A gray area

Leukodystrophies encompass a broad and heterogeneous range of rare genetic disorders that are characterized by brain white matter involvement as the most prominent abnormality. Evidence of gray matter disease alongside the characteristic white matter abnormalities has accumulated over the years. This thesis aims to explore the extent, clinical significance and potential relation to treatment of gray matter disease in leukodystrophies. A multidisciplinary approach is used, with a focus on quantitative MRI (qMRI) and its application towards analyzing gray matter in leukodystrophies. Our findings are summarized below. Chapter 2 describes a method to segment very low contrast MRI brain scans often seen in hypomyelinating disorders. A tensor-guided atlas-based segmentation method that is less reliant on tissue contrast is proposed. In chapter 3, we tested the applicability of qMRI methods promising for use in the leukodystrophy context. Two myelin water imaging (MWI) methods: multicompartment relaxometry diffusion-informed MWI (MCR-DIMWI), and multi-echo T2 relaxation imaging with compressed sensing (METRICS), and a multi shell DWI technique: neurite orientation dispersion and density imaging (NODDI) were tested for use on a broad cohort of various leukodystrophies. Chapter 4 illustrates the first application of the methods tested in chapter 3 in two well-defined leukodystrophies. Two patient groups with vanishing white matter (VWM) and metachromatic leukodystrophy (MLD), respectively, were compared to each other and to controls. We investigated whether quantitative MR measures of white matter can differentiate between the patients and controls, and whether the differences reflect the respective neuropathologies. Correlations with clinical scores were also explored. Chapter 5 describes patients with specific variants in POLR3A, normally associated with 4H leukodystrophy. This syndrome is classically characterized by pronounced hypomyelination on MRI, while basal ganglia involvement is not expected. Our study retrospectively reviewed genetic, clinical and MRI findings from nine patients with homozygous or compound heterozygous POLR3A variants and striatal involvement in order to characterize the striatal variant of POLR3A-associated disease. Chapter 6 covers a patient with a variant in UBA5 (c.895C > T p. [Pro299Ser]). UBA5 variants usually manifest as neurodevelopmental disorders with early-onset epileptic encephalopathy. Cerebral and cerebellar gray matter atrophy are often seen, while the white matter seems less affected. In the described case, pronounced hypomyelination alongside T2-hyperintensity of the thalamus were seen on MRI. In Chapter 7 we investigate MLD patients who declined clinically even after successful HSCT treatment with stable white matter pathology on MRI. We hypothesized that the clinical decline seen in such patients is attributable to a gray matter disease component of MLD. Clinical and MR volumetry analyses were performed. We also analyzed tissue from deceased HSCT treated and untreated MLD patients to further explore the possible cause of decline after treatment.