Different patterns of cerebellar abnormality and hypomyelination between POLR3A and POLR3B mutations

Takanashi, Jun‐ichi; Osaka, Hitoshi; Saitsu, Hirotomo; Sasaki, Masayuki; Mori, Hiromu; Shibayama, Hidehiro; Tanaka, Manabu; Nomura, Yasuo; Terao, Yasuo; Inoue, Ken; Matsumoto, Naomichi; Barkovich, A. James

doi:10.1016/j.braindev.2013.03.006

Cited by 27 publications

(32 citation statements)

References 14 publications

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“…There is only 1 other recent qualitative study looking at the presence of cerebellar atrophy and hypomyelination in a cohort of 6 Japanese patients with Pol III-related leukodystrophies. 20 Our study supports the reliability of all the MRI features proposed by Steenweg et al 3 applicable for Pol IIIrelated leukodystrophies. 3 The association of all the criteria (ie, T2 hypointensity of the pallida, anterolateral nuclei of the thalami, dentate nuclei and pyramidal tracts, or periventricular white matter and cerebellar atrophy) was present in the large majority of Pol III-related leukodystrophies in this small sample set.…”

Section: Discussionsupporting

confidence: 87%

Brain Magnetic Resonance Imaging (MRI) Pattern Recognition in Pol III-Related Leukodystrophies

et al. 2013

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Pol III-related leukodystrophies are caused by mutations in POLR3A and POLR3B genes and all share peculiar imaging and clinical features. The objectives of this study are (1) to define the neuroradiologic pattern in a cohort of POLR3A and POLR3B subjects and (2) to compare the neuroradiologic pattern of Pol III-related leukodystrophies with other hypomyelinating disorders. The magnetic resonance imaging (MRI) examinations of 13 patients with POLR3A and POLR3B mutations and of 14 patients with other hypomyelinating disorders were analyzed. All the subjects with Pol III-related leukodystrophies presented hypomyelination associated with T2 hypointensity of the thalami and/or the pallida. Twelve subjects (92%) presented T2 hypointensity of the optic radiations. Cerebellar atrophy was observed in most patients (92%). The combination of the analyzed criteria identified patients with Pol III-related leukodystrophies with a sensitivity of 84.6% and a specificity of 92.9%.

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Section: Discussionsupporting

confidence: 87%

Brain Magnetic Resonance Imaging (MRI) Pattern Recognition in Pol III-Related Leukodystrophies

et al. 2013

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“…Cerebellar atrophy was previously known to be associated with POLR3A or POLR3B mutations in more than 80% of the participants, always in combination with diffuse hypomyelination. [12][13][14]21 Focal, partly confluent T2-hyperintense white matter changes were present in some participants of both groups and located in the deep frontal and parietal white matter. The signal intensity of the abnormal areas corresponds to the one seen in hypomyelination, focal hypomyelination therefore being the most likely interpretation.…”

Section: Resultsmentioning

confidence: 97%

Diffuse hypomyelination is not obligate for POLR3-related disorders

et al. 2016

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Objective: To report atypical MRI patterns associated with POLR3A and POLR3B mutations.Methods: This was a multicenter retrospective study to collect neuroradiologic, clinical, and molecular data of patients with mutations in POLR3A and POLR3B without the classic MRI phenotype, i.e., diffuse hypomyelination associated with relative T2 hypointensity of the ventrolateral thalamus, globus pallidus, optic radiation, corticospinal tract at the level of the internal capsule, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum.Results: Eight patients were identified: 6 carried mutations in POLR3A and 2 in POLR3B. We identified 2 novel MRI patterns: 4 participants presented a selective involvement of the corticospinal tracts, specifically at the level of the posterior limbs of the internal capsules; 4 patients presented moderate to severe cerebellar atrophy. Incomplete hypomyelination was observed in 5 participants.Conclusion: Diffuse hypomyelination is not an obligatory feature of POLR3-related disorders.Two distinct patterns, selective involvement of the corticospinal tracts and cerebellar atrophy, are added to the MRI presentation of POLR3-related disorders. POLR3-related leukodystrophy is a rare autosomal recessive disease characterized by hypomyelination often accompanied by dental abnormalities and hypogonadotropic hypogonadism. [1][2][3][4][5] In its classical form, the association of these features is referred to as 4H syndrome.1,2 Mutations in the POLR3A and POLR3B genes, which encode for the 2 largest subunits of the RNA polymerase III (POLR3) complex, as well as in POLR1C, also encoding a POLR3 subunit, are responsible for this disease. [6][7][8][9][10][11] With the identification of the causative genes, patients with suggestive clinical or MRI picture can undergo genetic testing, confirming the diagnosis. 12 The MRI pattern of POLR3-related leukodystrophy is suggestive and characterized by diffuse hypomyelination associated with relative T2 hypointensity of the ventrolateral thalamus, globus pallidus, optic radiation, corticospinal tract at the level of the internal capsule and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum.12-14 Recognition of this pattern was proven effective in detecting patients with 4H leukodystrophy caused by POLR3A-B or POLR1C mutations and is therefore *These authors contributed equally to this work. ‡Dual last authors.

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“…Interestingly, although it was considered as one of the essential radiologic findings, 10 cerebellar atrophy is absent or mild in a substantial number of patients with POLR3A mutations, confirming the results from a previous small study on 6 patients. 15 We are still far from understanding the pathogenesis of 4H leukodystrophy. The combination of hypomyelination with the peculiar dental anomalies remains enigmatic.…”

Section: Resultsmentioning

confidence: 99%

Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations

et al. 2014

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Objective: To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B.Methods: We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. Results:The majority of patients presented before 6 years with gross motor delay or regression.Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the common c.1568T.A POLR3B mutation on one allele, homozygosity for which causes a mild phenotype. Systematic MRI review revealed that the combination of hypomyelination with relative T2 hypointensity of the ventrolateral thalamus, optic radiation, globus pallidus, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum suggests the diagnosis. Conclusions: 4H is a well-recognizable clinical entity if all features are present. Mutations inPOLR3A are associated with a more severe clinical course. MRI characteristics are helpful in addressing the diagnosis, especially if patients lack the cardinal non-neurologic features. 4H leukodystrophy (4H) (HLD7, OMIM 607694 and HLD8, OMIM 614381) is typically characterized by the triad of hypomyelination, hypodontia, and hypogonadotropic hypogonadism. It was first identified in 4 children too young for the assessment of pubertal development. Clinical hallmarks were early-onset ataxia, delayed dentition, and hypomyelination (ADDH).

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Different patterns of cerebellar abnormality and hypomyelination between POLR3A and POLR3B mutations

Cited by 27 publications

References 14 publications

Brain Magnetic Resonance Imaging (MRI) Pattern Recognition in Pol III-Related Leukodystrophies

Brain Magnetic Resonance Imaging (MRI) Pattern Recognition in Pol III-Related Leukodystrophies

Diffuse hypomyelination is not obligate for POLR3-related disorders

Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations

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