) in mice, generating homozygous knock-in (KI/KI) as well as compound heterozygous mice for one Polr3a KI and one null allele (KI/KO). Both KI/KI and KI/KO mice are viable and are able to reproduce. To establish if they manifest a motor phenotype, WT, KI/KI and KI/KO mice were submitted to a battery of behavioral tests over one year. The KI/KI and KI/KO mice have overall normal balance, muscle strength and general locomotion. Cerebral and cerebellar Luxol Fast Blue staining and measurement of levels of myelin proteins showed no significant differences between the three groups, suggesting that myelination is not overtly impaired in Polr3a KI/KI and KI/KO mice. Finally, expression levels of several Pol III transcripts in the brain showed no statistically significant differences. We conclude that the first transgenic mice with a leukodystrophy-causing Polr3a mutation do not recapitulate the childhood-onset HLD observed in the majority of human patients with POLR3A mutations, and provide essential information to guide selection of Polr3a mutations for developing future mouse models of the disease.

Abstract Introduction RNA polymerase III (Pol III)‐related leukodystrophies are a group of autosomal recessive neurodegenerative disorders caused by mutations in POLR3A and POLR3B. Recently a recessive mutation in POLR1C causative of Pol III‐related leukodystrophies was identified. Methods We report the case of a Tunisian girl of 14 years of age who was referred to our department for evaluation of progressive ataxia that began at the age of 5. Genetic diagnosis was performed by NGS and Sanger analysis. In silico predictions were performed using SIFT, PolyPhen‐2, and Mutation Taster. Results Neurological examination showed cerebellar and tetrapyramidal syndrome, mixed movement disorders with generalized dystonia and severe myoclonus leading to death at 25 years. Brain MRI scans showed diffuse hypomyelination associated with cerebellar atrophy. It also showed bilateral T2 hypointensity of the ventrolateral thalamus, part of the posterior limb of the internal capsule, the substantia nigra and the subthalamic nucleus. Next generation sequencing leukodystrophy panel including POLR3A and POLR3B was negative. Sanger sequencing of the coding regions of POLR1C revealed a novel homozygous mutation. Conclusion The clinical and imaging findings of patients with POLR1C hypomyelinating leukodystrophy are reviewed. Interestingly, severe myoclonic dystonia and T2 hypointensity of the substantia nigra and the subthalamic nucleus are not reported yet and could be helpful for the diagnosis of POLR1C hypomyelinating leukodystrophy.

Dynamin-1 (DNM1) is involved in synaptic vesicle recycling, and DNM1 mutations can lead to developmental and epileptic encephalopathy. The neuroimaging of DNM1 encephalopathy has not been reported in detail. We describe a severe phenotype of DNM1 encephalopathy showing characteristic neuroradiological features. In addition, we reviewed previously reported cases who have DNM1 pathogenic variants with white matter abnormalities. Our case presented drug-resistant seizures from 1 month of age and epileptic spasms at 2 years of age. Brain MRI showed no progression of myelination, progression of diffuse cerebral atrophy, and a thin corpus callosum. Proton magnetic resonance spectroscopy showed a decreased N-acetylaspartate peak and diffusion tensor imaging presented with less pyramidal decussation. Whole-exome sequencing revealed a recurrent de novo heterozygous variant of DNM1. So far, more than 50 cases of DNM1 encephalopathy have been reported. Among these patients, delayed myelination occurred in two cases of GTPase-domain DNM1 encephalopathy and in six cases of middle-domain DNM1 encephalopathy. The neuroimaging findings in this case suggest inadequate axonal development. DNM1 is involved in the release of synaptic vesicles with the inhibitory transmitter GABA, suggesting that GABAergic neuron dysfunction is the mechanism of refractory epilepsy in DNM1 encephalopathy. GABA-mediated signaling mechanisms play important roles in axonal development and GABAergic neuron dysfunction may be cause of white matter abnormalities in DNM1 encephalopathy., (© 2023 International League Against Epilepsy.)

