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.
NEURORADIOLOGYI n vanishing white matter (VWM), a form of leukodystrophy, the cerebral white matter is the only or the most prominently affected tissue (1). The MRI feature defining VWM is progressive rarefaction and cystic decay of the cerebral white matter, leading to a white matter signal close to or the same as that of cerebrospinal fluid (CSF) on proton density and fluid-attenuated inversion recovery (FLAIR) images (1). The rarefied and cystic white matter typically contains radiating stripes, suggesting relatively preserved perivascular tissue strands (1). The white matter involvement is extensive or diffuse (1); only the directly subcortical white matter may be spared (2). Neuropathologic evaluation confirms the interpretation of the MRI findings (3).VWM is caused by biallelic sequence variations in any of the EIF2B1-5 genes, which encode the five subunits of the eukaryotic translation initiation factor eIF2B (4,5). The onset of VWM is mainly in early childhood but ranges from the antenatal period to senescence (6). For onset before age 4 years, earlier manifestation is associated with faster clinical disease progression. Patients with onset after age 4 years tend to have a milder disease course, irrespective of the exact age at onset (6).Currently, there is no therapy for VWM, but various drugs are in clinical development and will be assessed in trials (7-9). Although clinical parameters provide primary outcome measures, MRI parameters may serve as secondary or surrogate outcome measures. For the past 3 decades, MRI has played an important role in the diagnosis of VWM (1). The time course of the cerebral white matter decay has, however, not been investigated, and systematic information on MRI evolution for different ages of onset is lacking. For MRI to play a role in therapeutic trials, this basic information is needed. We therefore studied the progression of cerebral white matter abnormalities at MRI in a large group of patients with genetically confirmed VWM, representing all ages of onset.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 wa...
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.
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