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Many conditions can present with accumulation of calcium in the brain and manifest with a variety of neurological symptoms. Brain calcifications can be primary (idiopathic or genetic) or secondary to various pathological conditions (e.g., calcium–phosphate metabolism derangement, autoimmune disorders and infections, among others). A set of causative genes associated with primary familial brain calcification (PFBC) has now been identified, and include genes such as SLC20A2, PDGFB, PDGFRB, XPR1, MYORG, and JAM2. However, many more genes are known to be linked with complex syndromes characterized by brain calcifications and additional neurologic and systemic manifestations. Of note, many of these genes encode for proteins involved in cerebrovascular and blood–brain barrier functions, which both represent key anatomical structures related to these pathological phenomena. As a growing number of genes associated with brain calcifications is identified, pathways involved in these conditions are beginning to be understood. Our comprehensive review of the genetic, molecular, and clinical aspects of brain calcifications offers a framework for clinicians and researchers in the field.

Primary brain calcification (PBC), genetically heterogeneous disorder, is characterized by abnormal calcification deposition in various brain regions, including the bilateral basal nuclei. The disease presents with a variety of symptoms, including cognitive impairment, parkinsonism, psychiatric signs or even remains asymptomatic. We herein present a case of a 39-year-old man with a homozygous rare variant with unknown pathological significance (c.284 T > C, pLeu95Pro) in the major causative gene, MYORG for PBC. He presented to the hospital with mild speech disorder and ataxia. Over the years, dysarthria and ataxia progressed. Brain computed tomography (CT) scans were performed almost annually and evaluated using the total calcification score (TCS). The calcified part of the brain was observed in three-dimensional while rotating, and the total calcification volume was measured using an image analyzer. The TCSs remained unchanged, however, the image analyzer clearly showed the calcified area in the brain and an increasing calcification volume in the same CT machine and under the same condition. The evaluation method is very useful for the three-dimensional observation and quantification of calcification. •A rare genetic variant in the MYORG gene was identified in a 39-year-old Japanese PBC patient.•The patient's symptoms progressed year by year without any change in TCS.•The calcified areas could be observed three-dimensionally using the image analyzer.•It was confirmed that the volume of the calcified areas tended to increase.•The evaluation method is very useful for the three-dimensional observation and quantification of calcification.

Purpose Transient improvement of aphasia, motor impairment, and disorders of consciousness after the use of zolpidem, a sedative, has been reported in several movement disorders and hyporesponsive syndromes. Here, we present a patient with Primary Familial Brain Calcification (PFBC), a rare neurodegenerative disease characterized by basal ganglia calcification, who experienced a transient improvement in speech following zolpidem administration. Methods Serendipitously, a 40-year-old female with PFBC and severe dysarthria experienced transient amelioration of dysarthria after treatment with zolpidem, which was prescribed for insomnia. We carried out a comprehensive clinical assessment before and three hours after administration of zolpidem tartrate 10 mg, including standardized evaluations of speech, aphasia, motor function, and patient-perceived difficulties. Results A transient improvement in speech was confirmed after zolpidem intake. However, notable side effects occurred, including worsening of fine motor control, coordination, postural stability, and bradykinesia. Conclusions This case suggests that zolpidem can influence PFBC related neurological symptoms, identifying the facilitation of internal globus pallidus inhibition as a new therapeutic target. Its use in individual patients warrants the weighing of positive and negative clinical effects, patients’ personal preferences, and wearing-off which invariable occurs after repeated use.

Background Primary brain calcification (PBC), is a rare genetic disorder involving idiopathic calcifications in the basal ganglia and other brain regions, often inherited autosomally. It must be distinguished from Fahr's syndrome, which is secondary to metabolic causes like parathyroid abnormalities. Diagnostic challenges arise when transient endocrine issues mimic secondary etiologies. Case description A 27-year-old female presented with a 12-year history of absence seizures, evolving to generalized tonic-clonic episodes, psychosis (commanding hallucinations, Capgras delusion), aggression, and cerebellar signs (dystonia, ataxia, tremors). Family history included a similarly affected brother. Imaging (NCCT and MRI) revealed bilateral calcifications in basal ganglia, thalamus, dentate nucleus, and cerebellum, with atrophy and infarct. Initial labs showed hypocalcemia and elevated PTH (100.8 pg/mL), suggesting secondary hyperparathyroidism, but normalization occurred post-vitamin D/calcium supplementation. Whole exome sequencing identified a homozygous pathogenic MYORG variant (c.488G>A, p.Trp163Ter), confirming PBC type 7. Management focused on antiepileptics, antipsychotics (e.g., olanzapine, lumateperone), and supplementation, with partial symptom control. Discussion This case illustrates PBC's heterogeneity, presenting with early seizures, psychosis, and cerebellar involvement despite autosomal recessive inheritance. The transient hyperparathyroidism, likely vitamin D-related, initially misled diagnosis, highlighting the role of genetic testing in resolving ambiguities. Symptomatic treatment prevails, with genetic counselling recommended.

