Underestimated disease prevalence and severe phenotypes in patients with biallelic variants: A cohort study of primary familial brain calcification from China

Chen, Si; Cen, Zhidong; Fu, Feng; Chen, You; Chen, Xinhui; Yang, Dehao; Wang, Haotian; Wu, Hongwei; Zheng, Xiaosheng; Xie, Fei; Ouyang, Zhiyuan; Tang, Weiguo; Zhang, Shuhong; Yin, Lili; Zhang, Yun‐Qian; Meng, Peiying; Zhu, Xuzhen; Zhang, Hongwei; Jiang, Feifei; Zhang, Kaiyu; He, Juan; Zhang, Danhong; Ming, Hanqiao; Song, Daqiao; Zhou, Zhiping; Luo, Yong; Gu, Qun; Su, Yongkun; Wu, Xinxiao; Tang, Haiyan; Wu, Chenglong; Chen, Weiqing; Liu, Jingyu; Luo, Wei; Huang, Xuerong; Fu, Shaowei; Chen, Wenhai; Huang, Yanjiang; Lan, Likang; Zhu, Xiaodong; Xu, Zhijun; Hu, Huang; Zhou, Lifeng; Chen, Zilong; Lou, Minfang; Wang, Binglan; Tan, Yan; Zhu, Manlian; Hong, Weijun; Wang, Feng; Pan, Gonghua; Shao, Aimin; Li, Weiying; Li, Haijun; Zhao, Na; Hu, Haoyu; Zhang, Yaxi; Lian, Mengjia; Li, Jieying; Cai, X R; Luo, Zixian; Zhou, Yan; Lu, Xihong; Ma, Li; Xia, Enkui; Zhang, Xiaoluo

doi:10.1016/j.parkreldis.2019.04.009

Cited by 17 publications

(15 citation statements)

References 25 publications

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“…Overall minimal prevalence of PFBC is estimated to be 2.1 to 6.6 per 1,000. 1,2 Affected individuals could remain asymptomatic throughout their lifetime or present with a wide spectrum of neurological and psychiatric symptoms. Since the finding of SLC20A2, 3 the first PFBC-associated gene, mutations in three other genes, PDGFRB, 4 PDGFB, 5 and XPR1, 6 have been consecutively identified to be responsible for autosomal-dominant PFBC (AD-PFBC).…”

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confidence: 99%

MYORG Mutation Heterozygosity Is Associated With Brain Calcification

et al. 2020

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A BS TRACT: Background: Biallelic mutations in the MYORG gene were first identified as the cause of recessively inherited primary familial brain calcification. Interestingly, some heterozygous carriers also exhibited brain calcifications.Objectives: To further investigate the role of single heterozygous MYORG mutations in the development of brain calcifications. Methods: A nation-wide cohort of Chinese primary familial brain calcification probands was enrolled from March 2016 ---

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MYORG Mutation Heterozygosity Is Associated With Brain Calcification

et al. 2020

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“…MSA is fatal, with median survival from onset to death of 6-10 years and median time from diagnosis to death of approximately 3 years. 1,2 Clinical and objective autonomic features such as urinary incontinence, falls, older age, greater degree of autonomic failure, and male sex have been associated with poor survival. [1][2][3] Vitamin B12 has been shown to inhibit α-synuclein fibrillation and cytotoxicity in neuronal cultures and cytotoxicity assays, as well as alleviate dopaminergic dysfunction in mouse models of Parkinson's disease, suggesting a potential disease-modifying effect.…”

Section: Supporting Datamentioning

confidence: 99%

“…1,2 Clinical and objective autonomic features such as urinary incontinence, falls, older age, greater degree of autonomic failure, and male sex have been associated with poor survival. [1][2][3] Vitamin B12 has been shown to inhibit α-synuclein fibrillation and cytotoxicity in neuronal cultures and cytotoxicity assays, as well as alleviate dopaminergic dysfunction in mouse models of Parkinson's disease, suggesting a potential disease-modifying effect. 4,5 Allosteric modulation of leucine-rich repeat kinase 2 (LRRK2) is thought to be one of the main neuroprotective mechanisms of vitamin B12.…”

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confidence: 99%

“…Primary familial brain calcification (PFBC) is another rare genetic disorder characterized by a variety of neurological and psychiatric features, including movement disorders, ataxia, psychiatric symptoms, dementia, and seizures . Notably, a high proportion of patients with PFBC (up to 80%) are asymptomatic . Brain computed tomography (CT) scans show calcium depositions in bilateral basal ganglia, thalamic nuclei, cerebellum, and subcortical regions.…”

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Novel Phenotype of 6p25 Deletion Syndrome Presenting Juvenile Parkinsonism and Brain Calcification

