Vanishing White Matter Disease Research Articles

GDF15 is a dynamic biomarker of the integrated stress response in the central nervous system.

Characterize Growth Differentiation Factor 15 (GDF15) as a secreted biomarker of the integrated stress response (ISR) within the central nervous system (CNS). We determined GDF15 levels utilizing invitro and invivo neuronal systems wherein the ISR was activated. Primarily, we used the murine model of vanishing white matter disease (VWMD), a neurological disease driven by persistent ISR in the CNS, to establish a link between levels of GDF15 in the cerebrospinal fluid (CSF) and ISR gene expression signature in the CNS. GDF15 was also determined in the CSF of VWM patients. GDF15 expression was increased concomitant to ISR activation in stress-induced primary astrocytes as well as in retinal ganglion cells following optic nerve crush, while treatment with 2Bact, a specific eIF2B activator, suppressed both the ISR and GDF15. In the VWMD model, CSF GDF15 levels corresponded with the magnitude of the ISR and were reduced by 2BAct. In VWM patients, mean CSF GDF15 was elevated >20-fold as compared to healthy controls, whereas plasma GDF15 was undifferentiated. These data suggest that CSF GDF15 is a dynamic marker of ISR activation in the CNS and may serve as a pharmacodynamic biomarker for ISR-modulating therapies.

Pridopidine subtly ameliorates motor skills in a mouse model for vanishing white matter.

The leukodystrophy vanishing white matter (VWM) is characterized by chronic and episodic acute neurological deterioration. Curative treatment is presently unavailable. Pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B) cause VWM and deregulate the integrated stress response (ISR). Previous studies in VWM mouse models showed that several ISR-targeting compounds ameliorate clinical and neuropathological disease hallmarks. It is unclear which ISR components are suitable therapeutic targets. In this study, effects of 4-phenylbutyric acid, tauroursodeoxycholic acid, or pridopidine (PDPD), with ISR targets upstream or downstream of eIF2B, were assessed in VWM mice. In addition, it was found that the composite ataxia score represented motor decline of VWM mice more accurately than the previously used neuroscore. 4-phenylbutyric acid and tauroursodeoxycholic acid did not improve VWM disease hallmarks, whereas PDPD had subtle beneficial effects on motor skills. PDPD alone does not suffice as treatment in VWM mice but may be considered for combination therapy. Also, treatments aimed at ISR components upstream of eIF2B do not improve chronic neurological deterioration; effects on acute episodic decline remain to be investigated.

Progress in leukodystrophies with zebrafish.

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.

A novel missense variant in EIF2B5 identified in a consanguineous Iranian family with vanishing white matter disease and a brief review of the literature

A novel missense variant in EIF2B5 identified in a consanguineous Iranian family with vanishing white matter disease and a brief review of the literature

Leukoencephalopathy with vanishing white matter disease: a case report study.

The authors report two cases of VWM disease. In the first case, an 8-month-old female child, brought to the pediatric clinic with seizure and loss of consciousness. The second case was a 24-month-old girl, presented with weakness, a disability to walk and swallow, and poor feeding. Her brain MRI demonstrated cystic changes (white matter rarefaction) in supratentorial peri-ventricular white matter and genetic testing result showed an EIF2B3 gene mutation. Leukoencephalopathy with VWM, also known as Cree encephalopathy is caused by mutations in the EIF2B gene. The disease is inherited in an autosomal recessive fashion. There are various agents leading to symptoms and signs of VWM disease. Physical stress like head trauma even in a mild degree, infections, and febrile diseases can be mentioned as causes of VWM. The eIF2B complex, plays a role as an important factor in the regulation of protein synthesis in cells under different conditions. As a conclusion, genetic counseling could be recommended to all individuals with VWM disease and their family members for next pregnancies and possible precautions for consanguineous marriages.

