RESUMO
Myelination of axons in the nervous system of vertebrates enables fast, saltatory impulse propagation, one of the best-understood concepts in neurophysiology. However, it took a long while to recognize the mechanistic complexity both of myelination by oligodendrocytes and Schwann cells and of their cellular interactions. In this review, we highlight recent advances in our understanding of myelin biogenesis, its lifelong plasticity, and the reciprocal interactions of myelinating glia with the axons they ensheath. In the central nervous system, myelination is also stimulated by axonal activity and astrocytes, whereas myelin clearance involves microglia/macrophages. Once myelinated, the long-term integrity of axons depends on glial supply of metabolites and neurotrophic factors. The relevance of this axoglial symbiosis is illustrated in normal brain aging and human myelin diseases, which can be studied in corresponding mouse models. Thus, myelinating cells serve a key role in preserving the connectivity and functions of a healthy nervous system.
Assuntos
Bainha de Mielina/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Axônios/fisiologia , Sistema Nervoso Central/metabolismo , Doença de Charcot-Marie-Tooth/metabolismo , Doença de Charcot-Marie-Tooth/patologia , Citoesqueleto/ultraestrutura , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Glucose/metabolismo , Humanos , Inflamação , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Camundongos , Microscopia Eletrônica , Proteínas da Mielina/fisiologia , Plasticidade Neuronal , Oligodendroglia/fisiologia , Sistema Nervoso Periférico/metabolismo , Células de Schwann/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
RNASET2-deficient leukodystrophy is a rare infantile white matter disorder mimicking a viral infection and resulting in severe psychomotor impairments. Despite its severity, there is little understanding of cellular mechanisms of pathogenesis and no treatments. Recent research using the rnaset2 mutant zebrafish model has suggested that microglia may be the drivers of the neuropathology, due to their failure to digest apoptotic debris during neurodevelopment. Therefore, we developed a strategy for microglial replacement through transplantation of adult whole kidney marrow-derived macrophages into embryonic hosts. Using live imaging, we revealed that transplant-derived macrophages can engraft within host brains and express microglia-specific markers, suggesting the adoption of a microglial phenotype. Tissue-clearing strategies revealed the persistence of transplanted cells in host brains beyond embryonic stages. We demonstrated that transplanted cells clear apoptotic cells within the brain, as well as rescue overactivation of the antiviral response otherwise seen in mutant larvae. RNA sequencing at the point of peak transplant-derived cell engraftment confirms that transplantation can reduce the brain-wide immune response and particularly, the antiviral response, in rnaset2-deficient brains. Crucially, this reduction in neuroinflammation resulted in behavioral rescue-restoring rnaset2 mutant motor activity to wild-type (WT) levels in embryonic and juvenile stages. Together, these findings demonstrate the role of microglia as the cellular drivers of neuropathology in rnaset2 mutants and that macrophage transplantation is a viable strategy for microglial replacement in the zebrafish. Therefore, microglia-targeted interventions may have therapeutic benefits in RNASET2-deficient leukodystrophy.
Assuntos
Encéfalo , Macrófagos , Microglia , Animais , Encéfalo/patologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Leucoencefalopatias/metabolismo , Macrófagos/metabolismo , Microglia/metabolismo , Microglia/patologia , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/metabolismoRESUMO
Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (pGlu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout, with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein, which expanded tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborisation were reduced in Csf1rE631K/+ mice, as in patients with ALSP. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/- mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that heterozygous disease-associated CSF1R mutations compromise CSF1R signalling. We speculate that leukoencephalopathy associated with dominant human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.