Hypomyelination is defined by the evidence of an unchanged pattern of deficient myelination on two MRIs performed at least 6 months apart in a child older than 1 year. When the temporal criteria are not fulfilled, and the follow-up MRI shows a progression of the myelination even if still not adequate for age, hypomyelination is excluded and the pattern is instead consistent with delayed myelination. This can be mild and nonspecific in some cases, while in other cases there is a severe delay that in the first disease stages could be difficult to differentiate from hypomyelination. In hypomyelinating leukodystrophies, hypomyelination is due to a primary impairment of myelin deposition, such as in Pelizaeus Merzabcher disease. Conversely, myelin lack is secondary, often to primary neuronal disorders, in delayed myelination and some condition with hypomyelination. Overall, the group of inherited white matter disorders with abnormal myelination has expanded significantly during the past 20 years. Many of these disorders have only recently been described, for many of them only a few patients have been reported and this contributes to make challenging the diagnostic process and the interpretation of Next Generation Sequencing results. In this chapter, we review the clinical and radiologic features of rare and lesser known forms of hypomyelination and delayed myelination not mentioned in other chapters of this handbook., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Inborn errors of metabolism (IEMs) are traditionally the domain of pediatricians and internists for metabolic diseases. In general, neurologists only become involved when these disorders are complicated by neurologic symptoms such as seizures, developmental delay, or motor problems. However, in recent years and mainly due to the successes of next-generation sequencing, the number of IEMs primarily presenting with neurologic symptoms and not detected by classic biochemical testing has grown significantly. This in particular relates to disorders in the biosynthesis of amino acids. Therefore, I will start by discussing defects in the synthesis pathways of the amino acids serine, glutamine, proline, and asparagine. In these disorders, the amino acid can be low in body fluids with biochemical testing, but more frequently are completely normal and although are in different metabolic pathways, they share many clinical features such as hypomyelination and white matter abnormalities. Next, I will discuss classic amino acid disorders and organic acid disorders due to defects in breakdown pathways characterized by elevations of key metabolites in body fluids and associated with neurologic abnormalities and white matter changes on MRI., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

The hallmark neuropathologic feature of all leukodystrophies is depletion or alteration of the white matter of the central nervous system; however increasing genetic discoveries highlight the genetic heterogeneity of white matter disorders. These discoveries have significantly helped to advance the understanding of the complexity of molecular mechanisms involved in the biogenesis and maintenance of healthy white matter. Accordingly, genetic discoveries and functional studies have enabled us to firmly establish that multiple distinct structural defects can lead to white matter pathology. Leukodystrophies can develop not only due to defects in proteins essential for myelin biogenesis and maintenance or oligodendrocyte function, but also due to mutations encoding myriad of proteins involved in the function of neurons, astrocytes, microglial cells as well as blood vessels. To a variable extent, some leukodystrophies also show gray matter, peripheral nervous system, or multisystem involvement. Depending on the genetic defect and its role in the formation or maintenance of the white matter, leukodystrophies can present either in early childhood or adulthood. In this chapter, the classification of leukodystrophies will be discussed from the cellular defect point of view, followed by a description of known neuropathologic alterations for all leukodystrophies., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Ataxia in children is a common clinical sign of numerous neurological disorders consisting of impaired coordination of voluntary muscle movement. Its most common form, cerebellar ataxia, describes a heterogeneous array of neurologic conditions with uncountable causes broadly divided as acquired or genetic. Numerous genetic disorders are associated with chronic progressive ataxia, which complicates clinical management, particularly on the diagnostic stage. Advances in omics technologies enable improvements in clinical practice and research, so we proposed a multi-omics approach to aid in the genetic diagnosis and molecular elucidation of an undiagnosed infantile condition of chronic progressive cerebellar ataxia. Using whole-exome sequencing, RNA-seq, and untargeted metabolomics, we identified three clinically relevant mutations (rs141471029, rs191582628 and rs398124292) and an altered metabolic profile in our patient. Two POLR1C diagnostic variants already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy was achieved. A mutation on the MMACHC gene, known to be associated with methylmalonic aciduria and homocystinuria cblC type, was also found. Additionally, preliminary metabolome analysis revealed alterations in our patient’s amino acid, fatty acid and carbohydrate metabolism. Our findings provided a definitive genetic diagnosis reinforcing the association between POLR1C mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics approaches to the disease.

The effect of perinatal asphyxia (PA) on oligodendrocyte (OL), neuroinflammation, and cell viability was evaluated in telencephalon of rats at postnatal day (P)1, 7, and 14, a period characterized by a spur of neuronal networking, evaluating the effect of mesenchymal stem cell (MSCs)-treatment. The issue was investigated with a rat model of global PA, mimicking a clinical risk occurring under labor. PA was induced by immersing fetus-containing uterine horns into a water bath for 21 min (AS), using sibling-caesarean-delivered fetuses (CS) as controls. Two hours after delivery, AS and CS neonates were injected with either 5 μL of vehicle (10% plasma) or 5 × 104 MSCs into the lateral ventricle. Samples were assayed for myelin-basic protein (MBP) levels; Olig-1/Olig-2 transcriptional factors; Gglial phenotype; neuroinflammation, and delayed cell death. The main effects were observed at P7, including: (i) A decrease of MBP-immunoreactivity in external capsule, corpus callosum, cingulum, but not in fimbriae of hippocampus; (ii) an increase of Olig-1-mRNA levels; (iii) an increase of IL-6-mRNA, but not in protein levels; (iv) an increase in cell death, including OLs; and (v) MSCs treatment prevented the effect of PA on myelination, OLs number, and cell death. The present findings show that PA induces regional- and developmental-dependent changes on myelination and OLs maturation. Neonatal MSCs treatment improves survival of mature OLs and myelination in telencephalic white matter.