Vanishing white matter disease: a case of combined saposin deficiency

Vanishing white matter disease (VWMD) is an autosomal recessive neurodegenerative disease often present during childhood and is exacerbated by trauma and other stressors. VWMD is caused by EIF2B gene mutation, which encodes eukaryotic initiation factor 2 B (EIF2B), a transcription factor activated by insulin that is a major protein synthesis regulator during the integrated stress response. Autosomal recessive combined saposin deficiency is a metachromatic leukodystrophy, a progressive neurological disorder characterized by motor delay, regression of gained skills, and nerve demyelination. Here, we present the case of an 11-year-old Hispanic male presenting with ataxia, dysphagia, and global developmental delay which was found to have VWMD on imaging. A genetic panel reveals the PSAP gene, a novel presentation in the setting of VWMD.

Clinical and Neurophysiological Features of Epilepsy in Pediatric Patients with Vanishing White Matter Disease-A single institute experience and literature review (P12-9.006)

<h3>Objective:</h3> Refractory epilepsy is a common presentation in Vanishing white matter disease (VWMD) patients. However, there is little literature describing the nature and evolution of seizures. We aim to study the electroencephalograpic findings in patients with a genetically confirmed diagnosis of VWMD, and their correlation with MRI progression and clinical status longitudinally. <h3>Background:</h3> Vanishing White Matter Disease (VWMD) is one of the most prevalent leukodystrophies in pediatric patients with unique clinical, pathological, and molecular features. It mostly affects children, but may develop at all ages, from birth to senescence. Incidence in one study is reported to be 1 in 80,000 live births. The molecular basis of the disease has been shown to be due to mutations in subunits of Eukaryotic Translation Initiation Factor 2B (eIF2B) ie eIF2B 1–5. <h3>Design/Methods:</h3> An IRB approved retrospective chart review was conducted at Children’s Medical Center, Dallas TX. The initial search pulled up 42 patients that had an associated diagnosis of leukodystrophy. Four of these 42 patients were found to have a genetically confirmed diagnosis of VWMD. <h3>Results:</h3> In our cohort, there were 3males and 1female. Age of diagnosis ranged between 2–10 years and mutations in EIF2B5 was the most common. The earliest seizure onset was noted at 2 years of age at the time of diagnosis. Patients that presented with intractable seizures were noted to have significant MRI changes. Average time of seizure onset from time of diagnosis was 1.6 years. Our patient that was diagnosed with VWMD at 10 years of age did not go on to develop seizures and his EEG did not have any epileptiform discharges. His MRI did not show significant white matter changes and clinically patient had mild to moderate deficits. <h3>Conclusions:</h3> We observe that there is a wide range of severity of epilepsy in these patients &amp; not all patients with a diagnosis of VWMD go on to develop seizures. <b>Disclosure:</b> Dr. Laheji has nothing to disclose. Dr. Lowden has nothing to disclose.

Teaching Neuro Images : Vanishing white matter ovarioleukodystrophy

A 21-year-old Pakistani woman with a history of 2 seizures at 20 months of age and consanguineous parents was diagnosed with premature ovarian failure and hyperprolactinemia. Her neurologic examination was normal. Brain imaging showed confluent white matter T2/fluid-attenuated inversion recovery hyperintensities with periventricular cavitations (figure). Genetic testing showed homozygosity for a p.Lys273Arg missense mutation in the EIF2B2 gene (NM_014239.3: c.818A>G), which had previously been reported as disease-causing,1 and confirmed vanishing white matter (VWM) ovarioleukodystrophy. At 2-year follow-up, she remains neurologically asymptomatic with stable imaging. There is phenotypic variation in VWM disease and neurologic deterioration is associated with stressors (head trauma, fever).1,2

Brain-specific glycosylation of protein tyrosine phosphatase receptor type Z (PTPRZ) marks a demyelination-associated astrocyte subtype.

