Primary Familial Brain Calcifications Research Articles

Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications

Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.

Report of a young patient with brain calcifications with a novel homozygous MYORG variant

Primary familial brain calcifications (PFBC) is characterized by bilateral and symmetrical deposition of inorganic phosphate, mainly in the basal ganglia, thalamus, cerebellum, and dentate nucleus. The symptoms resemble other neuropsychiatric conditions, such as Parkinsonism, dementia, migraine, and mood disorders. Pathogenic variants in six genes have been associated with this disorder, four linked to the autosomal dominant mode (SLC20A2, PDGFRB, PDGFB, and XPR1) and two linked to the recessive fashion (MYORG and JAM2). Herein, we report a young 24-year-old patient with a medical history of bilateral and symmetrical brain calcification and neuropsychiatric symptoms that include movement disturbances (chorea and dystonia), chronic migraine, unexplained tinnitus, and mood swings. After whole-exome sequencing, she was diagnosed with a novel homozygous MYORG variant (c.912_914del; p.(Ser305del)). In silico analysis showed that the variant is located on the extracellular domain of MYORG protein and is predicted to be disease-causing (likely pathogenic), implying that protein features might be affected. This study describes the second Brazilian case of MYORG PFBC-causative gene. Furthermore, it highlights the early age and onset of symptoms of the proband, especially in regard to movement disorders.

Germline Platelet-derived growth factor receptor beta p.R987W pathogenic variant in 2 children with brain tumors.

Unstructured summary Platelet-Derived Growth Factor Receptor Beta (PDGFRB) is critically implicated in development. Constitutional pathogenic variants (CPVs) in the gene encoding this receptor result in several inherited syndromes, including primary familial brain calcifications (PFBC) or infantile myofibromatosis, but have not been associated with brain tumors. Here, we describe a 9-year-old male with a DCTN1-ALK fused inflammatory myofibroblastic tumor of the brain and an 11-year-old female with a TRIM24-MET fused occipital glioneural tumor. Both probands carry the same constitutive PDGFRB c.2959C>T (p. Arg987Trp) CPV, raising the possibility that this variant, previously described in PFBC, may also promote tumor formation including in the brain.

Familial Brain Calcifications With Leukoencephalopathy: A Novel PDGFB Variant.

ObjectiveTo describe a family with primary familial brain calcifications (PFBCs) and leukoencephalopathy associated with a novel variant in PDGFB.MethodsWe present 3 generations of a family with PFBC associated with a previously unreported variant in PDGFB.ResultsA 24-year-old woman with migraine, bipolar disorder, and functional neurologic disorder was found to have bilateral calcifications of the basal ganglia and frontally predominant periventricular white matter disease. Her father had mild cognitive impairment and action tremor of the hands with basal ganglia and cerebellar calcifications found incidentally on head CT. Her paternal grandmother had severe parkinsonism and dementia with calcifications of the basal ganglia and cerebellum and diffuse, confluent periventricular white matter disease. Genetic testing in both the proband and her father revealed a PDGFB variant (NM_002608.3:c.298C>T:p.Arg100Cys) not reported in publicly available databases. Multiple in silico analysis tools support pathogenicity.DiscussionOur report identifies a novel PDGFB variant associated with PFBC and highlights the rare association of leukoencephalopathy with PDGFB-associated PFBC.

Primary familial brain calcifications: genetic and clinical update.

In the last 7 years, changes in five genes [SLC20A2, PDGFRB, PDGFB, XPR1, and MYORG] have been implicated in the pathogenesis of primary familial brain calcification (PFBC), allowing for genetic delineation of this phenotypically complex neurodegenerative disorder. This review explores how the ensuing plethora of reported PFBC patients and their disease-causing variants improved our understanding of disease, pathogenesis, clinical manifestation, and penetrance. In PFBC patients, pathogenic changes have been most frequently described in SLC20A2, accounting for approximately the same number of patients as the variants in the other four PFBC genes combined. There is no appreciable relationship between any combination of the following three variables: the type of disease-causing change, the pattern or extent of calcifications, and the presence or nature of clinical manifestation in PFBC patients. Nevertheless, elucidation of underlying genetic factors provided important recent insights into the pathogenic mechanisms of PFBC, which collectively point toward a compromised neurovascular unit. The ongoing clinical and molecular research increases our understanding of PFBC facilitating diagnosis and identifying potential therapeutic targets for this multifaceted and likely underdiagnosed condition.

