Digenic Variants as Possible Clinical Modifier of Primary Familial Brain Calcification Patients

Borges-Medeiros, Rayssa L.; Oliveira, João Ricardo Mendes de

doi:10.1007/s12031-019-01430-9

Cited by 6 publications

(3 citation statements)

References 17 publications

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“…Calcification degree and scope could be revealed by CT scan in the clinic, and these brain lesions had nearly complete penetrance for those harboring causative mutations, whereas its variable expressivity among patients with PFBC suggests the detrimental or protective effects of other genetic modifiers. Moreover, environmental factors could also affect the severity of brain calcification (de Oliveira et al, 2013;Donzuso et al, 2019;Grangeon et al, 2019;Borges-Medeiros and de Oliveira, 2020). The multisystem abnormalities and extensive brain calcifications found only in Slc20a2-HO mice might be explained by the discrepancy in gene dosage sensitivity between mice and humans.…”

Section: Gene Dosage Effect and Sensitivity In Mice And Patients With Pfbcmentioning

confidence: 99%

Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities

Ren

Shen

et al. 2021

Front. Genet.

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BackgroundPrimary familial brain calcification (PFBC, OMIM#213600), also known as Fahr’s disease, is a rare autosomal dominant or recessive neurodegenerative disorder characterized by bilateral and symmetrical microvascular calcifications affecting multiple brain regions, particularly the basal ganglia (globus pallidus, caudate nucleus, and putamen) and thalamus. The most common clinical manifestations include cognitive impairment, neuropsychiatric signs, and movement disorders. Loss-of-function mutations in SLC20A2 are the major genetic causes of PFBC.ObjectiveThis study aimed to investigate whether Slc20a2 knockout mice could recapitulate the dynamic processes and patterns of brain calcification and neurological symptoms in patients with PFBC. We comprehensively evaluated brain calcifications and PFBC-related behavioral abnormalities in Slc20a2-deficient mice.MethodsBrain calcifications were analyzed using classic calcium-phosphate staining methods. The Morris water maze, Y-maze, and fear conditioning paradigms were used to evaluate long-term spatial learning memory, working memory, and episodic memory, respectively. Sensorimotor gating was mainly assessed using the prepulse inhibition of the startle reflex program. Spontaneous locomotor activity and motor coordination abilities were evaluated using the spontaneous activity chamber, cylinder test, accelerating rotor-rod, and narrowing balance beam tests.ResultsSlc20a2 homozygous knockout (Slc20a2-HO) mice showed congenital and global developmental delay, lean body mass, skeletal malformation, and a high proportion of unilateral or bilateral eye defects. Brain calcifications were detected in the hypothalamus, ventral thalamus, and midbrain early at postnatal day 80 in Slc20a2-HO mice, but were seldom found in Slc20a2 heterozygous knockout (Slc20a2-HE) mice, even at extremely old age. Slc20a2-HO mice exhibited spatial learning memory impairments and sensorimotor gating deficits while exhibiting normal working and episodic memories. The general locomotor activity, motor balance, and coordination abilities were not statistically different between Slc20a2-HO and wild-type mice after adjusting for body weight, which was a major confounding factor in our motor function evaluations.ConclusionThe human PFBC-related phenotypes were highly similar to those in Slc20a2-HO mice. Therefore, Slc20a2-HO mice might be suitable for the future evaluation of neuropharmacological intervention strategies targeting cognitive and neuropsychiatric impairments.

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Section: Gene Dosage Effect and Sensitivity In Mice And Patients With Pfbcmentioning

confidence: 99%

Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities

Ren

Shen

et al. 2021

Front. Genet.

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“…All PFBC patients with biallelic SLC20A2 variants showed more severe phenotypes than their family members with heterozygous variants, which indicated that the second mutation might promote the development of PFBC. Coincidentally, PFBC patients with variants in both a PFBC pathogenic gene (SLC20A2 or PDGFRB) and another PFBC-unrelated gene (THAP1, CHRNB2, CASR, SCN2A or MEA6) were described as presenting more complex phenotypes, supporting the notion that a variant of a second gene may promote a heterogeneous phenotype in PFBC patients (Baker et al, 2014;Borges-Medeiros & de Oliveira, 2020;DeMeo et al, 2018;Fjaer et al, 2015;Fujioka et al, 2015;Knowles et al, 2018). The SLC20A2 c.1787A>G (p.His596Arg) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to PiT2 dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al, 2019).…”

Section: Discussionmentioning

confidence: 88%

Severe brain calcification and migraine headache caused by SLC20A2 and PDGFRB heterozygous mutations in a five‐year‐old Chinese girl

Sun

Cao

Gao

et al. 2021

Molec Gen & Gen Med

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Primary familial brain calcification (PFBC) is a rare inheritable neurodegenerative disease mainly characterized by symmetrical calcification in the basal ganglia, thalamus, cerebellum, and brainstem (Wang et al., 2012). Patients with PFBC may experience movement disorders, cognitive impairment, psychiatric signs, or other associated manifestations with diverse severity and variable onset age or may be asymptomatic throughout their lives (Nicolas et al., 2015;Wang et al., 2015).PFBC can be transmitted in an autosomal dominant or recessive manner. PFBC causative genes identified to date

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“…In contrast, PDGFRB has the lowest clinical penetrance (46%) [ 3 ]. The clinical variability and reduced penetrance may be influenced by other yet unidentified genetic modifiers [ 28 ].…”

Section: Clinical Presentationsmentioning

confidence: 99%

The Genetics of Primary Familial Brain Calcification: A Literature Review

Chen

et al. 2023

IJMS

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Primary familial brain calcification (PFBC), also known as Fahr’s disease, is a rare inherited disorder characterized by bilateral calcification in the basal ganglia according to neuroimaging. Other brain regions, such as the thalamus, cerebellum, and subcortical white matter, can also be affected. Among the diverse clinical phenotypes, the most common manifestations are movement disorders, cognitive deficits, and psychiatric disturbances. Although patients with PFBC always exhibit brain calcification, nearly one-third of cases remain clinically asymptomatic. Due to advances in the genetics of PFBC, the diagnostic criteria of PFBC may need to be modified. Hitherto, seven genes have been associated with PFBC, including four dominant inherited genes (SLC20A2, PDGFRB, PDGFB, and XPR1) and three recessive inherited genes (MYORG, JAM2, and CMPK2). Nevertheless, around 50% of patients with PFBC do not have pathogenic variants in these genes, and further PFBC-associated genes are waiting to be identified. The function of currently known genes suggests that PFBC could be caused by the dysfunction of the neurovascular unit, the dysregulation of phosphate homeostasis, or mitochondrial dysfunction. An improved understanding of the underlying pathogenic mechanisms for PFBC may facilitate the development of novel therapies.

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Digenic Variants as Possible Clinical Modifier of Primary Familial Brain Calcification Patients

Cited by 6 publications

References 17 publications

Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities

Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities

Severe brain calcification and migraine headache caused by SLC20A2 and PDGFRB heterozygous mutations in a five‐year‐old Chinese girl

The Genetics of Primary Familial Brain Calcification: A Literature Review

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