Astrocytes are the most abundant glial cell type in the brain, where they participate in various homeostatic functions. Transcriptomically, diverse astrocyte subpopulations play distinct roles during development and disease progression. However, the biochemical identification of astrocyte subtypes, especially by membrane surface protein glycosylation, remains poorly investigated. Protein tyrosine phosphatase receptor type zeta (PTPRZ) is a highly expressed membrane protein in CNS glia cells that can be modified with diverse glycosylation, including the unique HNK-1 capped O-mannosyl (O-Man) core M2 glycan mediated by brain-specific branching enzyme GnT-IX. Although PTPRZ modified with HNK-1 capped O-Man glycans (HNK-1-O-Man+ PTPRZ) is increased in reactive astrocytes of demyelination model mice, whether such astrocytes emerge in a broad range of disease-associated conditions or are limited to conditions associated with demyelination remains unclear. Here, we show that HNK-1-O-Man+ PTPRZ localizes in hypertrophic astrocytes of damaged brain areas in patients with multiple sclerosis. Furthermore, we show that astrocytes expressing HNK-1-O-Man+ PTPRZ are present in two demyelination mouse models (cuprizone-fed mice and a vanishing white matter disease model), while traumatic brain injury does not induce glycosylation. Administration of cuprizone to Aldh1l1-eGFP and Olig2KICreER/+ ;Rosa26eGFP mice revealed that cells expressing HNK-1-O-Man+ PTPRZ are derived from cells in the astrocyte lineage. Notably, GnT-IX but not PTPRZ mRNA was up-regulated in astrocytes isolated from the corpus callosum of cuprizone model mice. These results suggest that the unique PTPRZ glycosylation plays a key role in the patterning of demyelination-associated astrocytes.

Edaravone and mitochondrial transfer as potential therapeutics for vanishing white matter disease astrocyte dysfunction.

Previous research has suggested that vanishing white matter disease (VWMD) astrocytes fail to fully differentiate and respond differently to cellular stresses compared to healthy astrocytes. However, few studies have investigated potential VWMD therapeutics in monoculture patient-derived cell-based models. To investigate the impact of alterations in astrocyte expression and function in VWMD, astrocytes were differentiated from patient and control induced pluripotent stem cells and analyzed by proteomics, pathway analysis, and functional assays, in the absence and presence of stressors or potential therapeutics. Vanishing white matter disease astrocytes demonstrated significantly reduced expression of astrocyte markers and markers of inflammatory activation or cellular stress relative to control astrocytes. These alterations were identified both in the presence and absence of polyinosinic:polycytidylic acid stimuli, which is used to simulate viral infections. Pathway analysis highlighted differential signaling in multiple pathways in VWMD astrocytes, including eukaryotic initiation factor 2 (EIF2) signaling, oxidative stress, oxidative phosphorylation (OXPHOS), mitochondrial function, the unfolded protein response (UPR), phagosome regulation, autophagy, ER stress, tricarboxylic acid cycle (TCA) cycle, glycolysis, tRNA signaling, and senescence pathways. Since oxidative stress and mitochondrial function were two of the key pathways affected, we investigated whether two independent therapeutic strategies could ameliorate astrocyte dysfunction: edaravone treatment and mitochondrial transfer. Edaravone treatment reduced differential VWMD protein expression of the UPR, phagosome regulation, ubiquitination, autophagy, ER stress, senescence, and TCA cycle pathways. Meanwhile, mitochondrial transfer decreased VWMD differential expression of the UPR, glycolysis, calcium transport, phagosome formation, and ER stress pathways, while further modulating EIF2 signaling, tRNA signaling, TCA cycle, and OXPHOS pathways. Mitochondrial transfer also increased the gene and protein expression of the astrocyte marker, glial fibrillary acidic protein (GFAP) in VWMD astrocytes. This study provides further insight into the etiology of VWMD astrocytic failure and suggests edaravone and mitochondrial transfer as potential candidate VWMD therapeutics that can ameliorate disease pathways in astrocytes related to oxidative stress, mitochondrial dysfunction, and proteostasis.

Adult Vanishing White Matter Disease with a Novel EIF2B4 Mutation

Adult Vanishing White Matter Disease with a Novel EIF2B4 Mutation

The genetic and phenotypic spectra of adult genetic leukoencephalopathies in a cohort of 309 patients.

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.

