Diffusion tensor imaging of patients with proteolipid protein 1 gene mutations

Abstract

Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder of the central nervous system (CNS) caused by a wide variety of mutations affecting proteolipid protein 1 (PLP1). We assessed the effects of PLP1 mutations on water diffusion in CNS white matter by using diffusion tensor imaging. Twelve patients with different PLP1 point mutations encompassing a range of clinical phenotypes were analyzed, and the results were compared with a group of 12 age-matched controls. The parallel (λ// ), perpendicular (λ⊥ ), and apparent diffusion coefficients (ADC) and fractional anisotropy were measured in both limbs of the internal capsule, the genu and splenium of corpus callosum, the base of the pons, and the cerebral peduncles. The mean ADC and λ⊥ in the PMD patient group were both significantly increased in all selected structures, except for the base of the pons, compared with controls. PMD patients with the most severe disease, however, had a significant increase of both λ// and λ⊥ . In contrast, more mildly affected patients had much smaller changes in λ// and λ⊥ . These data suggest that myelin, the structure responsible in part for the λ⊥ barrier, is the major site of disease pathogenesis in this heterogeneous group of patients. Axons, in contrast, the structures mainly responsible for λ// , are much less affected, except within the subgroup of patients with the most severe disease. Clinical disability in patients with PLP1 point mutation is thus likely determined by the extent of pathological involvement of both myelin and axons, with alterations of both structures causing the most severe disease. © 2014 Wiley Periodicals, Inc.

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

“…Such MRI is highly representative of children with moderate to severe PMD and demonstrates both the ambiguity and convergence of clinical presentations across people with disparate PLP1 mutations. [54][55][56] To generate a renewable source of PMD-derived cells, we reprogrammed fibroblasts from all 12 individuals to hiPSCs (see Material and Methods). Two independently derived hiPSC lines per individual were ultimately selected for rigorous characterization.…”

Brain Diffusion Imaging and Tractography to Distinguish Clinical Severity of Human <b><i>PLP1</i></b>-Related Disorders

“…This result was surprising, as infratentorial WM is usually well myelinated on structural MRI in PLP1-related disorders regardless of clinical severity [19]. However, Laukka et al [13] also found changes in MD and RD in the cerebellar peduncle of PMD patients compared to controls. Moreover, infratentorial abnormalities had been described in a DTI study by Hassen et al [22] who found MD, AD, and RD variations in the spinal cord of a SPG2 mouse model.…”

“…Laukka et al [13] previously identified increased MD and RD and decreased FA in supratentorial WM regions in 12 PMD patients compared to controls, as expected in hypomyelinating brains. Steenweg et al [21] also found that RD in supratentorial WM was inversely correlated with motor handicap in a cohort of 28 patients with various hypomyelinating disorders.…”

“…In this study, we found a higher AD and RD in the most severely affected patients. Laukka et al [13] also found changes in AD, which is supposed to reflect axonal integrity, in only the most severely affected patients, whereas RD, which may reflect myelin integrity, was increased in all forms. In cortical and deep GM, the clinical severity of the MDS groups increased with the increase of diffusion (MD, AD, and RD) in several regions.…”

“…Using diffusion tensor imaging (DTI), Laukka et al [13] found that the WM mean and radial diffusivities of 12 PLP1-mutated patients were higher than those of controls, in accordance with the severe myelin deficiency observed in PMD. Axial diffusivity, which is assumed to be more specific to axon properties, was much less affected, except in the most severely affected patients.…”