2020

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Background: Chromosome 6p25 deletion syndrome is a rare neurocristopathy with variable clinical features. The objective of the current study was to describe a novel phenotype for autosomaldominant chromosome 6p25 deletion syndrome. The presentation included bilateral basal ganglia and subcortical calcifications and juvenile parkinsonism, resembling primary familial brain calcification. Methods: Phenotypic characterization, exome sequencing, and oligonucleotide array were carried out in the index family. Results: The index patient and her mother had a history of developmental delay, mild facial dysmorphism, Axenfield eye anomalies, slight intellectual disability, and subsequently developed levodopa-responsive parkinsonism in early adulthood. Brain-computed tomography showed bilateral basal ganglia and subcortical calcifications. Magnetic resonance imaging revealed diffuse white matter lesions. A 99mTc TRODAT singlephoton emission computed tomography scan revealed bilateral dopaminergic denervation. Whole-exome sequencing and oligonucleotide array-based comparative genomic hybridization revealed a 2.27-Mb chromosome 6pter-p24 deletion, which cosegregated within the family. Conclusions: Our findings extended the current phenotypic spectrum of chromosome 6p25 deletion syndrome.

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“…PFBC is a clinically and genetically heterogenous disease caused by mutations in at least in five genes – MYORG, PDGFB, PDGFRB, SLC20A2 and XPR1 21–25 . Of note, recent studies have estimated the minimal prevalence of PFBC ranges from 4-6 p. 10,000, depending of the causative gene mutation, thus suggesting that PFBC is not a rare disorder and is likely underdiagnosed 26, 27 . In addition, basal ganglia calcification is a common radiological finding, estimated in up to 20% of patients undergoing CT imaging 28, 29 .…”

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Microglia control small vessel calcification via TREM2

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Nassiri

Utz

et al. 2019

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23Microglia participate in CNS development and homeostasis and are often implicated in 24 modulating disease processes in the CNS. However, less is known about the role of microglia 25 in the biology of the neurovascular unit (NVU). In particular, data are scant on whether 26 microglia are involved in CNS vascular pathology. In this study, we use a mouse model of 27 primary familial brain calcification (PFBC) -Pdgfb ret/ret to investigate the role of microglia in 28 calcification of the NVU. We report that microglia enclosing vessel-calcifications, coined 29 calcification-associated microglia (CAM), display a distinct activation signature. 30Pharmacological ablation of microglia with the CSF1R inhibitor -PLX5622 leads to aggravated 31 vessel calcification. Additionally, depletion of microglia in wild-type and Pdgfb ret/ret mice 32 causes the development of bone protein (osteocalcin, osteopontin) containing axonal spheroids 33 in the white matter. Mechanistically, we show that microglia require functional TREM2 for 34 controlling vessel-associated calcification. In conclusion, our results demonstrate that 35 microglial activity in the setting of pathological vascular calcification is beneficial. In addition, 36we identify a new, previously unrecognized function of microglia in halting the expansion of 37 ectopic calcification. 38 39 2 injury results in microglial activation with the rapid development of processes that shield a 57 lesioned blood vessel section and phagocytose debris 2 . These findings support the important 58 role of microglia in vascular repair. 59Optimal functioning of the NVU, which mediates hyperaemia, is crucial for cerebral 60 perfusion 4 . Blood vessels play an integral role in brain development and provide a niche for 61 brain stem cells. In addition, cerebral vasculature senses the environment and communicates 62 changes to neural tissue, participates in glymphatic clearance, and controls immune quiescence 63 in the CNS [11][12][13][14][15] . Accordingly, dysfunction of the NVU accompanies or may even represent a 64 primary cause of many neurodegenerative diseases 4,16 . In the case of the primary familial brain 65 calcification (PFBC), bilateral basal ganglia calcification of blood vessels is a key diagnostic 66 criterion. The pathogenic mechanism points to a compromised NVU 17-20 . PFBC is a clinically 67 and genetically heterogenous disease caused by mutations in at least in five genes -MYORG, 68 PDGFB, PDGFRB, SLC20A2 and XPR1 21-25 . Of note, recent studies have estimated the 69 minimal prevalence of PFBC ranges from 4-6 p. 10,000, depending of the causative gene 70 mutation, thus suggesting that PFBC is not a rare disorder and is likely underdiagnosed 26,27 . In 71 addition, basal ganglia calcification is a common radiological finding, estimated in up to 20% 72 3 of patients undergoing CT imaging 28,29 . Although the effect of cerebral calcification on the 73 NVU and brain parenchyma is unknown, peripheral vascular calcification can lead to 74 cardiovascular morbidity and mortality...

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Underestimated disease prevalence and severe phenotypes in patients with biallelic variants: A cohort study of primary familial brain calcification from China

Cited by 17 publications

References 25 publications

MYORG Mutation Heterozygosity Is Associated With Brain Calcification

MYORG Mutation Heterozygosity Is Associated With Brain Calcification

Novel Phenotype of 6p25 Deletion Syndrome Presenting Juvenile Parkinsonism and Brain Calcification

Microglia control small vessel calcification via TREM2

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