Emerging cellular themes in leukodystrophies

Abstract

Leukodystrophies are a broad spectrum of neurological disorders that are characterized primarily by deficiencies in myelin formation. Clinical manifestations of leukodystrophies usually appear during childhood and common symptoms include lack of motor coordination, difficulty with or loss of ambulation, issues with vision and/or hearing, cognitive decline, regression in speech skills, and even seizures. Many cases of leukodystrophy can be attributed to genetic mutations, but they have diverse inheritance patterns (e.g., autosomal recessive, autosomal dominant, or X-linked) and some arise from de novo mutations. In this review, we provide an updated overview of 35 types of leukodystrophies and focus on cellular mechanisms that may underlie these disorders. We find common themes in specialized functions in oligodendrocytes, which are specialized producers of membranes and myelin lipids. These mechanisms include myelin protein defects, lipid processing and peroxisome dysfunction, transcriptional and translational dysregulation, disruptions in cytoskeletal organization, and cell junction defects. In addition, non-cell-autonomous factors in astrocytes and microglia, such as autoimmune reactivity, and intercellular communication, may also play a role in leukodystrophy onset. We hope that highlighting these themes in cellular dysfunction in leukodystrophies may yield conceptual insights on future therapeutic approaches.

Role of epigenetics and alterations in RNA metabolism in leukodystrophies

“…Moreover, in leukodystrophies and childhood ataxia with CNS hypomyelination/vanishing white matter, a correlation between mutations in the mitochondrial or cytoplasmic aminoacyl tRNA synthetases (ARS) and abnormal RNA regulation has also been also reported (Nowacki et al, 2022).…”

Nomogram for prediction of hearing rehabilitation outcome in children with congenital sensorineural hearing loss after cochlear implantation

“…Literature has reported that clinical information such as premature birth [ 9 , 10 ] and brain structural MRI assessment such as white matter lesions [ 11 , 12 ] being related to hearing loss in newborns. Additional factors such as age at CI surgery [ [13] , [14] , [15] ], preoperative speech rehabilitation training [ 16 ], the width of bony cochlear nerve canal [ 17 , 18 ] and the diameter of internal auditory canal [ 19 ] have been shown to be related to the rehabilitation outcome after CI surgery.…”

Primary microgliopathy presenting as degenerative dementias: A case series of novel gene mutations from India

“…Microglia exert a crucial role in the homeostasis of white matter integrity, and emerging evidence suggests that microglial dysfunction plays a significant role in leukodystrophy and neurodegeneration [1][2][3][4]. Primary microgliopathies refer to adult leukodystrophies linked to mutations in genes expressed in microglial cells and include adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), Nasu-Hakola disease (NHD), and leukodystrophies related to variants in the negative regulator of reactive oxygen species or pseudo-TORCH syndrome [5][6][7][8][9][10][11].…”