Chapter 20 - Primary familial brain calcifications

Primary familial brain calcification (PFBC) is a neurodegenerative disease with characteristic calcium deposits in the basal ganglia and other brain regions. The disease usually presents as a combination of abnormal movements, cognitive and psychiatric manifestations, clinically indistinguishable from other adult-onset neurodegenerative disorders. The differential diagnosis must be established with genetic and nongenetic disorders that can also lead to calcium deposits in encephalic structures. In the past years PFBC causal mutations have been discovered in genes related to calcium phosphate homeostasis (SLC20A2, XPR1) and in genes involved with endothelial function and integrity (PDGFB, PDGFRB). The most frequently mutated gene is SLC20A2, where mutations can affect any domain of the protein. There is no clearcut relationship between the specific mutation/gene, onset age, neuroimaging pattern, and severity of clinical manifestations. The discovery of the genetic basis of PFBC provides not only a diagnostic tool, but also an insight into the pathomechanisms and potential therapeutic trials for this rare disease.

Induced pluripotent stem cells derived from a patient with familial idiopathic basal ganglia calcification (IBGC) caused by a mutation in SLC20A2 gene

Idiopathic basal ganglia calcification (IBGC), also known as Fahr disease or primary familial brain calcifications (PFBC), is a rare neurodegenerative disorder characterized by calcium deposits in basal ganglia and other brain regions, causing neuropsychiatric and motor symptoms. We established human induced pluripotent stem cells (iPSCs) from an IBGC patient. The established IBGC-iPSCs carried SLC20A2 c.1848G>A mutation (p.W616* of translated protein PiT2), and also showed typical iPSC morphology, pluripotency markers, normal karyotype, and the ability of in vitro differentiation into three-germ layers. The iPSC line will be useful for further elucidating the pathomechanism and/or drug development for IBGC.

Primary familial brain calcifications linked with a novel SLC20A2 gene mutation in a Chinese family

It has been recently reported that mutations in SLC20A2 gene are a major cause of primary familial brain calcifications, a rare neurodegenerative disorder characterized by symmetrical and bilateral intracranial calcification. We conducted a pedigree study by performing next Generation Sequencing in a Chinese family with three generations. Three members in this family developed Parkinsonism in their sixth decade, also, the proband presented with schizophrenia for 40 years. Next Generation Sequencing identified a novel nonsense heterozygous substitution c.1158C > A (p.Thr 386*) of SLC20A2 gene, introducing a stop codon in exon 10. The mutation was present in symptomatic and asymptomatic individuals with intracranial calcification, but absent in the individual without calcification, suggesting the mutation segregates with brain calcification. mRNA expression was decreased by 35% in the proband. We are the first to demonstrate a novel c.1158C > A mutation of SLC20A2 gene in a Chinese family with primary familial brain calcifications.

Phosphate Transporters Expression in Patients with Primary Familial Brain Calcifications.

Primary familial brain calcification (PFBC), formerly known as Fahr disease, is a rare neurological disorder characterized by extensive calcification deposits in the brain. So far, four genes have been reported with variations associated with PFBC, SLC20A2, PDGFβ, PDGFRβ, and XPR1. Using real-time qPCR, we analyzed the expression of three inorganic phosphate (Pi) transporters (SLC20A1, SLC20A2, and XPR1) in patients with PFBC. Our results showed a significant reduction (~40%) of SLC20A2 expression in the patients carrying mutation whereas no significant change was observed within the patients without known mutations. No difference was detected in SLC20A1 and XPR1 expression between the groups compared to control. The results suggest that mutations in SLC20A2 gene by itself play an import role by reducing its expression in blood of PFBC patients. At the same time, we could not demonstrate a direct co-regulation between the three Pi transporters at mRNA level, once their expression did not change among the groups.

