Fahr’s syndrome and clinical correlation: a case series and literature review

Introduction

Fahr’s disease (FD) is characterized by idiopathic calcification within the basal ganglia, cerebellar dentate nuclei and bilateral white matter, so the term ‘bilateral striopallidodentate calcinosis’ (BSPDC) appears to be the most appropriate [43,44].
Clinical manifestation occurs at any age without overrepresented ages of onset. Idiopathic BSPDC is clinically heterogeneous. Patients with calcification may exhibit neurological and/or psychiatric symptoms with different degrees of severity and ages of onset. Others can remain asymptomatic throughout life [2]. The prevalence of BSPDC is unknown, but an incidence of basal ganglia calcification ranging from 0.3% to 1.2% has been reported in routine radiological examinations in older reports [27,72] and recently greatly increased (from 1.3% to 20.6%) in recent studies [52,71].
Between 2% and 12% of brain scanners detect the presence of calcification levels within the lymphatic vessels [14-17]. Small “physiological” calcifications, especially located in the globus pallidus, can be evidenced and their prevalence increases with age. When these findings are present in subjects younger than 40 years old, involving simultaneously the globus pallidus, putamen, cerebellar dentate nucleus and white matter (Pale-toothed grooved-calcinosis), they are considered to be pathological.
Normal serum levels of calcium and parathyroid hormone help to differentiate primary familial brain calcification from other disorders, such as hyperthyroidism or hypoparathyroidism.
The disease displays heterogeneity of symptoms, and some individuals with brain calcification can be asymptomatic [19,70]. Primary familial brain calcification is usually inherited in an autosomal dominant manner, and, thus far, mutations in three genes have been found to cause the disease: SLC20A2, PDGFB, and PDGFRB. SLC20A2 encodes for the sodium-dependent phosphate transporter 2 (PiT2). PDGFB and PDGFRB code for the platelet-derived growth factor beta (PDGFb) and its receptor, and the platelet-derived growth factor receptor beta (PDGFR-b), respectively [28,53,69].
The latest study identified in multiple families with PFBC mutations in XPR1, a gene encoding a retroviral receptor with phosphate export function. These mutations are implicating with phosphate homeostasis in PFBC [38].
In published studies, these three genes account for approximately 50% of cases [8,10,23,26,52,54, 73,74]. However, in most of these studies, only the SLC20A2 gene was examined, and only by Sanger sequencing. Comprehensive analyses of all the three genes are scarce as stated by a recent study [67].
One of known causes associated with basal ganglia calcinosis is hypoparathyroidism. Related causes can be infections, such as Epstein-Barr and human immunodeficiency [50], lupus erythematosus [57], perinatal hypoxia [58], radiation or chemotherapy [14], carbon monoxide poisoning and prolonged use of anticonvulsants [15].
The pathophysiological mechanism of calcium and other mineral deposits in extracellular and perivascular zones is still unknown. To date several hypotheses have been formulated, such as interruption of the local blood-brain barrier, altered metabolism within neuronal-glial calcium networks, changes in the extracellular matrix [6]. Calcium and other mineral deposits were found in the walls of capillaries, arterioles, and small veins and in perivascular spaces [23]. Neuronal degeneration and gliosis surrounding these accumulations have been reported [33].
Mucopolysaccharides, traces of aluminium, arsenic, cobalt, copper, molybdenum, iron, lead, manganese, magnesium, phosphorus, silver, and zinc are also present [23,42,51,64].
At the molecular level, calcification generally develops within the vessel wall and in the perivascular space, ultimately extending to the neuron.
Due to defective iron transport and free radical production, tissue damage occurs which leads to the initiation of calcification. It occurs secondarily around a Nidus composed of mucopolysaccharides and related substances. Progressive basal ganglia mineralization tends to compress the vessel lumen, thus initiating a cycle of impaired blood flow, neural tissue injury and mineral deposition. Basal ganglia concretions are recognized as basophilic globules tracking the vessels of arteries, veins and capillaries [59].
Electron microscopy also shows the evidence of a connection between spherical and hemispherical bodies formed in the adventitia of the blood vessel and surrounding glial cells while intima is usually preserved with deposits within the pericytes [30].
Mineral composition of the calcifications varies with the anatomical site and their proximity to vasculature calcifications. It may be due to the abnormal metabolism of calcium and phosphorus while some reports tend to contradict this finding [1,3,29].
In a review of 4219 computed tomography (CT) scans, it was deduced that most calcifications occur bilaterally and symmetrically while a few occur unilaterally and there was no abnormality in metabolism of calcium, denying the pathophysiologic significance of concurrent altered calcium metabolism [31]. Calcifications commonly occur in basal ganglia, thalamus, dentate nucleus, cerebral cortex, cerebellum subcortical white matter, and hippocampus [29,46].
It has been suggested that the hyperintense T2-weighted images in MRI sequences may reflect a slowly progressive metabolic or inflammatory process in the brain with consequent calcification, probably causing the neurologic deficits observed [2]. Single-photon emission computed tomography (SPECT) studies showed a marked blood flow decrease. The criteria for the diagnosis of bilateral striopallidodentate calcinosis (BSPDC) include [37,72] evidence for bilateral basal ganglia calcification; progressive neurological or neuropsychiatric manifestations; onset of symptomatology in the fourth or fifth decade of life (earlier onset is also likely to occur). There are no biochemical abnormalities and clinical features suggesting the presence of mitochondrial, metabolic disease or other systemic disorders; calcifications are not due to infection, trauma, or toxic causes; moreover, autosomal dominant inheritance (chromosome 14q9) for basal ganglia calcification has been discovered [17] (Table I). Brodaty et al. [7] excluded such a locus in the absence of neurological, cognitive and psychiatric symptoms. Further, in hypothyroidism the locus is on 11p [24]; in pseudohypoparathyroidism it is on 20q [37]; in Down’s syndrome it is on 21q [48], excluding the possibility that a single gene may be responsible for the calcium and other mineral deposits.
Bilateral striopallidodentate calcinosis is frequently suspected in normal aging [2,62]; never­theless, in the literature there is no clear evidence for establishing when calcifications can be attributed to normal aging or to a pathological process. Considering clinical presentations of BSPDC (Table II) in the presence of family history, diagnosis can be proposed in the absence of one of the first 2 criteria. Whereas when family history is negative, meeting the first 5 criteria is sufficient for the diagnosis of BSPDC only if the calcifications are typical of BSPDC [36,46]. Calcifications are more commonly reported in the globus pallidus; additional reported sites include putamen, caudate nucleus, internal capsule, dentate nucleus, thalamus, cerebellum, and cerebral white matter [44]. Several cases were diagnosed incidentally [25,61,65,68,72] during routine assessment of psychiatric or somatic symptoms, which may suggest the possibility of underestimated diagnosis of BSPDC.
This study describes three heterogeneous sporadic cases of BSPDC in the absence of demonstrated familiarity. The quantity of calcifications is correlated with the symptomatic status, even though different clinical features are not solely justified by location and severity of calcifications. Thus, the correlation between neurological impairment and symmetrical basal ganglia calcification is not always the same. Brain CT aspects were similar, whereas the clinical neurological manifestations were different. Nowadays, a literature review shows evidence that there is no definite pathogenesis of basal ganglia calcifications.
Genetic tests described in clinical cases were obtained in specialized centres for genetic research on rare diseases.