Assuntos
Leucoencefalopatias , Doenças Neurodegenerativas , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos , Animais , Humanos , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Camundongos , Mutação/genética , Doenças Neurodegenerativas/patologia , Neuroglia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genéticaRESUMO
Leukoencephalopathy with vanishing white matter (VWM) is a progressive incurable white matter disease that most commonly occurs in childhood and presents with ataxia, spasticity, neurological degeneration, seizures, and premature death. A distinctive feature is episodes of rapid neurological deterioration provoked by stressors such as infection, seizures, or trauma. VWM is caused by autosomal recessive mutations in one of five genes that encode the eukaryotic initiation factor 2B complex, which is necessary for protein translation and regulation of the integrated stress response. The majority of mutations are in EIF2B5. Astrocytic dysfunction is central to pathophysiology, thereby constituting a potential therapeutic target. Herein we characterize two VWM murine models and investigate astrocyte-targeted adeno-associated virus serotype 9 (AAV9)-mediated EIF2B5 gene supplementation therapy as a therapeutic option for VWM. Our results demonstrate significant rescue in body weight, motor function, gait normalization, life extension, and finally, evidence that gene supplementation attenuates demyelination. Last, the greatest rescue results from a vector using a modified glial fibrillary acidic protein (GFAP) promoter-AAV9-gfaABC(1)D-EIF2B5-thereby supporting that astrocytic targeting is critical for disease correction. In conclusion, we demonstrate safety and early efficacy through treatment with a translatable astrocyte-targeted gene supplementation therapy for a disease that has no cure.
Assuntos
Astrócitos , Dependovirus , Modelos Animais de Doenças , Fator de Iniciação 2B em Eucariotos , Terapia Genética , Vetores Genéticos , Leucoencefalopatias , Animais , Dependovirus/genética , Camundongos , Leucoencefalopatias/terapia , Leucoencefalopatias/genética , Leucoencefalopatias/etiologia , Terapia Genética/métodos , Vetores Genéticos/genética , Vetores Genéticos/administração & dosagem , Astrócitos/metabolismo , Astrócitos/patologia , Fator de Iniciação 2B em Eucariotos/genética , Fator de Iniciação 2B em Eucariotos/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Proteína Glial Fibrilar Ácida/genética , HumanosRESUMO
Vanishing white matter (VWM) is a fatal leukodystrophy caused by recessive mutations in subunits of the eukaryotic translation initiation factor 2B. Currently, there are no effective therapies for VWM. Here, we assessed the potential of adenine base editing to correct human pathogenic VWM variants in mouse models. Using adeno-associated viral vectors, we delivered intein-split adenine base editors into the cerebral ventricles of newborn VWM mice, resulting in 45.9% ± 5.9% correction of the Eif2b5R191H variant in the cortex. Treatment slightly increased mature astrocyte populations and partially recovered the integrated stress response (ISR) in female VWM animals. This led to notable improvements in bodyweight and grip strength in females; however, locomotor disabilities were not rescued. Further molecular analyses suggest that more precise editing (i.e., lower rates of bystander editing) as well as more efficient delivery of the base editors to deep brain regions and oligodendrocytes would have been required for a broader phenotypic rescue. Our study emphasizes the potential, but also identifies limitations, of current in vivo base-editing approaches for the treatment of VWM or other leukodystrophies.