Primary familial brain calcification (PFBC) is a genetic neurological disorder characterized by symmetric brain calcifications that manifest with variable neurological symptoms. This study aimed to explore the genetic basis of PFBC and elucidate the underlying pathophysiological mechanisms. Six patients from four pedigrees with brain calcification were enrolled. Whole-exome sequencing identified two novel homozygous variants, c.488G > T (p.W163L) and c.2135G > A (p.W712*), within the myogenesis regulating glycosidase ( MYORG ) gene. Cerebellar ataxia ( n  = 5) and pyramidal signs ( n  = 4) were predominant symptoms, with significant clinical heterogeneity noted even within the same family. An autopsy of one patient revealed extensive brainstem calcifications, sparing the cerebral cortex, and marked by calcifications predominantly in capillaries and arterioles. The pathological study suggested morphological alterations characterized by shortened foot processes within astrocytes in regions with pronounced calcification and decreased immunoreactivity of AQP4. The morphology of astrocytes in regions without calcification remains preserved. Neuronal loss and gliosis were observed in the basal ganglia, thalamus, brainstem, cerebellum, and dentate nucleus. Notably, olivary hypertrophy, a previously undescribed feature in MYORG -PFBC, was discovered. Neuroimaging showed reduced blood flow in the cerebellum, highlighting the extent of cerebellar involvement. Among perivascular cells constituting the blood-brain barrier (BBB) and neurovascular unit, MYORG is most highly expressed in astrocytes. Astrocytes are integral components of the BBB, and their dysfunction can precipitate BBB disruption, potentially leading to brain calcification and subsequent neuronal loss. This study presents two novel homozygous variants in the MYORG gene and highlights the pivotal role of astrocytes in the development of brain calcifications, providing insights into the pathophysiological mechanisms underlying PFBC associated with MYORG variants.

Purpose of ReviewUntil recently, the gene associated with the recessive form of familial brain calcification (PFBC, Fahr disease) was unknown. MYORG, a gene that causes recessive PFBC was only recently discovered and is currently the only gene associated with a recessive form of this disease. Here, we review the radiological and clinical findings in adult MYORG mutation homozygous and heterozygous individuals.Recent FindingsMYORG was shown to be the cause of a large fraction of recessive cases of PFBC in patients of different ethnic populations. Pathogenic mutations include inframe insertions and deletions in addition to nonsense and missense mutations that are distributed throughout the entire MYORG coding region. Homozygotes have extensive brain calcification in all known cases, whereas in some carriers of heterozygous mutation, punctuated calcification of the globus pallidus is demonstrated. The clinical spectrum in homozygotes ranges from the lack of neurological symptoms to severe progressive neurological syndrome with bulbar and cerebellar signs, parkinsonism and other movement disorders, and cognitive impairments. Heterozygotes are clinically asymptomatic.MYORG is a transmembrane protein localized to the endoplasmic reticulum and is mainly expressed in astrocytes. While the biochemical pathways of the protein are still unknown, information from its evolution profile across hundreds of species (phylogenetic profiling) suggests a role for MYORG in regulating ion homeostasis via its glycosidase domain.SummaryMYORG mutations are a major cause for recessive PFBC in different world populations. Future studies are required in order to reveal the cellular role of the MYORG protein.

Primary familial brain calcification (PFBC) is a neurogenetic disorder characterized by bilateral calcified deposits in the brain. We previously identified that MYORG as the first pathogenic gene for autosomal recessive PFBC, and established a Myorg -KO mouse model. However, Myorg -KO mice developed brain calcifications until nine months of age, which limits their utility as a facile PFBC model system. Hence, whether there is another typical animal model for mimicking PFBC phenotypes in an early stage still remained unknown. In this study, we profiled the mRNA expression pattern of myorg in zebrafish, and used a morpholino-mediated blocking strategy to knockdown myorg mRNA at splicing and translation initiation levels. We observed multiple calcifications throughout the brain by calcein staining at 2–4 days post-fertilization in myorg- deficient zebrafish, and rescued the calcification phenotype by replenishing myorg cDNA. Overall, we built a novel model for PFBC via knockdown of myorg by antisense oligonucleotides in zebrafish, which could shorten the observation period and replenish the Myorg -KO mouse model phenotype in mechanistic and therapeutic studies.

