Inherited white matter disorders: Hypomyelination (myelin disorders).

Hypomyelinating leukodystrophies are a subset of genetic white matter diseases characterized by insufficient myelin deposition during development. MRI patterns are used to identify hypomyelinating disorders, and genetic testing is used to determine the causal genes implicated in individual disease forms. Clinical course can range from severe, with patients manifesting neurologic symptoms in infancy or early childhood, to mild, with onset in adolescence or adulthood.

Biallelic pathogenic variants in alter tRNA transcription and cause a hypomyelinating leukodystrophy: A case report.

RNA polymerase III-related leukodystrophy (POLR3-related leukodystrophy) is a rare, genetically determined hypomyelinating disease arising from biallelic pathogenic variants in genes encoding subunits of RNA polymerase III (Pol III). Here, we describe the first reported case of POLR3-related leukodystrophy caused by biallelic pathogenic variants in , encoding the RPC4 subunit of Pol III. The individual, a female, demonstrated delays in walking and expressive and receptive language as a child and later cognitively plateaued.

Hypomyelination, hypodontia and craniofacial abnormalities in a Polr3b mouse model of leukodystrophy.

RNA polymerase III (Pol III)-related hypomyelinating leukodystrophy (POLR3-HLD), also known as 4H leukodystrophy, is a severe neurodegenerative disease characterized by the cardinal features of hypomyelination, hypodontia and hypogonadotropic hypogonadism. POLR3-HLD is caused by biallelic pathogenic variants in genes encoding Pol III subunits. While approximately half of all patients carry mutations in POLR3B encoding the RNA polymerase III subunit B, there is no in vivo model of leukodystrophy based on mutation of this Pol III subunit.

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.

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.

Protection From Radiation-Induced Neuroanatomic Deficits by CCL2 Deficiency Is Dependent on Sex.

Purpose: Cranial radiation therapy for the treatment of pediatric brain tumors results in changes to brain development that are detectable with magnetic resonance imaging. We have previously demonstrated similar structural changes in both humans and mice. The goal of the current study was to examine the role of inflammation in this response.

Distinguishing severe phenotypes associated with pathogenic variants in POLR3A.

A recent report by Majethia and Girisha described a patient with biallelic pathogenic variants in and Wiedemann-Rautenstrauch syndrome. In this correspondence, we compare the features of this patient to that of a cohort of patients with severe POLR3-related leukodystrophy and a similar genotype and clinical course. We comment on the phenotyping and classification of POLR3-related disorders.

POLR3-Related Leukodystrophy: Exploring Potential Therapeutic Approaches.

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.

Expanding the phenotypic and molecular spectrum of RNA polymerase III-related leukodystrophy.

Objective: To expand the phenotypic spectrum of severity of POLR3-related leukodystrophy and identify genotype-phenotype correlations through study of patients with extremely severe phenotypes.

Methods: We performed an international cross-sectional study on patients with genetically proven POLR3-related leukodystrophy and atypical phenotypes to identify 6 children, 3 males and 3 females, with an extremely severe phenotype compared with that typically reported. Clinical, radiologic, and molecular features were evaluated for all patients, and functional and neuropathologic studies were performed on 1 patient.