Assuntos
Dependovirus , Modelos Animais de Doenças , Fator de Iniciação 2B em Eucariotos , Edição de Genes , Leucoencefalopatias , Fenótipo , Animais , Camundongos , Fator de Iniciação 2B em Eucariotos/genética , Fator de Iniciação 2B em Eucariotos/metabolismo , Leucoencefalopatias/genética , Leucoencefalopatias/terapia , Leucoencefalopatias/patologia , Dependovirus/genética , Humanos , Vetores Genéticos/genética , Vetores Genéticos/administração & dosagem , Feminino , Mutação , Terapia Genética/métodos , Substância Branca/patologia , Substância Branca/metabolismo , Astrócitos/metabolismoRESUMO
Vanishing white matter (VWM) is a leukodystrophy caused by biallelic pathogenic variants in eukaryotic translation initiation factor 2B. To date, it remains unclear which factors contribute to VWM pathogenesis. Here, we investigated the basis of VWM pathogenesis using the 2b5ho mouse model. We first mapped the temporal proteome in the cerebellum, corpus callosum, cortex, and brainstem of 2b5ho and wild-type (WT) mice. Protein changes observed in 2b5ho mice were then cross-referenced with published proteomic datasets from VWM patient brain tissue to define alterations relevant to the human disease. By comparing 2b5ho mice with their region- and age-matched WT counterparts, we showed that the proteome in the cerebellum and cortex of 2b5ho mice was already dysregulated prior to pathology development, whereas proteome changes in the corpus callosum only occurred after pathology onset. Remarkably, protein changes in the brainstem were transient, indicating that a compensatory mechanism might occur in this region. Importantly, 2b5ho mouse brain proteome changes reflect features well-known in VWM. Comparison of the 2b5ho mouse and VWM patient brain proteomes revealed shared changes. These could represent changes that contribute to the disease or even drive its progression in patients. Taken together, we show that the 2b5ho mouse brain proteome is affected in a region- and time-dependent manner. We found that the 2b5ho mouse model partly replicates the human disease at the protein level, providing a resource to study aspects of VWM pathogenesis by highlighting alterations from early to late disease stages, and those that possibly drive disease progression.
Assuntos
Modelos Animais de Doenças , Leucoencefalopatias , Proteoma , Proteômica , Substância Branca , Animais , Camundongos , Humanos , Proteoma/metabolismo , Leucoencefalopatias/metabolismo , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Substância Branca/metabolismo , Substância Branca/patologia , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Fator de Iniciação 2B em Eucariotos/metabolismo , Fator de Iniciação 2B em Eucariotos/genética , Encéfalo/metabolismo , Encéfalo/patologia , Camundongos Endogâmicos C57BL , Cerebelo/metabolismo , Cerebelo/patologiaRESUMO
BACKGROUND: Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far. METHODS: As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals. RESULTS: The core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the ZNF148 gene. Heterozygous deletion including the entire ZNF148 gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families. CONCLUSION: The GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term 'GDACCF syndrome' with 'ZNF148-related neurodevelopmental disorder'.
Assuntos
Deficiência Intelectual , Leucoencefalopatias , Humanos , Criança , Corpo Caloso , Fácies , Mutação/genética , Fenótipo , Genótipo , Deficiência Intelectual/genética , Deficiência Intelectual/diagnóstico , Síndrome , Deficiências do Desenvolvimento/patologia , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genéticaRESUMO
White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.
Assuntos
Transtornos Cerebrovasculares , Transtornos Cognitivos , Disfunção Cognitiva , Leucoencefalopatias , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos , Substância Branca , Animais , Camundongos , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/patologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Leucoencefalopatias/genética , Leucoencefalopatias/metabolismo , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Receptores de Fator Estimulador de Colônias/metabolismo , Substância Branca/patologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismoRESUMO
ABHD16A (abhydrolase domain-containing protein 16A, phospholipase) encodes the major phosphatidylserine (PS) lipase in the brain. PS lipase synthesizes lysophosphatidylserine, an important signaling lipid that functions in the mammalian central nervous system. ABHD16A has not yet been associated with a human disease. In this report, we present a cohort of 11 affected individuals from six unrelated families with a complicated form of hereditary spastic paraplegia (HSP) who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls. Our findings add ABHD16A to the growing list of lipid genes in which dysregulation can cause complicated forms of HSP and begin to describe the molecular etiology of this condition.
