The Cerebro-Morphological Fingerprint of a Progeroid Syndrome: White Matter Changes Correlate with Neurological Symptoms in Xeroderma Pigmentosum

Abstract

BackgroundXeroderma pigmentosum (XP) is a rare autosomal recessive progeroid syndrome. It has recently been shown that the underlying DNA repair defect plays a central role in the aging process. In addition to skin symptoms, various premature neurological abnormalities have been reported.Methodology/Principal FindingsWe present the clinical neurological phenotype in 14 XP patients (seven subtypes), in seven of these patients together with conventional and multiparametric advanced MRI data to assess the macrostructural and microstructural cerebral morphology in comparison to controls, including volumetric measurements, MR spectroscopy (1H MRS), and diffusion tensor imaging (DTI). Clinical hallmarks were spinocerebellar ataxia, pyramidal tract signs, and mild cognitive deficits. DTI demonstrated significantly reduced WM directionality in all regions investigated, i.e. the thalamus, the corticospinal tracts and the dorsal corpus callosum. Single patients showed a marked relative hippocampal volume reduction, but the patients were not different from controls in the volumetric measurements of hippocampal and whole brain volumes at group level. However, 1H MRS demonstrated that the hippocampal formation was metabolically altered.ConclusionsThe most prominent feature was the white matter affectation, as assessed by DTI, with volume and directionality reductions of the fiber projections involving both the craniocaudal fibers and the interhemispheric connections. These findings, although heterogeneous among the study sample, could be correlated with the clinico-neurological symptoms. The imaging findings support the position that myelin structures degrade prematurely in the brain of XP patients.

Diffusion Tensor Magnetic Resonance Imaging in the Analysis of Neurodegenerative Diseases

“…These findings, although heterogeneous among the study sample, could be correlated with the clinico-neurological symptoms. The imaging findings support the position that myelin structures degrade prematurely in the brain of XP patients, as discussed in 41 .…”

“…A multiparametric MRI approach to characterize the cerebromorphological phenotype was used in seven XP patients of different subtypes in order to assess the macrostructural and microstructural cerebral morphology in comparison to controls 41 , including DTI, volumetric measurements, and MR spectroscopy ( 1 H MRS).…”

DNA damage in the oligodendrocyte lineage and its role in brain aging

“…Like CS, XP is caused by autosomal recessive mutations in one of a family of the seven DNA repair genes for NER (XP-A to XP-G), with XP-A and XP-C being the most common forms. It has long been recognized that the peripheral nerves of XP patients are poorly myelinated (Hakamada et al, 1982; Kanda et al, 1990), and estimates are that about 70% of XP patients also develop neurological deficits early in life (Kassubek et al, 2012). For example, patients with XP-A mutations develop neurological symptoms before eight years age, and their cognitive decline is proportional to the overall cerebral and cerebellar atrophy, where WMHs are found (Anttinen et al, 2008).…”

“…For example, patients with XP-A mutations develop neurological symptoms before eight years age, and their cognitive decline is proportional to the overall cerebral and cerebellar atrophy, where WMHs are found (Anttinen et al, 2008). Apart from WMHs, MRI-diffusion tensor imaging (DTI) of the WM tracts clearly showed that the volume and directionality of individual myelinated tracts were critically reduced in the corticospinal pathway, thalamus and corpus callosum, regardless of the XP mutation variants (Kassubek et al, 2012). Myelin pallors were found in the temporal lobe, frontal lobe of the cerebrum, basal ganglia as well as in the cerebellum (Lai et al, 2013).…”

Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration

“…chorea, ataxia, etc. ), and dysfunction of the corticospinal tract (Kassubek et al, 2012). Magnetic resonance imaging (MRI) of patients with XP demonstrates cerebral and cerebellar atrophy and accompanying ventricular enlargement (Kraemer et al, 2007).…”