A gray area
Authors:   , Al-Saady Murtadha Luay 
Published: December 2024

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.