Clinical cases

Case 1

A 55-year-old man presented with a five-year progressive cognitive decline including dysexecutive syndrome, apathy, along with severe disturbance of reasoning, calculation and sequential tasks.
Moreover, memory loss and depressive mood were expressed without any other psychiatric disorders, such as delusions or hallucinations. Finally, he was unable to perform daily life activities, with decreased verbal fluency, apathy and inability to make decisions. His family history was positive for mood and cognitive impairment; however, brain CT scan did not prove calcifications. Neurological examination disclosed extrapyramidal features with postural tremor and orofacial dyskinesia at lips and tongue.
Mini Mental State Examination (MMSE) score was 23/30 (Italian version); neuropsychological tests showed immediate and recent memory deficits, particularly in remote memory. Despite hospitalisation in psychiatry ward, he continued to wander, interaction was absent, he demonstrated poor self-care and disorganised behaviour (e.g. handling the faeces). Nevertheless, the patient was spatiotemporally oriented and was able to recognise people. He was consistent in his verbal responses with rapid and unclear speech (dysarthric speech) and sometimes words could not be understood. Routine blood tests disclosed normal ionic calcium levels (1.12 mmol/l) including calcium, phosphorus, thyroid hormones and parathormone. Serologic tests for syphilis and HIV were negative. He was treated with carbolithium (600 mg/day) and selective serotonin reuptake inhibitor (SSRI). Brain CT showed extensive bilateral calcifications in the dentate nuclei of the cerebellum, basal ganglia and centrum semiovale (Fig. 1). Brain magnetic resonance imaging confirmed multiple small patchy hypersignals in the same areas (Fig. 2). Molecular diagnosis was made by sequencing of the entire coding region of SLC20A2, PDGFRB, and PDGFB and copy number analysis of SLC20A2 giving normal findings. Bilateral striopallidodentate calcinosis was therefore possible based on clinical features and neuroimaging (bilateral basal ganglia calcification, dysarthria and neuropsychiatric symptoms). The patient showed partial improvement in behavioural symptoms with Carbolithium discontinuation; hence quetiapine (25 mg/day) was added. Symptomatology ameliorated within the 60 following days, specifically with the reduction of orofacial dyskinesia at lips and tongue. Despite partial initial benefits, he showed progression of the disease with a severe depressive syndrome.

