Core protocol development for phase 2/3 clinical trials in the leukodystrophy vanishing white matter: a consensus statement by the VWM consortium and patient advocates.

Background: The leukodystrophy "Vanishing White Matter" (VWM) is an orphan disease with neurological decline and high mortality. Currently, VWM has no approved treatments, but advances in understanding pathophysiology have led to identification of promising therapies. Several investigational medicinal products are either in or about to enter clinical trial phase.

Gross Motor Function in Pediatric Onset -Related Leukodystrophy: GMFM-88 Performance and Validation of GMFC-MLD in .

pathogenic variants are associated with a spectrum of neurologic impairments including movement disorders and leukodystrophy. With the development of targeted therapies, there is an urgent unmet need for validated tools to measure mobility impairment. Our aim is to explore gross motor function in a pediatric-onset -related leukodystrophy cohort with existing gross motor outcome tools.

Hypomyelination caused by a novel homozygous pathogenic variant in FOLR1: complete clinical and radiological recovery with oral folinic acid therapy and review of the literature.

Background: Neurodegeneration due to cerebral folate transport deficiency is a rare autosomal recessive disorder caused by biallelic pathogenic variants in FOLR1. Onset typically occurs in late infancy and is characterized by psychomotor regression, epilepsy, and a hypomyelinating leukodystrophy on magnetic resonance imaging. If left untreated, progressive neurodegeneration occurs.

A Recurrent Variant in Causes a Hypomyelinating Leukodystrophy.

pathogenic variants in have recently been reported as a novel genetic cause of leukoencephalopathy. Here, we describe a male individual who presented in the first year of life with clinical features resembling Pelizaeus-Merzbacher disease (PMD), including nystagmus, hypotonia, and global developmental delay, and which later progressed to include ataxia and spasticity. Brain MRI at the age of two revealed diffuse hypomyelination.

Knockdown of Rab7B, But Not of Rab7A, Which Antagonistically Regulates Oligodendroglial Cell Morphological Differentiation, Recovers Tunicamycin-Induced Defective Differentiation in FBD-102b Cells.

In the central nervous system (CNS), insulative myelin sheaths are generated from the differentiated plasma membranes of oligodendrocytes (oligodendroglial cells) and surround neuronal axons to achieve saltatory conduction. Despite the functional involvement of myelin sheaths in the CNS, the molecular mechanism by which oligodendroglial cells themselves undergo differentiation of plasma membranes remains unclear. It also remains to be explored whether their signaling mechanisms can be applied to treating diseases of the oligodendroglial cells.

The Experience of Parents of Children With Genetically Determined Leukoencephalopathies With the Health Care System: A Qualitative Study.

Parents of children with genetically determined leukoencephalopathies play a major role in their children's health care. We sought to gain a better understanding of their experience with the public health care system in Quebec, Canada, to obtain suggestions for improving their services, and to identify modifiable factors to improve their quality of life. We conducted interviews with 13 parents.

Mechanisms of Diseases Associated with Mutation in GJC2/Connexin 47.

Connexins are members of a family of integral membrane proteins that provide a pathway for both electrical and metabolic coupling between cells. Astroglia express connexin 30 (Cx30)- and Cx43-, while oligodendroglia express Cx29/Cx31.3-, Cx32-, and Cx47-.

Decreased RNA polymerase III subunit expression leads to defects in oligodendrocyte development.

Introduction: RNA polymerase III (Pol III) is a critical enzymatic complex tasked with the transcription of ubiquitous non-coding RNAs including rRNA and all tRNA genes. Despite the constitutive nature of this enzyme, hypomorphic biallelic pathogenic variants in genes encoding subunits of Pol III lead to tissue-specific features and cause a hypomyelinating leukodystrophy, characterized by a severe and permanent deficit in myelin. The pathophysiological mechanisms in POLR3- related leukodystrophy and specifically, how reduced Pol III function impacts oligodendrocyte development to account for the devastating hypomyelination seen in the disease, remain poorly understood.

Redox Imbalance in Neurological Disorders in Adults and Children.

Oxygen is a central molecule for numerous metabolic and cytophysiological processes, and, indeed, its imbalance can lead to numerous pathological consequences. In the human body, the brain is an aerobic organ and for this reason, it is very sensitive to oxygen equilibrium. The consequences of oxygen imbalance are especially devastating when occurring in this organ.

A Rare Case of Hypomyelinating Leukodystrophy and Its Management: A Case Report and Literature Review.

A subset of hereditary white matter disorders called hypomyelinating leukodystrophies (HLD) is characterized primarily by the absence of myelin deposition. Although the clinical presentation can be mild and the development of symptoms can occur in adolescence or adulthood, the majority of severe cases present during infancy and early childhood with significant neurological impairments. The clinical features vary from muscle stiffness to seizures and developmental delay.

Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing.

Introduction: Rare neurodevelopmental disorders, including inherited white matter disorders or leukodystrophies, often present a diagnostic challenge on a genetic level given the large number of causal genes associated with a range of disease subtypes. This study aims to demonstrate the challenges and lessons learned in the genetic investigations of leukodystrophies through presentation of a series of cases solved using exome or genome sequencing.

Methods: Each of the six patients had a leukodystrophy associated with hypomyelination or delayed myelination on MRI, and inconclusive clinical diagnostic genetic testing results.

