Primary familial brain calcification (PFBC), also known as Fahr\'s disease, is a central nervous system calcium deposition disorder with symmetrical basal ganglia calcification. Most PFBC cases are caused by SLC20A2 gene variant. We report a Chinese female patient with PFBC and dopamine-responsive parkinsonism who had motor fluctuations and dyskinesia and recovered effectively after symptomatic medication adjustment. A novel heterozygous missense variant was found by whole-exome sequencing and proven harmful by family validation and genetic analysis. This example expands the phenotype of SLC20A2-associated PFBC patients and shows the clinical efficacy of dopaminergic replacement treatment.

This case report describes an exceptionally rare case in which a prior diagnosis of schizophrenia was later determined to be early-onset Fahr\'s disease, linked to a genetic mutation in the SLC20A2 gene. Initially, the patient exhibited symptoms resembling schizophrenia, including aggression and hostility, and was highly susceptible to medication side effects such as restlessness and Parkinsonism. Despite maintaining independent activities of daily living, his neurological examinations revealed hidden weakness on the left side. Following adjustments to the medication regimen, stability was achieved with residual psychotic symptoms under treatment with Risperidone 1.5mg/day, Valproic acid 1500mg/day, and Quetiapine 37.5mg/day. This case underscores the importance of conducting comprehensive imaging studies at the time of initial psychiatric diagnosis, regardless of the apparent typicality of the presentation. Additionally, it emphasizes the need for patience and adherence to the \"Start Low and Go Slow\" approach in medication management to minimize the risk of exacerbating psychiatric symptoms and aggression.

Fahr\'s disease is a rare neurodegenerative disorder with brain calcifications and neuropsychiatric symptoms. It can have variable phenotypic expression and intermittent symptomatology, making diagnosis challenging. In this report, we describe a young female patient presenting with symptoms of psychosis and confusion, which could be indicative of a delirium superimposed on the cerebral vulnerability associated with Fahr\'s disease. Notably, about two years prior, she experienced multiple episodes of tonic-clonic seizures that spontaneously resolved without pharmacological intervention. She had no previous psychiatric history. Following comprehensive investigations, other organic causes were ruled out, and Fahr\'s disease was diagnosed based on bilateral symmetrical brain calcifications seen on a head CT scan. Her treatment regimen encompassed antipsychotics and anticonvulsants. This case highlights the importance of considering Fahr\'s disease as a differential diagnosis in patients with new-onset neuropsychiatric symptoms. The case also explores the atypical early onset and intermittent nature of symptoms in the absence of a positive family history, highlighting the complexity of Fahr\'s disease. A multidisciplinary approach and regular follow-up are crucial for optimizing patient care and monitoring disease progression. Further research is needed to enhance our understanding of Fahr\'s disease and develop standardized treatment strategies for this rare condition.

Background: It is unclear whether patients with basal ganglia calcifications (BGC) should undergo infectious disease testing as part of their diagnostic work-up. We investigated the occurrence of possibly associated infections in patients with BGC diagnosed with Fahr\'s disease or syndrome and consecutively performed a systematic review of published infectious diseases associated with BGC. Methods: In a cross-sectional study, we evaluated infections in non-immunocompromised patients aged ≥ 18 years with BGC in the Netherlands, who were diagnosed with Fahr\'s disease or syndrome after an extensive multidisciplinary diagnostic work-up. Pathogens that were assessed included the following: Brucella sp., cytomegalovirus, human herpesvirus type 6/8, human immunodeficiency virus (HIV), Mycobacterium tuberculosis, rubella virus, and Toxoplasma gondii. Next, a systematic review was performed using MEDLINE and Embase (2002-2023). Results: The cross-sectional study included 54 patients (median age 65 years). We did not observe any possible related infections to the BGC in this population. Prior infection with Toxoplasma gondii occurred in 28%, and in 94%, IgG rubella antibodies were present. The positive tests were considered to be incidental findings by the multidisciplinary team since these infections are only associated with BGC when congenitally contracted and all patients presented with adult-onset symptoms. The systematic search yielded 47 articles, including 24 narrative reviews/textbooks and 23 original studies (11 case series, 6 cross-sectional and 4 cohort studies, and 2 systematic reviews). Most studies reported congenital infections associated with BGC (cytomegalovirus, HIV, rubella virus, Zika virus). Only two studies reported acquired pathogens (chronic active Epstein-Barr virus and Mycobacterium tuberculosis). The quality of evidence was low. Conclusions: In our cross-sectional study and systematic review, we found no convincing evidence that acquired infections are causing BGC in adults. Therefore, we argue against routine testing for infections in non-immunocompromised adults with BGC in Western countries.