Case 2

A 70-year-old woman with a previous history of bronchial asthma and hypertension with neurological symptoms occurring for 20 years, showed mild tremor in the upper limbs. Hypothyroidism was disclosed; T3 and T4 results were always normal. During the following 10-15 years tremor increased progressively up to involving the chin and the voice.
Two years later, memory loss and depressive mood were demonstrated. Mini Mental State Examination (MMSE) score was 23/30 (Italian version); other neuropsychological tests showed deficit in attentional capacity, in spatiotemporal orientation and praxis functions. Complete haematochemical examinations, including thyroid and parathyroid hormones, phosphorus/calcium, liver function tests, complete blood count, along with sedimentation, were normal even when frequently repeated over years. Electroencephalogram (EEG) was unremarkable. Brain CT scan highlighted the symmetrical distribution of mineral deposits in the lenticular nuclei, medial thalamic paraventricular nuclei and in the white matter (Fig. 3). The patient’s overall clinical features alongside instrumental examinations allowed to make a diagnosis of BSPDC. After obtaining informed consent, diagnostic genetic testing was performed by sequencing of SLC20A2, PDGFRB, and PDGFB with normal findings. Levodopa was administered but the patient did not tolerate it; beta-blockers could not be used because of bronchial asthma. Within 60 days of alprazolam introduction (3 mg/day), the patient showed partial improvement in behavioural symptoms and essential tremor went into remission.
Regular follow-up during the next three years disclosed tremor recurrence with exclusive involvement of the chin.

Case 3

A 32-year-old man complained of progressive mild tremor at hands in the previous year.
His personal history was positive for Hashimoto thyroiditis. Neurological examination showed only mild rest and action tremor without further signs of extrapyramidal features. Neither dismetry nor any other cerebellar signs were present. General examinations were normal. The patient’s relatives were examined and no abnormalities were detected. The thyroid test, parathyroid hormone, phosphorus/calcium, liver function tests, complete blood count, sedimentation and ionic calcium level were normal. Serologic tests for syphilis and HIV were negative. Cerebrospinal fluid (CSF) analysis was normal. Mini Mental State Examination (MMSE) score was 30/30 (Italian version); other neuropsychological tests were normal. Brain CT scan showed extensive bilateral calcifications in the dentate nuclei of the cerebellum, basal ganglia and bilateral white matter. Magnetic resonance imaging confirmed severe hypointense focal areas with a maximum diameter of about 10 x 7 mm in capsular and peritrigonal areas (Fig. 4). No therapy was administered because of slight symptomatology.
After informed consent to diagnostic genetic testing was obtained, sequencing of SLC20A2, PDGFRB, and PDGFB was performed giving normal findings.
2-year or regular follow-up disclosed no sign of disease progression.

