Idiopathic Basal Ganglia Calcification Research Articles

Idiopathic Basal Ganglia Calcifications in a Patient with Pediatric Onset Multiple Sclerosis

Idiopathic Basal Ganglia Calcifications in a Patient with Pediatric Onset Multiple Sclerosis

Inter-and intrarater agreement of Computed Tomographic brain calcification scoring in Primary Familial Brain Calcification.

The Total Calcification Score (TCS) is a visual rating scale to measure Primary Familial Brain Calcification (PFBC) related calcification severity on Computed Tomography (CT). We investigated the inter-and intrarater agreement of a modified TCS. Patients aged ≥18 years with PFBC or Fahr's syndrome who visited the outpatient clinic of a Dutch academic hospital were included. The TCS was modified, for example by adding hippocampal calcification, and ranged from 0 to 95 points. Fifteen raters evaluated all CTs, of whom three evaluated the CTs twice. Their Entrustable Professional Activity (EPA) level ranged from II (medical student) to V (neuroradiologist). Agreement was assessed using the intraclass correlation coefficient (ICC) for the total score. Kendall's W and weighted Cohen's Kappa were used to determine the inter- and intrarater agreement for individual locations, respectively. Forty patients were included (mean age 60 years, 53% female). The median modified TCS was 34 (range 4-76). For all EPA levels, the interrater agreement of the modified TCS was excellent (ICC=0.97 (95% CI 0.95-0.98)). Kendall's W's were good to excellent for commonly affected locations, but poor to moderate for less commonly affected locations for raters with lower levels of expertise. The intrarater agreement of the modified TCS was excellent. Kappa's of most locations were substantial to almost perfect. The modified TCS can be used with excellent reproducibility of the overall amount of brain calcifications and with limited training, although for some individual calcification locations more expertise is needed. CI, Confidence Interval; CT, Computed Tomography; EPA, Entrustable Professional Activity; IBGC, Idiopathic Basal Ganglia Calcification; ICC, Intraclass Correlation Coefficient; IQR, Interquartile Range; PFBC, Primary Familial Brain Calcification; SD, Standard Deviation, TCS, Total Calcification Score; UMCU, University Medical Center Utrecht.

Fahr’s Disease and its neuropsychiatrist manifestations: A case report

IntroductionFahr’s Disease, also known as Fahr’s Syndrome, is a rare genetically dominant disease, characterized by the abnormal accumulation of calcium deposits, or calcifications, in various areas of the brain, particularly the basal ganglia. These calcifications, which are typically bilateral and symmetrical, can lead to a wide range of neurological and psychiatric symptoms, making diagnosis and management challenging. It usually manifests between the ages of 40 and 60, primarily after the age of 30.ObjectivesTo contribute to the medical literature by sharing this rare case, thereby increasing awareness and knowledge about Fahr’s Disease among healthcare professionals.MethodsNon systematic review of the literature and access to the medical history of the patient.ResultsWe present a case of a 42 year old woman, who came to our hospital with behavior changes, with increasing confusion and new mystical beliefs, insomnia and agitation.According to the patient’s husband, the patient sounded confused and inappropriate in her speech. The patient was admitted for evaluation of altered mental status. The patient was alert and oriented to person, place, time, and situation in the emergency department, with shudder while neurologically intact. The patient was unpolite, agitated.Psychiatry was consulted for evaluation. We decided to admit the patient and did a posterior study with a CT scan and MRI. The MRI, as well as CT scan revealed “dense calcification of the dentate nuclei and the basal ganglia”, highly suggestive of Fahr’s syndrome. The patient’s phosphorus level was 3.5 mg/dl (normal level: 2.5-4.5 mg/dl). Parathyroid hormone (PTH) intact was 53 pg/ml (normal level: 15-65 pg/ml), and calcium level was 10,3 mg/dl (normal level: 8.4-10.5 mg/dl). The vitamin D 25-hydroxy concentration was 43,5 ng/ml (normal level: 30-60 ng/ml).ConclusionsIn conclusion, Fahr’s Disease is a rare and complex neurological disorder characterized by idiopathic calcification of the bilateral basal ganglia, resulting in a diverse range of neurological and psychiatric symptoms. Diagnosis involves clinical evaluation and neuroimaging, while treatment is primarily symptomatic. Further research is needed to better understand the underlying genetic and biochemical mechanisms driving calcification in the brain and to develop more effective therapeutic strategies for this challenging condition.Disclosure of InterestNone Declared

Genomic Diagnoses for Ectopic Intracerebral Calcifications.