Assuntos
Paralisia Cerebral/patologia , Deficiência Intelectual/patologia , Leucoencefalopatias/patologia , Monoacilglicerol Lipases/genética , Mutação , Paraplegia Espástica Hereditária/patologia , Adolescente , Adulto , Paralisia Cerebral/etiologia , Paralisia Cerebral/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Deficiência Intelectual/etiologia , Deficiência Intelectual/metabolismo , Leucoencefalopatias/etiologia , Leucoencefalopatias/metabolismo , Masculino , Monoacilglicerol Lipases/deficiência , Linhagem , Fenótipo , Paraplegia Espástica Hereditária/etiologia , Paraplegia Espástica Hereditária/metabolismo , Adulto JovemRESUMO
Inherited leukodystrophies are genetic disorders characterized by abnormal white matter in the central nervous system. Although individually rare, there are more than 400 distinct types of leukodystrophies with a cumulative incidence of 1 in 4500 live births. The pathophysiology of most leukodystrophies is poorly understood, there are treatments for only a few, and there is significant morbidity and mortality, suggesting a critical need for improvements in this field. A variety of animal, cell, and induced pluripotent stem cell-derived models have been developed for leukodystrophies, but with significant limitations in all models. Many leukodystrophies lack animal models, and extant models often show no or mixed recapitulation of key phenotypes. Zebrafish (Danio rerio) have become increasingly used as disease models for studying leukodystrophies due to their early onset of disease phenotypes and conservation of molecular and neurobiological mechanisms. Here, we focus on reviewing new zebrafish disease models for leukodystrophy or models with recent progress. This includes discussion of leukodystrophy with vanishing white matter disease, X-linked adrenoleukodystrophy, Zellweger spectrum disorders and peroxisomal disorders, PSAP deficiency, metachromatic leukodystrophy, Krabbe disease, hypomyelinating leukodystrophy-8/4H leukodystrophy, Aicardi-Goutières syndrome, RNASET2-deficient cystic leukoencephalopathy, hereditary diffuse leukoencephalopathy with spheroids-1 (CSF1R-related leukoencephalopathy), and ultra-rare leukodystrophies. Zebrafish models offer important potentials for the leukodystrophy field, including testing of new variants in known genes; establishing causation of newly discovered genes; and early lead compound identification for therapies. There are also unrealized opportunities to use humanized zebrafish models which have been sparsely explored.
Assuntos
Adrenoleucodistrofia , Leucodistrofia de Células Globoides , Leucodistrofia Metacromática , Leucoencefalopatias , Animais , Peixe-Zebra/genética , Leucodistrofia Metacromática/genética , Leucodistrofia Metacromática/terapia , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/terapia , Adrenoleucodistrofia/genética , Leucoencefalopatias/terapiaRESUMO
BACKGROUND AIMS: White matter diseases are commonly associated with microglial activation and neuroinflammation. Mesenchymal stromal cells (MSCs) have immunomodulatory properties and thus have the potential to be developed as cell therapy for white matter disease. MSCs interact with resident macrophages to alter the trajectory of inflammation; however, the impact MSCs have on central nervous system macrophages and the effect this has on the progression of white matter disease are unclear. METHODS: In this study, we utilized numerous assays of varying complexity to model different aspects of white matter disease. These assays ranged from an in vivo spinal cord acute demyelination model to a simple microglial cell line activation assay. Our goal was to investigate the influence of human umbilical cord tissue MSCs on the activation of microglia. RESULTS: MSCs reduced the production of tumor necrosis factor (TNF) by microglia and decreased demyelinated lesions in the spinal cord after acute focal injury. To determine if MSCs could directly suppress the activation of microglia and to develop an efficient potency assay, we utilized isolated primary microglia from mouse brains and the Immortalized MicroGlial Cell Line (IMG). MSCs suppressed the activation of microglia and the release of TNF after stimulation with lipopolysaccharide, a toll-like receptor agonist. CONCLUSIONS: In this study, we demonstrated that MSCs altered the immune response after acute injury in the spinal cord. In numerous assays, MSCs suppressed activation of microglia and release of the pro-inflammatory cytokine TNF. Of these assays, IMG could be standardized and used as an effective potency assay to determine the efficacy of MSCs for treating white matter disease or other neuroinflammatory conditions associated with microglial activation.