Pelizaeus-Merzbacher Disease in a 4-Year-Old Female Child: "A Rare Case Report".

Pelizaeus-Merzbacher disease, a rare X-linked recessive disease occurring predominantly in males, is a disorder of proteolipid protein expression in myelin formation in the central nervous system. The disease is clinically manifested by neurodevelopmental delay, ataxia, hypotonia, and pendular eye movement. It is best confirmed by genetic study.

Clinical application of long-read nanopore sequencing in a preimplantation genetic testing pre-clinical workup to identify the junction for complex Xq chromosome rearrangement-related disease.

Objective: Xq chromosome duplication with complex rearrangements is generally acknowledged to be associated with neurodevelopmental disorders, such as Pelizaeus-Merzbacher disease (PMD) and MECP2 duplication syndrome. For couples who required a PGT-M (pre-implantation genetic testing for monogenic disease) for these disorders, junction-specific PCR is useful to directly detect pathogenic variants. Therefore, pre-clinical workup for PGT-M requires the identification of the junction of duplicated segments in PMD and MECP2 duplication syndrome, which is generally difficult.

Pelizaeus-Merzbacher Disease: A Caregiver Assessment of Disease Impact.

Pelizaeus-Merzbacher disease is a rare X-linked leukodystrophy accompanied by central nervous system hypomyelination with a spectrum of clinical phenotypes. This is the first survey of caregivers of individuals with Pelizaeus-Merzbacher disease to investigate the presenting symptoms, path to diagnosis, identity and impact of most bothersome symptoms, and needs that future treatment should address. One hundred participants completed the survey.

In Silico Structural Analysis Predicting the Pathogenicity of PLP1 Mutations in Multiple Sclerosis.

The X chromosome gene encodes myelin proteolipid protein (PLP), the most prevalent protein in the myelin sheath surrounding the central nervous system. X-linked dysmyelinating disorders such as Pelizaeus-Merzbacher disease (PMD) or spastic paraplegia type 2 (SPG2) are typically caused by point mutations in . Nevertheless, numerous case reports have shown individuals with missense point mutations which also presented clinical symptoms and indications that were consistent with the diagnostic criteria of multiple sclerosis (MS), a disabling disease of the brain and spinal cord with no current cure.

Identification of Tau protein as a novel marker for maturation and pathological changes of oligodendrocytes.

Microtubule-associated protein Tau is primarily expressed in axons of neurons, but also in Olig2-positive oligodendrocytes in adult rodent and monkey brains. In this study, we sought to determine at what cell stage Tau becomes expressed in the oligodendrocyte lineage. We performed immunostaining of adult mouse brain sections using well-known markers of oligodendrocyte lineage and found that Tau is expressed in mature oligodendrocytes, but not in oligodendrocyte progenitors and immature pre-oligodendrocytes.

Early recognition of patients with leukodystrophies.

Leukodystrophies are defined as differences in normal myelin development and maintenance in the central nervous system. They typically present as white matter imaging abnormalities in young children with delayed developmental milestones. As the scientific community begins to better understand and research the mechanisms underlying leukodystrophies, clinical trials and approved therapies for specific disorders are becoming available.

Riluzole partially restores RNA polymerase III complex assembly in cells expressing the leukodystrophy-causative variant POLR3B R103H.

The mechanism of assembly of RNA polymerase III (Pol III), the 17-subunit enzyme that synthesizes tRNAs, 5 S rRNA, and other small-nuclear (sn) RNAs in eukaryotes, is not clearly understood. The recent discovery of the HSP90 co-chaperone PAQosome (Particle for Arrangement of Quaternary structure) revealed a function for this machinery in the biogenesis of nuclear RNA polymerases. However, the connection between Pol III subunits and the PAQosome during the assembly process remains unexplored.

Epidural Anesthesia and Continuous Epidural Analgesia in a Pediatric Patient With Pelizaeus-Merzbacher Disease: A Case Report.

Pelizaeus-Merzbacher disease (PMD) is a genetic leukodystrophy, which is a progressive and degenerative central nervous system abnormality caused by dysmyelination. Because the incidence of PMD is extremely low, only a few case reports have been published regarding its anesthetic management. In particular, epidural anesthesia has only been reported in one case of general anesthesia combined with caudal anesthesia.

Identification of PMD subgroups using a myelination score for PMD.

Background: The clinical spectrum of Pelizaeus-Merzbacher disease (PMD), a common hypomyelinating leukodystrophy, ranges between severe neonatal onset and a relatively stable presentation with later onset and mainly lower limb spasticity. In view of emerging treatment options and in order to grade severity and progression, we developed a PMD myelination score.

Methods: Myelination was scored in 15 anatomic sites (items) on conventional T2-and T1w images in controls (n = 328) and 28 PMD patients (53 MRI; n = 5 connatal, n = 3 transitional, n = 10 classic, n = 3 intermediate, n = 2 PLP0, n = 3 SPG2, n = 2 female).

Antisense Oligonucleotide Therapy for the Nervous System: From Bench to Bedside with Emphasis on Pediatric Neurology.

Antisense oligonucleotides (ASOs) are disease-modifying agents affecting protein-coding and noncoding ribonucleic acids. Depending on the chemical modification and the location of hybridization, ASOs are able to reduce the level of toxic proteins, increase the level of functional protein, or modify the structure of impaired protein to improve function. There are multiple challenges in delivering ASOs to their site of action.