Ectopic intracerebral calcifications (EICs) in the basal ganglia, thalamus, cerebellum, or white matter are seen in a variety of disease states or may be found incidentally on brain imaging. The clinical significance and proportion of cases attributable to an underlying genetic cause is unknown. This retrospective cohort study details the clinical, imaging, and genomic findings of 44 patients with EICs who had no established diagnosis despite extensive medical workup. In total, 15 of 44 patients received a diagnosis through genomic testing explaining their calcifications, and 2 more received a diagnosis that has not been previously associated with EICs. Six of the 15 were found to have one of the 4 genes (PDGFB, PDGFRB, SLC20A2, and XPR1) conventionally associated with the phenotypic term "idiopathic basal ganglia calcifications." These findings support the use of genomic testing for symptomatic patients with EICs.

Neuropsychiatric symptoms in idiopathic brain calcification

INTRODUCTION: Idiopathic basal ganglia calcification (IBGC) is a rare neurological disease characterized by the deposition of calcium in the brain, without calcium metabolism abnormalities. IBGC may be asymptomatic or clinically evident, causing predominantly movement disorders (parkinsonism, chorea, tremor, dystonia, dyskinesia) and a wide range of neuropsychiatric symptoms (dementia, psychosis, mood disorders, anxiety), which are currently poorly defined in literature. The aim of this study is to deepen the knowledge on psychiatric disorders associated with IBGC, providing an accurate description of eleven cases and summarizing information from the review of literature.EVIDENCE ACQUISITION: From our clinical database, we selected patients meeting the diagnostic criteria for IBGC and collected demographic, clinical, genetic, and neuroradiological data. Psychiatric assessment was performed using the 18-item Brief Psychiatric Rating Scale, the Positive and Negative Syndrome Scale, the Hamilton Anxiety Rating Scale and the Hamilton Depression Rating Scale. We also searched the PubMed database for papers dealing with psychiatric features in IBGC, and the related treatments.EVIDENCE SYNTHESIS: Eight of the eleven patients included in the study reported at least one psychiatric symptom during the course of the disease. The assessment through the HDRS21 and HAM-A Scale confirmed the presence of mild depression and anxiety as the main psychiatric disturbs associated with IBGC. Mean total PANSS and BPRS scores were 40.3±12.4 and 27.6±8.6 respectively, with a major involvement in specific items such as depressive mood, anxiety, tension, motor retardation and disorientation. Data from literature confirmed a significant psychiatric involvement in IBGC. Available case reports mainly concern atypical presentations of IBGC with abrupt onset psychotic symptoms. An in-depth analysis of psychiatric features associated with IBGC is lacking.CONCLUSIONS: Neuropsychiatric involvement is frequent in IBGC. A neuropsychiatric evaluation is highly recommended in patients with evidence of brain calcifications. Conversely, IBGC should be considered in patients presenting with psychiatric symptoms, especially if movement disorders and neurocognitive impairment are co-existing features.

Teaching Neuro Images : Fahr syndrome caused by hypoparathyroidism

A 57-year-old woman with a remote history of thyroidectomy but no prior neurologic symptoms developed seizures, fever, and coma. Limited evaluation at her local hospital in rural Haiti demonstrated serum hypocalcemia (4 mg/dL) and extensive bilateral subcortical calcification in the cerebral and cerebellar hemispheres on CT (figure). This pattern of calcification can occur in inherited conditions such as familial idiopathic basal ganglia calcification (Fahr disease) and acquired conditions (referred to as Fahr syndrome) including parathyroid dysfunction and intrauterine infection.1,2 Given our patient's severe hypocalcemia, Fahr syndrome was attributed to presumed hypoparathyroidism related to prior thyroidectomy in her case.

Role of phosphate transporter PiT-2 in the pathogenesis of primary brain calcification

Primary brain calcification (PBC), also known as idiopathic basal ganglia calcification (IBGC), primary familial brain calcification (PFBC) and so on, is a rare intractable disease characterized by abnormal mineral deposits, including mostly calcium in the basal ganglia, thalamus, and cerebellum. The causative gene of familial PBC is SLC20A2, which encodes the phosphate transporter PiT-2. Despite this knowledge, the molecular mechanism underlying SLC20A2-associated PBC remains unclear. In the present study, we investigated whether haploinsufficiency or a dominant-negative mechanism reduced Pi uptake in two PiT-2 variants (T115 M and R467X). We demonstrated that the presence of T115 M or R467X had no dominant-negative effect on Pi transport activity of wild-type (WT). In addition, the subcellular localization of R467X completely differed from that of WT, indicating that there is no interaction between R467X and WT. Conversely, T115 M and WT showed almost the same localization. Therefore, we examined the interaction between T115 M and WT using the bioluminescence resonance energy transfer (BRET) method. Although WT and T115 M interact with each other, T115 M does not inhibit WT's Pi transport activity. These results suggest that the role of SLC20A2 in the pathogenesis of PBC may involve decreased intracellular Pi uptake by a haploinsufficiency mechanism rather than a dominant-negative mechanism; agents promoting PiT-2 dimerization may be promising potential therapeutic agents for PBC.