Vanishing White Matter Disease- Report of two Cases

Vanishing white matter (VWM) disease is a chronic progressive childhood onset leukodystrophy that result in central nervous system demyelination, often precipitated by some stressful events. There is wide phenotypic variation buy typical MRI findings are diagnostic in most of the patients. Here we report two cases of vanishing white matter disease with typical MRI findings. J Bangladesh Coll Phys Surg 2022; 40: 314-317

EIF2B2 gene mutation causing early onset vanishing white matter disease: a case report

BackgroundLeukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive neurological disease. The physiopathology of disease is still little understood, but it seems to involve impairment in maturation of astrocytes; as a consequence white matter is more prone to cellular stress. Disease is caused by mutations in five genes encoding subunits of the translation initiation factor eIF2B. We know five different types of VWM syndrome classified based different ages of onset (prenatal, infantile, childhood, juvenile and adult onset).Case presentationWe report the case of a 4-month-old boy with early seizure onset, recurrent hypoglycemia and post mortem diagnosis of vanishing white matter disease (VMD). At the admission he presented suspected critical episodes, resolved after intravenous administration of benzodiazepines. The brain MRI showed total absence of myelination that suggested hypomyelination leukoencephalopathy. The whole exome sequencing (WES) revealed a variant of EIF2B2 gene (p. Val308Met) present in homozygosity. In this case report we also describe the clinical evolution of seizures, in fact the epileptic seizures had a polymorphic aspect, from several complex partial seizures secondarily generalized to status epilepticus.ConclusionInfantile and early childhood onset forms are associated with chronic progressive neurological signs, with episodes of rapid neurological worsening, and poor prognosis, with death in few months or years. Clinical presentation of epilepsy is poorly documented and do not include detailed information about the type, time of onset and severity of seizures. No therapeutic strategies for VWM disease have been reported.

Identification of a Novel Heterozygous Mutation in the EIF2B4 Gene Associated With Vanishing White Matter Disease

Vanishing white matter disease (VWM) is one of the most common childhood inherited leukoencephalopathies with autosomal recessive inheritance. Mutations in five genes, EIF2B1-5, have been identified as the major cause of VWM. In this study, a targeted gene capture sequencing panel comprising 160 known pathogenic genes associated with leukoencephalopathies was performed in a large Han Chinese family affected by adult-onset VWM, and a novel heterozygous missense mutation (c.1337G > A [p. R446H]) in EIF2B4 (NM_001034116.2) was detected. Further functional studies in HEK 293 cells showed dramatically reduced EIF2Bδ protein levels in the mutated group compared with the wild-type group. This study revealed that a heterozygous missense mutation (c.1337G > A [p. R446H]) in EIF2B4 was potentially associated with the adult-onset mild phenotype of VWM. In contrast to previous reports, autosomal dominant inheritance was also observed in adult-onset VWM.

Regulation and function of elF2B in neurological and metabolic disorders.

Eukaryotic initiation factor 2B, eIF2B is a guanine nucleotide exchange, factor with a central role in coordinating the initiation of translation. During stress and disease, the activity of eIF2B is inhibited via the phosphorylation of its substrate eIF2 (p-eIF2α). A number of different kinases respond to various stresses leading to the phosphorylation of the alpha subunit of eIF2, and collectively this regulation is known as the integrated stress response, ISR. This targeting of eIF2B allows the cell to regulate protein synthesis and reprogramme gene expression to restore homeostasis. Advances within structural biology have furthered our understanding of how eIF2B interacts with eIF2 in both the productive GEF active form and the non-productive eIF2α phosphorylated form. Here, current knowledge of the role of eIF2B in the ISR is discussed within the context of normal and disease states focusing particularly on diseases such as vanishing white matter disease (VWMD) and permanent neonatal diabetes mellitus (PNDM), which are directly linked to mutations in eIF2B. The role of eIF2B in synaptic plasticity and memory formation is also discussed. In addition, the cellular localisation of eIF2B is reviewed and considered along with the role of additional in vivo eIF2B binding factors and protein modifications that may play a role in modulating eIF2B activity during health and disease.

