To identify the phenotypic, neuroimaging, and genotype-phenotype expression of MYORG mutations.

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.

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.

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.

鉴定MYORG突变的表型、神经影像学和基因型-表型表达。

使用下一代测序，我们筛选了来自 60 个具有常染色体隐性遗传或无家族史且 SLC20A2、PDGFRB、PDGBB和XPR1突变阴性的家族的 86 名原发性家族性脑钙化 (PFBC) 患者。在这里报告的所有病例中都进行了深入的表型分析和神经影像学调查。

我们在 PFBC 的 60 个家族中的 7 个中鉴定了 12 个不同的有害MYORG变体。总体而言，双等位基因MYORG突变占我们队列中 PFBC 家族的 11.6%。在中位发病年龄为 56.4 岁、帕金森症、小脑体征和认知衰退的可变组合的家庭内部和家庭之间发现了异质的表型表达。精神障碍不是一个突出的特征。认知评估显示 62.5% 的病例认知功能受损。与垂直核凝视麻痹相关的帕金森症是 1/3 病例的初始临床表现，并与中央脑桥钙化有关。37% 的病例出现脑皮质萎缩。

这项大型多中心研究表明，双等位基因MYORG突变在常染色体隐性遗传 PFBC 中占很大比例。我们建议在所有原发性脑钙化和常染色体隐性遗传或阴性家族史的患者中筛查MYORG突变，特别是当临床表现为非典型帕金森症和脑 CT 上存在桥脑钙化时。