SLC20A2-Associated Idiopathic basal ganglia calcification (Fahr disease): a case family report

BackgroundIdiopathic basal ganglia calcification (IBGC) is a genetic disorder of the nervous system commonly known as Fahr disease. IBGC patients with a genetic background are considered to have primary familial brain calcification (PFBC), also known as familial basal ganglia calcification (FBGC), or familial Fahr disease. It is a rare degenerative neurological disorder characterized by extensive bilateral basal ganglia calcification that can lead to a range of extrapyramidal symptoms and neuropsychiatric manifestations. Studies have suggested that more than 50 variants of SLC20A2 gene mutations account for approximately 50% of IBGC cases. There is a wide spectrum of mutation types, including frameshift, nonsense, and splice site mutations in addition to deletion and missense mutations. Here we report a case of familial basal ganglia calcification caused by a frameshift mutation in the SLC20A2 gene. We identified a heterozygous mutation in the SLC20A2 gene, c.1097delG (p.G366fs*89). To our knowledge, this mutation site has not been reported before.Case presentationA 57-year-old male patient was admitted to the hospital with “unstable walking and involuntary movements between the eyes and eyebrows for 6 months”. Based on the patient’s family history, symmetrical calcification foci in the bilateral caudate nucleus head, thalamus, cerebellum and parietal lobe indicated by head CT, and gene test results, the diagnosis of familial Fahr disease caused by mutations in the SLC20A2 gene, c.1097delG p.G366fs*89) was confirmed.ConclusionFor the first time, we identified c.1097delG (p.G366fs*89) as a frameshift mutation in the IBGC family. This frameshift mutation caused the condition in this family of patients. This mutation not only broadens the range of known SLC20A2 mutations but also aids in the genetic diagnosis of IBGC.

Hemiplegia revealing Fahr's disease: A case report

Fahr's disease or idiopathic basal ganglia calcification is a rare pathology. The most common clinical manifestations are movement disorders, psychiatric disorders, cerebellar syndrome, seizures and cognitive disorders. We report the case of a 47-year-old female patient with Fahr's disease revealed by brutal right hemiplegia.

Homozygous SLC20A2 mutations cause congenital CMV infection-like phenotype.

Idiopathic basal ganglia calcification, also known as Fahr's disease, it is a neurological disease characterized by intracranial calcification caused by heterozygous SLC20A2 mutations. Patients with calcifications can either be asymptomatic or show a wide spectrum of neuropsychiatric symptoms, including parkinsonism, tremor, dystonia, ataxia, and seizures. The aim of this study was to investigating the clinical implications of the SLCA20A2 gene and identifying a new phenotype through a family. Two siblings with growth retardation, bilateral cataracts, microcephaly, and convulsion were included in the study. The MRI showed cerebral atrophy, corpus callosum hypoplasia, microcalcifications. Chromosomal microarray analysis was performed to identify the existence of copy number variation. The whole exome sequencing analysis of the individual IV-I was performed, and Sanger sequencing was performed for segregation. Whole exome sequencing revealed a homozygous NM_006749.5:c.1794 + 1G > A of the SLC20A2 gene. The Sanger sequencing confirmed the affected siblings were homozygous and the parents were heterozygous. SLC20A2 gene heterozygous mutations were associated with the adult-onset phenotype, while homozygous SLC20A2 mutations in the two affected siblings we reported in our study resulted in a severe clinic including growth retardation, bilateral cataracts, microcephaly, and convulsion. We showed that biallelic mutations in the SLC20A2 gene that cause the Fahr's disease lead to more severe phenotypes contrary to what is known. The two siblings, showing similar phonotypic and genotypic characteristics, would be the youngest cases in the pediatric age group published in the literature.

Fahr's Disease and Hypoparathyroidism - A Missing Link.

Fahr's disease is an idiopathic basal ganglia calcification with autosomal dominant inheritance. Prior to diagnosing Fahr's disease based on computed tomography (CT) and/or magnetic resonance imaging (MRI) of the brain, one should rule out hypoparathyroidism (HP), and pseudohypoparathyroidism (PHP). Treatments of these conditions are entirely different. HP- and PHP-related hypocalcemia requires calcium, calcitriol, and vitamin D therapy in a long run to avoid recurrent seizures whereas Fahr's disease is treated with an antiepileptic alone.