Myelin oligodendrocyte glycoprotein antibodies in genetic leukodystrophies

Accumulation of intermediate metabolites due to enzyme deficiencies and demyelination can provoke inflammation in genetic leukodystrophies. Thirty patients with genetic leukodystrophy and 48 healthy control sera were tested for anti-myelin oligodendrocyte glycoprotein (MOG) antibodies by fixed and/or live cell-based assays. MOG-IgG was detected in two late infantile metachromatic leukodystrophy (MLD) cases, both of which were also weakly positive for IgG1, and one with IgG3 as the dominant anti-MOG IgG subclass. MOG-IgG was borderline positive in a vanishing white matter (VWM) disease patient. These results suggest that inherited metabolic or degenerative processes can have an autoimmune component, possibly as an epiphenomenon.

Genotypic and phenotypic characteristics of juvenile/adult onset vanishing white matter: a series of 14 Chinese patients.

Vanishing white matter (VWM) is one of the most prevalent leukoencephalopathies and is caused by recessive mutations in gene eIF2B1-5. The onset may vary from an antenatal disorder that is rapidly fatal to an adult-onset disorder with chronic progressive deterioration. Based on a comprehensive study of 14 juvenile/adult patients diagnosed in our department as well as a review of 71 previously reported cases of genetically confirmed juvenile/adult-onset VWM since 2001, we attempted to delineate the clinical symptoms, disease evolution, episodic aggravation, associated symptoms, MRI findings and genotypic characteristics of adult VWM. The onset age of neuropsychiatric symptoms was 23.4 ± 10.6years, and the mean follow-up time was 8.1 ± 4.8years. Major clinical symptoms included headache, epilepsy, cognitive decline, cerebellar ataxia, and urinary disturbances. Episodic aggravation was found in 42.9% of the patients in our series. Molecular studies revealed fourteen novel missense mutations. Diffuse abnormal signals characterized by T1-weighted hypointensity and T2-weighted hyperintensity were observed in the supratentorial white matter. The symmetrical leukoencephalopathy must be considered in patients of any age with premature ovarian failure or optic neuropathy. The VWM disease spectrum consists of characteristicimaging findings in combinationwith extremely wide variability in VWM patients.

Therapy Trial Design in Vanishing White Matter: An Expert Consortium Opinion.

Vanishing white matter (VWM) is a leukodystrophy caused by recessive variants in the genes EIF2B1-EIF2B5. It is characterized by chronic neurologic deterioration with superimposed stress-provoked episodes of rapid decline. Disease onset spans from the antenatal period through senescence. Age at onset predicts disease evolution for patients with early onset, whereas disease evolution is unpredictable for later onset; patients with infantile and early childhood onset consistently have severe disease with rapid neurologic decline and often early death, whereas patients with later onset have highly variable disease. VWM is rare, but likely underdiagnosed, particularly in adults. Apart from measures to prevent stressors that could provoke acute deteriorations, only symptomatic care is currently offered. With increased insight into VWM disease mechanisms, opportunities for treatment have emerged. EIF2B1-EIF2B5 encode the 5-subunit eukaryotic initiation factor 2B complex, which is essential for translation of mRNAs into proteins and is a principal regulator of the integrated stress response (ISR). ISR deregulation is central to VWM pathology. Targeting components of the ISR has proven beneficial in mutant VWM mouse models, and several drugs are now in clinical development. However, clinical trials in VWM pose considerable challenges: low numbers of known patients with VWM, unpredictable disease course for patients with onset after early childhood, absence of intermediate biomarkers, and novel first-in-human molecular targets. Given these challenges and considering the critical need to offer therapies, we have formulated recommendations for enhanced diagnosis, drug trial setup, and patient selection, based on our expert evaluation of molecular, laboratory, and clinical data.

Vanishing White Matter Disease Presenting as Acute Febrile Encephalopathy: Case Report

AbstractA 3.5-year-old male child patient with mild developmental delay presented with history of acute onset fever, encephalopathy, and dyskinesia. The patient was investigated for common etiologies and was managed supportively. His neuroimaging was suggestive of vanishing white matter (VWM) disease which was confirmed by clinical exome sequencing. The child had an eventful hospital stay followed by near-total recovery after 4 weeks. The case attempts to sensitize readers about the current perspectives pertaining to VWM disease.