Assuntos
Leucoencefalopatias , Células-Tronco Mesenquimais , Camundongos , Animais , Humanos , Microglia/metabolismo , Macrófagos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Leucoencefalopatias/metabolismoRESUMO
Monoallelic pathogenic HMBS variants are a well-established cause of acute intermittent porphyria (AIP), whereas biallelic pathogenic variants may cause HMBS-related leukoencephalopathy which remains a poorly characterized disorder. We describe an 8-year-old girl with hypotonia, hearing impairment, horizontal nystagmus, bilateral strabismus, impaired visual acuity, and optic nerve atrophy. She had no epilepsy but sleep electroencephalogram showed paroxysmal changes in the right hemisphere with secondary generalizations. Brain magnetic resonance imaging was unremarkable apart from a few small white matter hyperintensities. Exome sequencing (ES) initially prioritized a SCN3A c.3822G>A de novo variant whose sole causative role was eventually questioned as not fully compatible with symptoms. ES reanalysis revealed a homozygous c.674G>A HMBS variant. In the monoallelic form this variant is a known cause of AIP, whereas in trans with another HMBS pathogenic variant it was associated with the HMBS-related leukoencephalopathy in four individuals. Despite lack of signs/symptoms of porphyria, literature analysis suggested that HMBS c.674G>A likely contributed to the disease either as the sole cause or together with SCN3A c.3822G>A as a part of blended phenotype. Our report adds to the relatively small number of described cases of HMBS-related leukoencephalopathy and emphasizes that autosomal recessive form of HMBS disease can be present in the absence of porphyria symptoms.
Assuntos
Transtornos do Neurodesenvolvimento , Fenótipo , Criança , Feminino , Humanos , Sequenciamento do Exoma , Genes Recessivos , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Leucoencefalopatias/diagnóstico por imagem , Imageamento por Ressonância Magnética , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Linhagem , Hidroximetilbilano Sintase/genética , Hidroximetilbilano Sintase/metabolismoRESUMO
Metabolic pathways are known to generate byproducts-some of which have no clear metabolic function and some of which are toxic. Nicotinamide adenine dinucleotide phosphate hydrate (NAD(P)HX) is a toxic metabolite that is produced by stressors such as a fever, infection, or physical stress. Nicotinamide adenine dinucleotide phosphate hydrate dehydratase (NAXD) and nicotinamide adenine dinucleotide phosphate hydrate epimerase (NAXE) are part of the nicotinamide repair system that function to break down this toxic metabolite. Deficiency of NAXD and NAXE interrupts the critical intracellular repair of NAD(P)HX and allows for its accumulation. Clinically, deficiency of NAXE manifests as progressive, early onset encephalopathy with brain edema and/or leukoencephalopathy (PEBEL) 1, while deficiency of NAXD manifests as PEBEL2. In this report, we describe a case of probable PEBEL2 in a patient with a variant of unknown significance (c.362C>T, p.121L) in the NAXD gene who presented after routine immunizations with significant skin findings and in the absence of fevers.