(1) Background: Primary Familial Brain Calcification (PFBC) is a neurodegenerative disease characterized by bilateral calcifications of the basal ganglia and other intracranial areas. Many patients experience symptoms of motor dysfunction and cognitive disorders. The aim of this study was to investigate the association between the amount and location of intracranial calcifications with these symptoms. (2) Methods: Patients with suspected PFBC referred to our outpatient clinic underwent a clinical work-up. Intracranial calcifications were visualized on Computed Tomography (CT), and a Total Calcification Score (TCS) was constructed. Logistic and linear regression models were performed. (3) Results: Fifty patients with PFBC were included in this study (median age 64.0 years, 50% women). Of the forty-one symptomatic patients (82.0%), 78.8% showed motor dysfunction, and 70.7% showed cognitive disorders. In multivariate analysis, the TCS was associated with bradykinesia/hypokinesia (OR 1.07, 95%-CI 1.02-1.12, p < 0.01), gait ataxia (OR 1.06, 95%-CI 1.00-1.12, p = 0.04), increased fall risk (OR 1.04, 95%-CI 1.00-1.08, p = 0.03), and attention/processing speed disorders (OR 1.06, 95%-CI 1.01-1.12, p = 0.02). Calcifications of the lentiform nucleus and subcortical white matter were associated with motor and cognitive disorders. (4) Conclusions: cognitive and motor symptoms are common among patients with PFBC, and there is an association between intracranial calcifications and these symptoms.

BACKGROUND: Fahr\'s disease and syndrome are rare disorders leading to calcification of the small arteries in the basal ganglia of the brain, resulting in a wide range of symptoms comprising cognitive decline, movement disorders and neuropsychiatric symptoms. No disease-modifying therapies are available. Studies have shown the potential of treatment of ectopic vascular calcifications with bisphosphonates. This paper describes the rationale and design of the CALCIFADE trial which evaluates the effects of etidronate in patients with Fahr\'s disease or syndrome.
METHODS: The CALCIFADE trial is a randomised, placebo-controlled, double-blind trial which evaluates the effects of etidronate 20 mg/kg during 12 months follow-up in patients aged ≥ 18 years with Fahr\'s disease or syndrome. Etidronate and placebo will be administered in capsules daily for two weeks on followed by ten weeks off. The study will be conducted at the outpatient clinic of the University Medical Center Utrecht, the Netherlands. The primary endpoint is the change in cognitive functioning after 12 months of treatment. Secondary endpoints are the change in mobility, neuropsychiatric symptoms, volume of brain calcifications, dependence in activities of daily living, and quality of life.
RESULTS: Patient recruitment started in April 2023. Results are expected in 2026 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences.
CONCLUSIONS: Fahr\'s disease and syndrome are slowly progressive disorders with a negative impact on a variety of health outcomes. Etidronate might be a new promising treatment for patients with Fahr\'s disease or syndrome.
BACKGROUND: ClinicalTrials.gov, NCT05662111. Registered 22 December 2022, https://clinicaltrials.gov/ct2/show/NCT01585402 .

Fahr\'s disease (FD) is a rare disorder, characterized by basal ganglia calcification and presenting with movement disorders, speech impairment, cognitive deficits, and neuropsychiatric symptoms. Psychotic disorders related to FD are barely described in the literature, and knowledge is missing concerning pathophysiology, course, and management. Here, we report on the long-term follow-up of a patient who had three acute episodes of FD-psychosis characterized by bizarre delusions and behavioral disorganization, without hallucinations. Genetic and metabolic causes of FD were ruled out. In all three episodes, olanzapine monotherapy rapidly and completely resolved psychosis, without inducing metabolic syndrome and extrapyramidal symptoms. In addition to the acute decompensations, the patient presented a tame, introverted, industrious, and perfectionistic personality, which we could interpret as the \"parkinsonian personality\" described for many other basal ganglia disorders. Moreover, bizarre appearance, reduced affectivity, abulia, concrete speech, and stiff motricity in the context of a mild asymmetric extrapyramidal syndrome characterized the mental status. The cognitive profile was initially marked by executive difficulties and partial agnosia, with an IQ of 86. In the course of 10 years, the patient suffered from an ischemic stroke in the left superior temporal gyrus, which provoked a decline in memory and executive functions, without any impact on the psychiatric picture. Antiphospholipid antibody syndrome emerged as the underlying cause; thus, for the first time in the literature, an overlap of FD and antiphospholipid antibody syndrome is described here. This case report stresses once more the need for better integration of psychiatry and neurology and for the investigation of secondary causes of late-onset psychosis.

