Dataset Information

MYORG-related disease is associated with central pontine calcifications and atypical parkinsonism.

ABSTRACT: Objective:To identify the phenotypic, neuroimaging, and genotype-phenotype expression of MYORG mutations. Methods:Using next-generation sequencing, we screened 86 patients with primary familial brain calcification (PFBC) from 60 families with autosomal recessive or absent family history that were negative for mutations in SLC20A2, PDGFRB, PDGBB, and XPR1. In-depth phenotyping and neuroimaging investigations were performed in all cases reported here. Results:We identified 12 distinct deleterious MYORG variants in 7 of the 60 families with PFBC. Overall, biallelic MYORG mutations accounted for 11.6% of PFBC families in our cohort. A heterogeneous phenotypic expression was identified within and between families with a median age at onset of 56.4 years, a variable combination of parkinsonism, cerebellar signs, and cognitive decline. Psychiatric disturbances were not a prominent feature. Cognitive assessment showed impaired cognitive function in 62.5% of cases. Parkinsonism associated with vertical nuclear gaze palsy was the initial clinical presentation in 1/3 of cases and was associated with central pontine calcifications. Cerebral cortical atrophy was present in 37% of cases. Conclusions:This large, multicentric study shows that biallelic MYORG mutations represent a significant proportion of autosomal recessive PFBC. We recommend screening MYORG mutations in all patients with primary brain calcifications and autosomal recessive or negative family history, especially when presenting clinically as atypical parkinsonism and with pontine calcification on brain CT.

SUBMITTER: Chelban V

PROVIDER: S-EPMC7073457 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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<i>MYORG</i>-related disease is associated with central pontine calcifications and atypical parkinsonism.

Chelban Viorica V Carecchio Miryam M Rea Gillian G Bowirrat Abdalla A Kirmani Salman S Magistrelli Luca L Efthymiou Stephanie S Schottlaender Lucia L Vandrovcova Jana J Salpietro Vincenzo V Salsano Ettore E Pareyson Davide D Chiapparini Luisa L Jan Farida F Ibrahim Shahnaz S Khan Fatima F Qarnain Zul Z Groppa Stanislav S Bajaj Nin N Balint Bettina B Bhatia Kailash P KP Lees Andrew A Morrison Patrick J PJ Wood Nicholas W NW Garavaglia Barbara B Houlden Henry H

Neurology. Genetics 20200220 2

<h4>Objective</h4>To identify the phenotypic, neuroimaging, and genotype-phenotype expression of <i>MYORG</i> mutations.<h4>Methods</h4>Using next-generation sequencing, we screened 86 patients with primary familial brain calcification (PFBC) from 60 families with autosomal recessive or absent family history that were negative for mutations in <i>SLC20A2</i>, <i>PDGFRB</i>, <i>PDGBB</i>, and <i>XPR1</i>. In-depth phenotyping and neuroimaging investigations were performed in all cases reported he ...[more]

PMID: 32211515

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Project description:Conventional single tensor diffusion analysis models have provided mixed findings in the substantia nigra of Parkinson's disease, but recent work using a bi-tensor analysis model has shown more promising results. Using a bi-tensor model, free-water values were found to be increased in the posterior substantia nigra of Parkinson's disease compared with controls at a single site and in a multi-site cohort. Further, free-water increased longitudinally over 1 year in the posterior substantia nigra of Parkinson's disease. Here, we test the hypothesis that other parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy have elevated free-water in the substantia nigra. Equally important, however, is whether the bi-tensor diffusion model is able to detect alterations in other brain regions beyond the substantia nigra in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy and to accurately distinguish between these diseases. Free-water and free-water-corrected fractional anisotropy maps were compared across 72 individuals in the basal ganglia, midbrain, thalamus, dentate nucleus, cerebellar peduncles, cerebellar vermis and lobules V and VI, and corpus callosum. Compared with controls, free-water was increased in the anterior and posterior substantia nigra of Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. Despite no other changes in Parkinson's disease, we observed elevated free-water in all regions except the dentate nucleus, subthalamic nucleus, and corpus callosum of multiple system atrophy, and in all regions examined for progressive supranuclear palsy. Compared with controls, free-water-corrected fractional anisotropy values were increased for multiple system atrophy in the putamen and caudate, and increased for progressive supranuclear palsy in the putamen, caudate, thalamus, and vermis, and decreased in the superior cerebellar peduncle and corpus callosum. For all disease group comparisons, the support vector machine 10-fold cross-validation area under the curve was between 0.93-1.00 and there was high sensitivity and specificity. The regions and diffusion measures selected by the model varied across comparisons and are consistent with pathological studies. In conclusion, the current study used a novel bi-tensor diffusion analysis model to indicate that all forms of parkinsonism had elevated free-water in the substantia nigra. Beyond the substantia nigra, both multiple system atrophy and progressive supranuclear palsy, but not Parkinson's disease, showed a broad network of elevated free-water and altered free-water corrected fractional anisotropy that included the basal ganglia, thalamus, and cerebellum. These findings may be helpful in the differential diagnosis of parkinsonian disorders, and thereby facilitate the development and assessment of targeted therapies.

Dataset Information

MYORG-related disease is associated with central pontine calcifications and atypical parkinsonism.

Publications

<i>MYORG</i>-related disease is associated with central pontine calcifications and atypical parkinsonism.

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