Assuntos
Encefalopatias , Imunização , Humanos , Imunização/efeitos adversos , Leucoencefalopatias/etiologia , Racemases e Epimerases/deficiência , Racemases e Epimerases/genética , Hidroliases/deficiência , Hidroliases/genética , Encefalopatias/etiologiaRESUMO
It is very crucial to investigate key molecules that are involved in myelination to gain an understanding of brain development and injury. We have reported for the first time that pathogenic variants p.R477H and p.P505S in KARS, which encodes lysyl-tRNA synthetase (LysRS), cause leukoencephalopathy with progressive cognitive impairment in humans. The role and action mechanisms of KARS in brain myelination during development are unknown. Here, we first generated Kars knock-in mouse models through the CRISPR-Cas9 system. Kars knock-in mice displayed significant cognitive deficits. These mice also showed significantly reduced myelin density and content, as well as significantly decreased myelin thickness during development. In addition, Kars mutations significantly induced oligodendrocyte differentiation arrest and reduction in the brain white matter of mice. Mechanically, oligodendrocytes' significantly imbalanced expression of differentiation regulators and increased capase-3-mediated apoptosis were observed in the brain white matter of Kars knock-in mice. Furthermore, Kars mutations significantly reduced the aminoacylation and steady-state level of mitochondrial tRNALys and decreased the protein expression of subunits of oxidative phosphorylation complexes in the brain white matter. Kars knock-in mice showed decreased activity of complex IV and significantly reduced ATP production and increased reactive oxygen species in the brain white matter. Significantly increased percentages of abnormal mitochondria and mitochondrion area were observed in the oligodendrocytes of Kars knock-in mouse brain. Finally, melatonin (a mitochondrion protectant) significantly attenuated mitochondrion and oligodendrocyte deficiency in the brain white matter of KarsR504H/P532S mice. The mice treated with melatonin also showed significantly restored myelination and cognitive function. Our study first establishes Kars knock-in mammal models of leukoencephalopathy and cognitive impairment and indicates important roles of KARS in the regulation of mitochondria, oligodendrocyte differentiation and survival, and myelination during brain development and application prospects of melatonin in KARS (or even aaRS)-related diseases.
Assuntos
Lisina-tRNA Ligase , Melatonina , Bainha de Mielina , Oligodendroglia , Animais , Camundongos , Aminoacil-tRNA Sintetases/genética , Aminoacil-tRNA Sintetases/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Técnicas de Introdução de Genes , Leucoencefalopatias/genética , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Melatonina/metabolismo , Mutação , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Lisina-tRNA Ligase/genéticaRESUMO
BACKGROUND: Leukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive disorder affecting the white matter of the brain. It typically manifests during childhood, with clinical features including sudden and severe neurological deterioration triggered by stressors such as febrile illness, minor head trauma, or stressful events. Adult-onset cases of VWM are exceptionally uncommon. CASE PRESENTATION: In this case, we present an adult patient who exhibited late-onset progressive VWM characterized by ataxia, postural instability, cognitive impairment, and emotional disturbances. Comprehensive screening for endocrine, metabolic, tumor, and immunologic disorders yielded normal or negative results. Brain imaging revealed diffuse and confluent hyperintensity in the white matter on T2-weighted images, along with periventricular cavitations. Genetic testing confirmed the diagnosis of VWM, identifying two heterozygous variants in the eukaryotic translation initiation factor 2B subunit γ (EIF2B3) gene: a pathogenic variant, c.1037 T > C (p.I346T), and a variant of undetermined significance, c.22A > T (p.M8L). Upon a 2-year follow-up, the patient's symptoms deteriorated rapidly following a COVID-19 infection. CONCLUSIONS: In conclusion, we have presented a case of classical adult-onset VWM. Since there are no cures or definitive treatments for the disease, it's extremely important to focus on early diagnosis and the prevention of stressors to avoid acute deterioration.