Fahr\'s disease, or primary familial brain calcification (PFBC), is a rare genetic neurologic disease characterized by abnormal calcification of the basal ganglia, subcortical white matter and cerebellum. Common clinical features include parkinsonism, neuropsychiatric symptoms, and cognitive decline. Genes implicated in Fahr\'s disease include PDGFB, PDGFRB, SLC20A2, XPR1, MYORG, and JAM2. We present the case of a 51-year-old woman who developed subacute cognitive and behavioral changes primarily affecting frontal-subcortical pathways and parkinsonism in association with extensive bilateral calcifications within the basal ganglia, subcortical white matter, and cerebellum on neuroimaging. Relevant family history included a paternal aunt with parkinsonism at age 50. Normal parathyroid hormone and calcium levels in the patient\'s serum ruled out hypoparathyroidism or pseudohypoparathyroidism as causes for the intracranial calcifications. Genetic panel sequencing revealed a variant of unknown significance in the PDGFRB gene resulting in a p.Arg919Gln substitution in the tyrosine kinase domain of PDGFRB protein. To our knowledge this is the first report of a p.Arg919Gln variant in the PDGFRB gene associated with PFBC. Although co-segregation studies were not possible in this family, the location of the variant is within the tyrosine kinase domain of PDGFRB and pathogenicity calculators predict it is likely to be pathogenic. This report adds to the list of genetic variants that warrant functional analysis and could underlie the development of PFBC, which may help to further our understanding of its pathogenesis and the development of targeted therapies for this disorder.

Brain calcifications, previously known as Fahr\'s disease, is a rare neurological disorder marked by various clinical symptoms, including movement disorders, cognitive impairment, and psychiatric disturbances. Despite its clinical importance, its pathophysiology is unclear and there are no specific treatments. We present four cases of brain calcifications from our tertiary care center, with three female patients (75%) and an average age of 63 years. Our cohort featured both genetic and endocrine etiologies, including one primary familial brain calcification case with a c.852del frameshift mutation in the SLC20A2 gene, and two endocrinopathy-related cases. One patient had an acute stroke which may have been contributed by brain calcifications. Computerized tomography and magnetic resonance imaging scans revealed basal ganglia and dentate nucleus calcifications. Treatment involved physical and occupational therapy in all patients. Hypoparathyroidism-related brain calcifications were treated with oral supplementation with calcitriol, calcium, and vitamin D. Three patients showed improvement or stability of their symptoms. This case series underscores the diverse clinical presentations and etiologies of brain calcifications. The complex pathophysiology involves disrupted Ca+2-PO43- homeostasis, deficient cellular PO43- transport, and vascular irregularities in genetic etiologies. Future research should focus on identifying novel genetic mutations, understanding molecular pathways, and refining diagnostic techniques. Integrating multidisciplinary approaches may improve diagnosis, management, and prognosis for patients with this intricate neurological disorder.

Fahr\'s syndrome is defined by the presence of striato-pallido-dentate calcifications. It is a rare entity with clinical polymorphism, and it occurs in patients with dysparathyroidism, especially those with hypoparathyroidism. It must be distinguished from Fahr\'s disease (FD), which is defined by the presence of intracerebral calcifications without phosphocalcic metabolism abnormality. In this paper, we report the particulars of five patients diagnosed with Fahr\'s syndrome revealed by neurological and cognitive disorders, seizures, and abnormal movements associated with tetany crisis. In all cases, brain imaging and biological examinations led to the diagnosis of Fahr\'s syndrome related to hypoparathyroidism. The evolution was favorable after treatment. Fahr\'s syndrome is a rare and serious condition for which treatment is simple and effective. Our observations shed light on the necessity of evaluating phosphocalcic metabolism and exploring cerebral calcifications in patients with neurological disorders.