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

Abstract

ObjectiveTo identify the phenotypic, neuroimaging, and genotype-phenotype expression of MYORG mutations.MethodsUsing 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.ResultsWe 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.ConclusionsThis 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.

Mutation Analysis of MYORG in a Chinese Cohort With Primary Familial Brain Calcification

“…Parkinsonism with vertical nuclear gaze palsy was uncommon in MYORG mutation carriers, but occurred in case 4, thus, extending the phenotypic spectrum of MYORG-related PFBC. Parkinsonism with vertical nuclear gaze palsy was reported to be associated with pontine calcifications, which were also noticed in the brain CT of case 4 (Chelban et al, 2020). In our study, homozygous or truncating mutations of MYORG could be associated with a more severe phenotype, such as in case 1 and case 4.…”

“…We screened a total of 245 Chinese subjects including 21 subjects from 10 possibly autosomal recessive families and 224 sporadic cases. Eight MYORG variants were identified in six sporadic cases, while four of the eight variants were previously reported (c.103A > G, p.M35V; c.782_783GC > TT, p. R261L; c.1092_1097delCTTCGA, p.365_366delFD; and c.1967T > C, p. I656T) (Supplementary Figures S1A-D) (Yao et al, 2018;Forouhideh et al, 2019;Chelban et al, 2020;Chen et al, 2020). Notably, four novel variants in MYORG were identified: two nonsense variants (c.442C > T, p. Q148*; c.972C > A, p. Y324*) and two missense variants (c.1969G>C, p. G657R; c.2033C > G, p. P678R) (Figures 1A-D).…”

Hereditary and non-hereditary etiologies associated with extensive brain calcification: case series

“…A detailed laboratory examination did not show significant difference between the cases. Interestingly, the pontine calcification (observed in Case 1, 4, 5) was not detected in our two SLC20A2 cases, in line with the literature (Nicolas et al 2013a, b); Chelban et al (2020) reported that pontin calcification on head CT may refer to MYORG mutation. These two cases point out that involvement of the same gene, partly depending on the different site of mutation, may also have different phenotypes.…”

Spastic paraplegia preceding PSEN1‐related familial Alzheimer's disease

“…Reads alignment using the hg19 human genome reference, variant calling and annotation were performed as described previously. 21 All cases were screened and were negative for known HSP-related genes.…”