Assuntos
Fator de Iniciação 2B em Eucariotos , Leucoencefalopatias , Humanos , Fator de Iniciação 2B em Eucariotos/genética , Leucoencefalopatias/genética , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Masculino , Feminino , COVID-19/genética , COVID-19/complicações , Heterozigoto , Pessoa de Meia-IdadeRESUMO
Genetic leukoencephalopathies (gLEs) are a highly heterogeneous group of rare genetic disorders. The spectrum of gLEs varies among patients of different ages. Distinct from the relatively more abundant studies of gLEs in children, only a few studies that explore the spectrum of adult gLEs have been published, and it should be noted that the majority of these excluded certain gLEs. Thus, to date, no large study has been designed and conducted to characterize the genetic and phenotypic spectra of gLEs in adult patients. We recruited a consecutive series of 309 adult patients clinically suspected of gLEs from Beijing Tiantan Hospital between January 2014 and December 2021. Whole-exome sequencing, mitochondrial DNA sequencing and repeat analysis of NOTCH2NLC, FMR1, DMPK and ZNF9 were performed for patients. We describe the genetic and phenotypic spectra of the set of patients with a genetically confirmed diagnosis and summarize their clinical and radiological characteristics. A total of 201 patients (65%) were genetically diagnosed, while 108 patients (35%) remained undiagnosed. The most frequent diseases were leukoencephalopathies related to NOTCH3 (25%), NOTCH2NLC (19%), ABCD1 (9%), CSF1R (7%) and HTRA1 (5%). Based on a previously proposed pathological classification, the gLEs in our cohort were divided into leukovasculopathies (35%), leuko-axonopathies (31%), myelin disorders (21%), microgliopathies (7%) and astrocytopathies (6%). Patients with NOTCH3 mutations accounted for 70% of the leukovasculopathies, followed by HTRA1 (13%) and COL4A1/2 (9%). The leuko-axonopathies contained the richest variety of associated genes, of which NOTCH2NLC comprised 62%. Among myelin disorders, demyelinating leukoencephalopathies (61%)-mainly adrenoleukodystrophy and Krabbe disease-accounted for the majority, while hypomyelinating leukoencephalopathies (2%) were rare. CSF1R was the only mutated gene detected in microgliopathy patients. Leukoencephalopathy with vanishing white matter disease due to mutations in EIF2B2-5 accounted for half of the astrocytopathies. We characterized the genetic and phenotypic spectra of adult gLEs in a large Chinese cohort. The most frequently mutated genes were NOTCH3, NOTCH2NLC, ABCD1, CSF1R and HTRA1.
Assuntos
Leucoencefalopatias , Criança , Humanos , Adulto , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Mutação/genética , Bainha de Mielina/patologia , Análise de Sequência de DNA , Receptor Notch3/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Proteína do X Frágil da Deficiência IntelectualRESUMO
We report on a patient with delayed post-hypoxic leukoencephalopathy (DPHL) who showed akinetic mutism and gait disturbance, neural injuries that were demonstrated on diffusion tensor tractography (DTT). A patient was exposed to carbon monoxide (CO) and rapidly recovered; however, two weeks after onset, he began to show cognitive impairment and gait disturbance. At six weeks after CO exposure, he showed akinetic mutism and gait inability. DTT at 6-weeks post-exposure showed discontinuations in neural connectivities of the caudate nucleus to the medial prefrontal and orbitofrontal cortex in both hemispheres. In addition, the corticoreticulospinal tract revealed severe thinning in both hemispheres.
Assuntos
Afasia Acinética , Imagem de Tensor de Difusão , Transtornos Neurológicos da Marcha , Leucoencefalopatias , Humanos , Afasia Acinética/etiologia , Afasia Acinética/fisiopatologia , Masculino , Leucoencefalopatias/etiologia , Leucoencefalopatias/fisiopatologia , Leucoencefalopatias/complicações , Leucoencefalopatias/diagnóstico por imagem , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Hipóxia Encefálica/complicações , Hipóxia Encefálica/diagnóstico por imagem , Pessoa de Meia-Idade , AdultoRESUMO
PURPOSE: To characterize Vanishing White Matter Disease (VWM) cases from a Brazilian University Tertiary hospital, focusing on brain magnetic resonance image (MRI) aspects, clinical and molecular data. METHODS: Medical records and brain MRI of 13 genetically confirmed VWM patients were reviewed. Epidemiological data such as age at symptom onset, gender and main symptoms were analyzed, along with genetic mutations and MRI characteristics, such as the distribution of white matter lesions and atrophy. RESULTS: The majority of patients were female, with the age of symptom onset ranging from 1 year and 6 months to 40 years. All mutations were identified in the EIF2B5 gene, the most prevalent being c.338G > A (p.Arg113His), and a novel mutation related to the disease was discovered, c.1051G > A (p.Gly351Ser). Trauma or infection were significant triggers. The most frequent symptoms were ataxia and limb spasticity. All MRI scans displayed deep white matter involvement, cystic degeneration, with U-fibers relatively spared and a predilection for the frontoparietal region. Lesions in the corpus callosum and posterior fossa were present in all patients. Follow-up exams revealed the evolution of white matter lesions and cerebral atrophy, which correlated with clinical deterioration. CONCLUSIONS: VWM affects various age groups, with a significant clinical and genetic variability. A novel mutation associated with the disease is highlighted. MRI reveals a typical pattern of white matter involvement, characterized by diffuse lesions in the periventricular and deep regions, with subsequent extension to the subcortical areas, accompanied by cystic degeneration, and plays a crucial role in diagnosis and follow-up.