Nomenclature of genetic movement disorders: Recommendations of the International Parkinson and Movement Disorder Society task force.

The system of assigning locus symbols to specify chromosomal regions that are associated with a familial disorder has a number of problems when used as a reference list of genetically determined disorders,including (I) erroneously assigned loci, (II) duplicated loci, (III) missing symbols or loci, (IV) unconfirmed loci and genes, (V) a combination of causative genes and risk factor genes in the same list, and (VI) discordance between phenotype and list assignment. In this article, we report on the recommendations of the International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders and present a system for naming genetically determined movement disorders that addresses these problems. We demonstrate how the system would be applied to currently known genetically determined parkinsonism, dystonia, dominantly inherited ataxia, spastic paraparesis, chorea, paroxysmal movement disorders, neurodegeneration with brain iron accumulation, and primary familial brain calcifications. This system provides a resource for clinicians and researchers that, unlike the previous system, can be considered an accurate and criterion-based list of confirmed genetically determined movement disorders at the time it was last updated.

Progressive brain calcifications and signs in a family with the L9R mutation in the PDGFB gene.

Primary familial brain calcifications (PFBC) are a heterogeneous group of rare autosomal dominant disorders. Mutations in the PDGFB gene are the second most common cause of PFBC. A model for PDGFB-associated PFBC, hypomorphic PDGFB (ret/ret) mouse, displays impaired blood-brain barrier (BBB), progressive brain calcifications and increased flux of the oxysterol 24S-hydroxycholesterol from the brain into the circulation.(1,2) Only 8 families and 2 sporadic cases with PDGFB mutations have been identified so far, one of them a Swedish-Finnish family previously described as F13.(1,3-6) Very little is known about the natural history of PDGFB-associated PFBC. Here, we provide a comprehensive long-term follow-up of the F13 family.

Nomenclature of genetic movement disorders: Recommendations of the international Parkinson and movement disorder society task force.

The system of assigning locus symbols to specify chromosomal regions that are associated with a familial disorder has a number of problems when used as a reference list of genetically determined disorders,including (I) erroneously assigned loci, (II) duplicated loci, (III) missing symbols or loci, (IV) unconfirmed loci and genes, (V) a combination of causative genes and risk factor genes in the same list, and (VI) discordance between phenotype and list assignment. In this article, we report on the recommendations of the International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders and present a system for naming genetically determined movement disorders that addresses these problems. We demonstrate how the system would be applied to currently known genetically determined parkinsonism, dystonia, dominantly inherited ataxia, spastic paraparesis, chorea, paroxysmal movement disorders, neurodegeneration with brain iron accumulation, and primary familial brain calcifications. This system provides a resource for clinicians and researchers that, unlike the previous system, can be considered an accurate and criterion-based list of confirmed genetically determined movement disorders at the time it was last updated.

The genetics of primary familial brain calcifications.

Bilateral accumulation of calcium in the brain, most commonly in the basal ganglia, but also in the cerebellum, thalamus, and brainstem can be inherited in an autosomal dominant fashion and is then referred to as primary familial brain calcifications (PFBC). Clinical manifestations include a spectrum of movement disorders and neuropsychiatric abnormalities. In the past 2 years, 3 genes have been identified to cause PFBC, (ie, SLC20A2, PDGFRB, and PDGFB). SCL20A2 encodes the Type III sodium-dependent inorganic phosphate (Pi) transporter 2 (PiT2) and, when mutated, uptake of Pi is severely impaired likely causing buildup of calcium phosphate. The second identified cause of PFBC is mutations in PDGFRB, which codes for platelet-derived growth factor receptor β (PDGF-Rβ). Interestingly, the third PFBC gene is PDGFB that encodes the ligand of PDGF-Rβ, which is secreted during angiogenesis to recruit pericytes, thereby implying impairment of the blood-brain barrier as a disease mechanism of PFBC.