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.

Mitochondrial dysfunction is involved in the pathogenesis of atherosclerosis, the primary risk factor for ischemic stroke. This study aims to explore the role of mitochondrial genomic variations in ischemic stroke, and to uncover the nuclear genes involved in this relationship. Eight hundred and thirty Taiwanese patients with a history of ischemic stroke and 966 normal controls were genotyped for their mitochondrial haplogroup (Mthapg). Cytoplasmic hybrid cells (cybrids) harboring different Mthapgs were used to observe functional differences under hypoxia-ischemia. RNA sequencing (RNASeq) was conducted to identify the particularly elevated mRNA. The patient study identified an association between Mthapg F1 and risk of ischemic stroke (OR 1.72:1.27–2.34, p = 0.001). The cellular study further demonstrated an impeded induction of hypoxic inducible factor 1α in the Mthapg F1 cybrid after hypoxia-ischemia. Additionally, the study demonstrated that Mthapg F cybrids were associated with an altered mitochondrial function, including decreased oxygen consumption, higher mitochondrial ROS production, and lower mitochondrial membrane potential. Mthapg F cybrids were also noted to be prone to inflammation, with increased expression of several inflammatory cytokines and elevated matrix metalloproteinase 9. The RNASeq identified significantly elevated expressions of angiopoietin-like 4 in Mthapg F1 cybrids after hypoxia-ischemia. Our study demonstrates an association between Mthapg F and susceptibility to ischemic stroke.

Hippocampal malrotation (HIMAL) is an increasingly recognized neuroimaging feature but the clinical correlation and significance in epilepsies remain under debate. It is characterized by rounded hippocampal shape, deep collateral, or occipitotemporal sulcus, and medial localization of the hippocampus. In this review, we describe the embryonic development of the hippocampus and HIMAL, the qualitative and quantitative diagnosis issues, and the pathological findings of HIMAL. HIMAL can be bilateral or unilateral and more on the left side. Furthermore, the relevance of HIMAL diagnosis in clinical practice, including its role in epileptogenesis and the impact on the pre-surgical decision are reviewed. Finally, the relationship between HIMAL and hippocampal sclerosis (HS) and the possible role of genetics in the etiology of HIMAL are discussed. The evidence so far suggested that HIMAL does not have a significant role in epileptogenesis or surgical decision. HIMAL could be a genetic developmental imaging feature that represents a more diffuse but subtle structural error during brain development. Many questions remain to be explored, such as possible cognitive alteration associated with HIMAL and whether HIMAL predisposes to the development of HS. Further studies using high-quality MRI, unified consensus qualitative and quantitative diagnostic criteria, and comprehensive cognitive assessment are recommended.