Assuntos
Leucoencefalopatias , Imageamento por Ressonância Magnética , Humanos , Feminino , Masculino , Brasil , Adulto , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Criança , Adolescente , Imageamento por Ressonância Magnética/métodos , Lactente , Pré-Escolar , Mutação , Adulto Jovem , Fator de Iniciação 2B em Eucariotos/genéticaRESUMO
Caseinolytic peptidase B homolog (CLPB) is a mitochondrial protein which is highly expressed in brain. Its deficiency may be associated with severe neonatal encephalopathy. This report describes a case of fatal neonatal encephalopathy associated with biallelic stop-gain mutation in CLPB (NM_001258392.3:c.1159C>T/p.Arg387*). Neurologic disorder encompasses pre- and post-natal features including polyhydramnios, intrauterine growth restriction, respiratory insufficiency, lethargy, excessive startle reflex, generalized hypertonia, and epileptic seizures. Brain macroscopic examination demonstrates frontal severe periventricular cystic leukoencephalopathy, along with mild ex-vacuo tri-ventricular dilatation. The most striking immunohistopathologic features are striato-thalamic neurodegeneration and deep white matter loss associated with strong reactive astrogliosis. This report supports that CLPB deficiency should be considered among the neurometabolic disorders associated with severe prenatal-onset neurologic impairment that may result from cystic leukoencephalopathy.
Assuntos
Epilepsia , Doenças do Recém-Nascido , Leucoencefalopatias , Recém-Nascido , Feminino , Gravidez , Humanos , Endopeptidase Clp/genética , Endopeptidase Clp/metabolismo , Encéfalo/patologia , Epilepsia/metabolismo , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Leucoencefalopatias/metabolismo , Códon sem Sentido/metabolismo , Doenças do Recém-Nascido/patologiaRESUMO
Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase α (polα)/primase-dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. We identified a homozygous POT1 S322L substitution (POT1(CP)) in two siblings with CP. POT1(CP)induced a proliferative arrest that could be bypassed by telomerase. POT1(CP)was expressed at normal levels, bound TPP1 and telomeres, and blocked ATR signaling. POT1(CP)was defective in regulating telomerase, leading to telomere elongation rather than the telomere shortening observed in other telomeropathies. POT1(CP)was also defective in the maintenance of the telomeric C strand, causing extended 3' overhangs and stochastic telomere truncations that could be healed by telomerase. Consistent with shortening of the telomeric C strand, metaphase chromosomes showed loss of telomeres synthesized by leading strand DNA synthesis. We propose that CP is caused by a defect in POT1/CST-dependent telomere fill-in. We further propose that deficiency in the fill-in step generates truncated telomeres that halt proliferation in cells lacking telomerase, whereas, in tissues expressing telomerase (e.g., bone marrow), the truncations are healed. The proposed etiology can explain why CP presents with features distinct from those associated with telomerase defects (e.g., dyskeratosis congenita).