The Impact of COVID-19 Infection on a Neurologically Compromised Male With Fahr’s Disease Presenting With Acute Delirium and Aspiration Pneumonia: A Case Report

Fahr’s disease or idiopathic basal ganglia calcification is a rare, sporadic, genetically dominant, and inherited neurological condition that manifests with dysphagia and Parkinson’s disease. The computed tomography (CT) scan is the method of choice to diagnose basal ganglia calcifications seen in Fahr’s disease. This case report elaborates on the emergency management of a 58-year-old male patient with acute respiratory distress, acute delirium, schizophrenia, Fahr’s syndrome, and history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019 or COVID-19) infection. The patient’s chest X-ray, laboratory workup, and vital signs were suggestive of aspiration pneumonia-induced sepsis and acute hypoxemic respiratory failure. Post-admission antibiotic management reduced sepsis complications without improving the altered mental status. A comprehensive clinical assessment suggested the attribution of Fahr’s disease to the patient’s aspiration pneumonia and other clinical complications. In addition, COVID-19 infection, sepsis-induced inflammatory processes, and pre-existing neurological compromise possibly deteriorated the patient’s neurological outcomes, overall prognosis, and recovery.

Fahr’s Disease With Late Onset: A Case Report

Fahr's disease is a rare genetically dominant disease. It is characterized by the idiopathic deposition of calcium in the basal ganglia and cerebral cortex. The condition may cause motor impairment, impaired muscle tone, dementia, seizures, impairment of eye movements, speech, abnormal hand movements, cognitive impairment, and ataxia. The thalamus, white matter, and basal ganglia can be involved. A 77-year-old man with multiple comorbidities presented with a complaint of increasing confusion, altered mental status, dystonia, tremor, and hallucinations. The patient's daughter reported that he sounded confused and inappropriate in his speech. A computerized tomography (CT) scan of the head without contrast revealed a "dense calcification of the dentate nuclei and the basal ganglia" and "subcortical calcification of the frontal and occipital lobes." The patient was diagnosed with late-onset Fahr's disease. Fahr's disease is caused by idiopathic calcification of the bilateral basal ganglia. A wide variety of symptoms are associated with this condition. Fahr's disease should be considered in the differential diagnosis in geriatric patients suffering from cognitive impairment and movement disorders.

PDGF-BB is involved in phosphate regulation via the phosphate transporters in human neuroblastoma SH-SY5Y cells

Inorganic phosphate (Pi) is the second most abundant inorganic ion in the body. Since abnormalities in Pi metabolism are risk factors for various diseases, serum Pi levels are strictly controlled. Type-III sodium-dependent Pi transporters, PiT-1 (encoded by SLC20A1) and PiT-2 (encoded by SLC20A2), are distributed throughout the tissues of the body, including the central nervous system, and are known to be responsible for extracellular to intracellular Pi transport. Platelet-derived growth factor (PDGF) is a major growth factor of mesenchymal cells. PDGF-BB, a homodimer of PDGF-B, regulates intracellular Pi by increasing PiT-1 expression in vascular smooth muscle cells. However, the effects of PDGF-BB on Pi transporters in neurons have yet to be reported. Here, we investigated the effect of PDGF-BB on Pi transporters in human neuroblastoma SH-SY5Y cells. PDGF-BB did not induce SLC20A1 mRNA expression, but it increased the intracellular uptake of Pi via PiT-1 in SH-SY5Y cells. Among the signaling pathways associated with PDGF-BB, AKT signaling was shown to be involved in the increase in Pi transport. In addition, the PDGF-BB-induced increase in Pi mediated neuroprotective effects in SLC20A2-suppressed cells, in an in vitro model of the pathological condition found in idiopathic basal ganglia calcification. Moreover, the increase in Pi uptake was found to occur through promotion of intracellular PiT-1 translocation to the plasma membrane. Overall, these results indicate that PDGF-BB exerts neuroprotective effects via Pi transport, and they demonstrate the potential utility of PDGF-BB against abnormal Pi metabolism in neurons.

Fahr's Syndrome- An Interesting Case Presentation

Idiopathic basal ganglia calcification (IBGC), commonly referred to as Fahr’s disease, is a rare neurological disorder characterized by the abnormal, symmetrical, and bilateral calcification of the basal ganglia and other brain regions. Patients typically present in their forties and fifties with various neurologic and/or psychiatric symptoms, including movement disorders, Parkinsonism, psychosis, and depression. The pathophysiology of this disease is not completely understood; however, several gene mutations have been identified in the pathogenesis of Fahr’s disease. These mutations display an autosomal dominant inheritance pattern. Furthermore, the regional phenotypic expression of calcifications differs greatly from patient to patient, as do their clinical presentations. Here, we describe a patient who presented with psychiatric manifestations and imaging consistent with Fahr’s disease.