Background Primary ciliary dyskinesia (PCD) is an autosomal recessive hereditary disease characterized by recurrent respiratory infections. In clinical manifestations, DNAH5 (NM_001361.3) is one of the recessive pathogenic genes. Primary familial brain calcification (PFBC) is a neurodegenerative disease characterized by bilateral calcification in the basal ganglia and other brain regions. PFBC can be inherited in an autosomal dominant or recessive manner. A family with PCD caused by a DNAH5 compound heterozygous variant and PFBC caused by a MYORG homozygous variant was analyzed. Methods In this study, we recruited three generations of Han families with primary ciliary dyskinesia combined with primary familial brain calcification. Their clinical phenotype data were collected, next-generation sequencing was performed to screen suspected pathogenic mutations in the proband and segregation analysis of families was carried out by Sanger sequencing. The mutant and wild-type plasmids were constructed and transfected into HEK293T cells instantaneously, and splicing patterns were detected by Minigene splicing assay. The structure and function of mutations were analyzed by bioinformatics analysis. Results The clinical phenotypes of the proband (II10) and his sister (II8) were bronchiectasis, recurrent pulmonary infection, multiple symmetric calcifications of bilateral globus pallidus and cerebellar dentate nucleus, paranasal sinusitis in the whole group, and electron microscopy of bronchial mucosa showed that the ciliary axoneme was defective. There was also total visceral inversion in II10 but not in II8. A novel splice variant C.13,338 + 5G > C and a frameshift variant C.4314delT (p. Asn1438lysfs *10) were found in the DNAH5 gene in proband (II10) and II8. c.347_348dupCTGGCCTTCCGC homozygous insertion variation was found in the MYORG of the proband. The two pathogenic genes were co-segregated in the family. Minigene showed that DNAH5 c.13,338 + 5G > C has two abnormal splicing modes: One is that part of the intron bases where the mutation site located is translated, resulting in early translation termination of DNAH5 ; The other is the mutation resulting in the deletion of exon76. Conclusions The newly identified DNAH5 splicing mutation c.13,338 + 5G > C is involved in the pathogenesis of PCD in the family, and forms a compound heterozygote with the pathogenic variant DNAH5 c.4314delT lead to the pathogenesis of PCD.

Primary familial brain calcification (PFBC) is a well-known genetic condition that has recently had a surge of autosomal recessive cases. We recently reported a case of autosomal recessive PFBC on a 54-year-old Brazilian patient with a novel homozygous variant on MYORG. Interestingly, that patient also had a series of uncommon signs and symptoms, including Hashimoto’s thyroiditis, polyneuropathy, optic nerve head drusen (ONHD), and persistent anemia. We chose to perform whole exome sequencing (WES) to possibly detect other unknown genetic conditions that could explain the extra-neurological findings reported. WES confirmed the presence of the MYORG variant previously reported by us, and determined the presence of a heterozygous nonsense variant on HBB (c.118C > T, p.Q40*), defining a diagnosis of beta-thalassemia. Based on literature review, the new WES finding explains the persistent anemia and polyneuropathy shown by the patient, while still leaving the ONHD and autoimmune thyroiditis without a clear genetic link. This way, we propose that these novel clinical findings could be linked to MYORG, but still encourage further studies to evaluate this possibility.

Primary familial brain calcification (PFBC) is a rare disorder mostly characterized by calcium deposits in the basal ganglia and a wide spectrum of neurologic and psychiatric symptoms, typically inherited as an autosomal dominant trait. Recently, MYORG was reported as the first autosomal recessive causal gene in PFBC patients of Chinese and Middle Eastern origin. Herein, we describe the first PFBC patient of European descent found to carry a novel homozygous MYORG mutation (p.N511Tfs*243). Interestingly, the patient’s father, a heterozygous carrier of the same mutation, showed diffuse bilateral cerebral calcifications with no symptoms other than very mild postural tremor.