Applicability of multiple quantitative magnetic resonance methods in genetic brain white matter disorders

Background and purpose: Magnetic resonance imaging (MRI) measures of tissue microstructure are important for monitoring brain white matter (WM) disorders like leukodystrophies and multiple sclerosis. They should be sensitive to underlying pathological changes. Three whole-brain isotropic quantitative methods were applied and compared within a cohort of controls and leukodystrophy patients: two novel myelin water imaging (MWI) techniques (multi-compartment relaxometry diffusion-informed MWI: MCR-DIMWI, and multi-echo T2 relaxation imaging with compressed sensing: METRICS) and neurite orientation dispersion and density imaging (NODDI).// Methods: For 9 patients with different leukodystrophies (age range 0.4-62.4 years) and 15 control subjects (2.3-61.3 years), T1-weighted MRI, fluid-attenuated inversion recovery, multi-echo gradient echo with variable flip angles, METRICS, and multi-shell diffusion-weighted imaging were acquired on 3 Tesla. MCR-DIMWI, METRICS, NODDI, and quality control measures were extracted to evaluate differences between patients and controls in WM and deep gray matter (GM) regions of interest (ROIs). Pearson correlations, effect size calculations, and multi-level analyses were performed.// Results: MCR-DIMWI and METRICS-derived myelin water fractions (MWFs) were lower and relaxation times were higher in patients than in controls. Effect sizes of MWF values and relaxation times were large for both techniques. Differences between patients and controls were more pronounced in WM ROIs than in deep GM. MCR-DIMWI-MWFs were more homogeneous within ROIs and more bilaterally symmetrical than METRICS-MWFs. The neurite density index was more sensitive in detecting differences between patients and controls than fractional anisotropy. Most measures obtained from MCR-DIMWI, METRICS, NODDI, and diffusion tensor imaging correlated strongly with each other.// Conclusion: This proof-of-concept study shows that MCR-DIMWI, METRICS, and NODDI are sensitive techniques to detect changes in tissue microstructure in WM disorders

Homozygous UBA5 Variant Leads to Hypomyelination with Thalamic Involvement and Axonal Neuropathy

The enzyme ubiquitin-like modifier activating enzyme 5 (UBA5) plays an important role in activating ubiquitin-fold modifier 1 (UFM1) and its associated cascade. UFM1 is widely expressed and known to facilitate the post-translational modification of proteins. Variants in UBA5 and UFM1 are involved in neurodevelopmental disorders with early-onset epileptic encephalopathy as a frequently seen disease manifestation. Using whole exome sequencing, we detected a homozygous UBA5 variant (c.895C > T p. [Pro299Ser]) in a patient with severe global developmental delay and epilepsy, the latter from the age of 4 years. Magnetic resonance imaging showed hypomyelination with atrophy and T2 hyperintensity of the thalamus. Histology of the sural nerve showed axonal neuropathy with decreased myelin. Functional analyses confirmed the effect of the Pro299Ser variant on UBA5 protein function, showing 58% residual protein activity. Our findings indicate that the epilepsy currently associated with UBA5 variants may present later in life than previously thought, and that radiological signs include hypomyelination and thalamic involvement. The data also reinforce recently reported associations between UBA5 variants and peripheral neuropathy

POLR3A variants with striatal involvement and extrapyramidal movement disorder

Biallelic variants in POLR3A cause 4H leukodystrophy, characterized by hypomyelination in combination with cerebellar and pyramidal signs and variable non-neurological manifestations. Basal ganglia are spared in 4H leukodystrophy, and dystonia is not prominent. Three patients with variants in POLR3A, an atypical presentation with dystonia, and MR involvement of putamen and caudate nucleus (striatum) and red nucleus have previously been reported. Genetic, clinical findings and 18 MRI scans from nine patients with homozygous or compound heterozygous POLR3A variants and predominant striatal changes were retrospectively reviewed in order to characterize the striatal variant of POLR3A-associated disease. Prominent extrapyramidal involvement was the predominant clinical sign in all patients. The three youngest children were severely affected with muscle hypotonia, impaired head control, and choreic movements. Presentation of the six older patients was milder. Two brothers diagnosed with juvenile parkinsonism were homozygous for the c.1771-6C > G variant in POLR3A; the other seven either carried c.1771-6C > G (n = 1) or c.1771-7C > G (n = 7) together with another variant (missense, synonymous, or intronic). Striatal T2-hyperintensity and atrophy together with involvement of the superior cerebellar peduncles were characteristic. Additional MRI findings were involvement of dentate nuclei, hila, or peridentate white matter (3, 6, and 4/9), inferior cerebellar peduncles (6/9), red nuclei (2/9), and abnormal myelination of pyramidal and visual tracts (6/9) but no frank hypomyelination. Clinical and MRI findings in patients with a striatal variant of POLR3A-related disease are distinct from 4H leukodystrophy and associated with one of two intronic variants, c.1771-6C > G or c.1771-7C > G, in combination with another POLR3A variant

Mri natural history of the leukodystrophy vanishing white matter

Background: In vanishing white matter (VWM), a form of leukodystrophy, earlier onset is associated with faster clinical progression. MRI typically shows rarefaction and cystic destruction of the cerebral white matter. Information on the evolution of VWM according to age at onset is lacking. Purpose: To determine whether nature and progression of cerebral white matter abnormalities in VWM differ according to age at onset. Materials and Methods: Patients with genetically confirmed VWM were stratified into six groups according to age at onset: Younger than 1 year, 1 year to younger than 2 years, 2 years to younger than 4 years, 4 years to younger than 8 years, 8 years to younger than 18 years, and 18 years or older. With institutional review board approval, all available MRI scans obtained between 1985 and 2019 were retrospectively analyzed with three methods: (a) ratio of the width of the lateral ventricles over the skull (ventricle-to-skull ratio [VSR]) was measured to estimate brain atrophy; (b) cerebral white matter was visually scored as percentage normal, hyperintense, rarefied, or cystic on fluid-attenuated inversion recovery (FLAIR) images and converted into a white matter decay score; and (c) the intracranial volume was segmented into normal-appearing white and gray matter, abnormal but structurally present (FLAIRhyperintense) and rarefied or cystic (FLAIR-hypointense) white matter, and ventricular and extracerebral cerebrospinal fluid (CSF). Multilevel regression analyses with patient as a clustering variable were performed to account for the nested data structure. Results: A total of 461 examinations in 270 patients (median age, 7 years [interquartile range, 3-18 years]; 144 female patients) were evaluated; 112 patients had undergone serial imaging. Patients with later onset had higher VSR [F(5) = 8.42; P <.001] and CSF volume [F(5) = 21.7; P <.001] and lower white matter decay score [F(5) = 4.68; P <001] and rarefied or cystic white matter volume [F(5) = 13.3; P <001]. Rate of progression of white matter decay scores [b = -1.6, t(109) = -3.9; P , .001] and VSRs [b = -0.05, t (109) = -3.7; P<.001] were lower with later onset. Conclusion: A radiologic spectrum based on age at onset exists in vanishing white matter. The earlier the onset, the faster and more cystic the white matter decay, whereas with later onset, white matter atrophy and gliosis predominate