Familial Idiopathic Basal Ganglia Calcification: A Father-Son Dyad Demonstrate Heterogeneity of Presentation and Disease Progression.

Familial idiopathic basal ganglia calcification (FIBGC) is a rare, heritable disease characterized by calcium deposition in the basal ganglia and other brain regions. Clinical presentations are diverse, featuring an array of neurologic, psychiatric, and/or cognitive symptoms. This dyad report presents neurogenetic, neuroimaging, neurological, and serial neuropsychological data from a father (S1) and son (S2) with FIBGC. The SLC20A2 genetic mutation c.1828-1831delTCCC was identified for each patient, both of whom evidenced similar patterns of brain calcification mainly in the basal ganglia and cerebellum on neuroimaging. S1's onset was in his late 60s with primary motor abnormalities followed by cognitive decline; S2's younger onset (late 30s) was characterized by predominant psychiatric symptoms and mild cognitive changes. Our unique, detailed longitudinal study revealed that both subjects demonstrated largely stable performance across most neuropsychological domains assessed. The subjects' differences in presentation demonstrate the variable expressivity in FIBGC even with the same pathogenic variant within a single family. Distinct phenotypes may be associated with age of onset even in persons with the same mutation, consistent with past research. Disease progression may feature an initial period of notable change from baseline followed by relative stability, as seen both on imaging and neuropsychological evaluation.

Human induced pluripotent stem cells generated from a patient with idiopathic basal ganglia calcification

Idiopathic basal ganglia calcification (IBGC) is a rare neurodegenerative disease, characterized by abnormal calcium deposits in basal ganglia of the brain. The affected individuals exhibit movement disorders, and progressive deterioration of cognitive and psychiatric ability. The genetic cause of the disease is mutation in one of several different genes, SLC20A2, PDGFB, PDGFRB, XPR1 or MYORG, which inheritably or sporadically occurs. Here we generated an induced pluripotent stem cell (iPSC) line from an IBGC patient, which is likely be a powerful tool for revealing the pathomechanisms and exploring potential therapeutic candidates of IBGC.

Idiopathic basal ganglia calcification (Fahr’s disease) in a 9-year-old Nigerian child

Fahr’s disease is a rare neurodegenerative disorder characterized by deposition of calcium on the walls of blood vessels of the Basal ganglia and Dentate nuclei of the Cerebellum. Patient can present with diverse array of symptoms including but not limited to seizure, extrapyramidal symptoms and mental retardation. We report a case of a 9-year-old female child with history of recurrent seizure. Brain CT showed symmetrical calcification in the basal ganglia.

MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor.

ObjectiveTo describe a possible novel genetic mechanism for cerebral small vessel disease (cSVD) and stroke.MethodsWe studied a Swedish kindred with ischemic stroke and intracerebral hemorrhage, tremor, dysautonomia, and mild cognitive decline. Members were examined clinically, radiologically, and by histopathology. Genetic workup included whole-exome sequencing (WES) and whole-genome sequencing (WGS) and intrafamilial cosegregation analyses.ResultsFifteen family members were examined clinically. Twelve affected individuals had white matter hyperintensities and 1 or more of (1) stroke episodes, (2) clinically silent lacunar ischemic lesions, and (3) cognitive dysfunction. All affected individuals had tremor and/or atactic gait disturbance. Mild symmetric basal ganglia calcifications were seen in 3 affected members. Postmortem examination of 1 affected member showed pathologic alterations in both small and large arteries the brain. Skin biopsies of 3 affected members showed extracellular amorphous deposits within the subepidermal zone, which may represent degenerated arterioles. WES or WGS did not reveal any potentially disease-causing variants in known genes for cSVDs or idiopathic basal ganglia calcification, but identified 1 heterozygous variant, NM_004672.4 MAP3K6 c.322G>A p.(Asp108Asn), that cosegregated with the disease in this large family. MAP3K6 has known functions in angiogenesis and affects vascular endothelial growth factor expression, which may be implicated in cerebrovascular disease.ConclusionsOur data strongly suggest the MAP3K6 variant to be causative for this novel disease phenotype, but the absence of functional data and the present lack of additional families with this disease and MAP3K6 mutations still limit the formal evidence for the variant's pathogenicity.

Idiopathic basal ganglia calcification – Fahr's syndrome

Idiopathic basal ganglia calcification – Fahr's syndrome