Discussion

Bilateral striopallidodentate calcinosis is mostly associated with a disorder of calcium and phosphate metabolism, especially hypoparathyroidism (HPT) [2,20,55,60]; however, different aetiology must be considered, including infectious, metabolic, and genetic diseases [65].
Our clinical series did not reveal abnormalities in calcium, phosphate, parathyroid levels and other dysmetabolism responsible or calcium deposition.
Furthermore, there was no family history of the disease in all of the three cases reported.
Genetic analysis for SLC20A2, PDGFRB, and PDGFB genes detected no mutations.
Recent reports have highlighted novel hypothesis regarding the possible causes and etiopathological processes of PFBC [21]. In particular, mutations in 3 different genes have been identified as causative agents of PFBC. First, SLC20A2 (OMIM158378) was described in February 2012 as coding for type III sodium-dependent inorganic phosphate (Pi) transporter 2 (PiT-2). The second reported gene, PDGFRB (OMIM173410), was described in January 2013 as encoding 1 of 2 receptors for platelet-derived growth factor. The gene encoding its major ligand, PDGFB (OMIM190040), was the third gene identified in September 2013 [28]. The different mutations in all the 3 genes share loss of function as the probable cause of pathology. Mutations in the SLC20A2 gene lead to accumulation of Pi and subsequently to calcium phosphate deposition. Mutations in PDGFB and PDGFRB also result in calcification through indirect processes. Although the receptor and its ligand are also expressed in neurons, data from selective knockout studies indicate impaired recruitment of pericytes to endothelial cells, resulting in a dysfunctional blood-brain barrier and thereby contributing to brain calcification.
Disease progression is heterogeneous even within the same family. The prevalence of extrapyramidal disorders (parkinsonism, dystonia, dyskinesia) and cerebellar signs (ataxia and dysarthria) is reported; neuropsychiatric symptoms, including schizo-morphous psychosis [9], changes of personality [34], lability of mood and compulsive [18,35,40] obsessive disturbance, were evidenced. Nevertheless a progressive subcortical cognitive impairment could occur.
In a study combining 38 cases recruited through a registry and 61 cases reported in the literature, movement disorders were found as the most common manifestations of BSPDC accounting for 55% of symptomatic patients. The most common movement disorders were parkinsonism (57% of cases), chorea (19%), tremor (8%), dystonia (8%), athetosis (5%) and orofacial dyskinesia (3%).
Measurements of the total volume of calcification suggest a significantly larger amount of calcification in symptomatic patients compared with asymptomatic patients [46].
Neuropsychiatric symptoms can be either the first or the most prominent manifestation ranging from mild concentration or memory impairment, personality and behaviour changes, to psychosis and dementia. About 40% of patients with basal ganglia calcification (BGC) may initially present psychiatric features [5], such as psychotic syndrome and mood changes, but even cognitive disorders are common [13]. Paranoid and psychotic features often begin in patients aged between 20 and 40 [19]. In FD two patterns of psychotic presentation are described: early onset (mean age 30.7 years) with minimal movement disorder and late onset (mean age 49.4 years) associated with dementia and movement disorders [12]. Nevertheless, all the symptoms may vary during the course of disease. Calcification extension and subarachnoid space dilatation correlate with the presence of psychiatric manifestations [41]. Other clinical findings in patients with BSPDC are cranio-cerebral trauma, stroke, meningitis, encephalitis, brain tumours, cerebral aneurysm, arteriovenous malformation, subdural hematoma, and mastoiditis [36]. Cases presenting with BSPDC and disturbed calcium metabolism were associated with idiopathic hypoparathyroidism, hyperparathyroidism, pseudo-hypoparathyroidism, and postoperative hypoparathyroidism. Patients having parathyroid hormone deficiencies due to thyroidectomy showed more severe mental deterioration [41]. In the three cases reported in our study, the beginning of symptomatology was different and characterised by tremor, psychiatric disorders or movement disorders. The patient with a higher quantity of calcium in TC (case 2) showed onset with predominant psychiatric symptoms, whereas the cases with less (case 2) or earlier (case 3) calcium deposition had prevailing tremor without parkinsonism signs. Besides, aetiology of calcium deposition remains mostly undetermined and no metabolic causes came up in the cases observed.
The exact pathological process responsible for the calcification of brain structures is still poorly understood; it could be secondary to a progressive metabolic or inflammatory process, which subsequently causes the neurological impairments observed [2]. Neuroradiological findings are also different in CT and MRI. The areas involved were basal ganglia, dentate nuclei of cerebellum, medial thalamic paraventricular nuclei, white matter and no correlations were found with clinical manifestations.
These data were confirmed by the literature, especially the non-specificity of lesions for localisation, extension and correlated symptoms.
Moreover, our patients were examined in regular follow-ups and all of them had no progression of symptomatology since the beginning of disease.
It is still unknown why the basal ganglia are the most vulnerable site for calcium deposition, but even in other conditions they are a favourite target, like bilirubin in kernicterus or 1-methyl-4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) and carbon mono­xide causing parkinsonism.
Although correction of dysmetabolic causes, such as hypoparathyroidism or mitochondrial encephalo­pathy, can improve neuropsychiatric syndrome, there are no specific treatments at the moment that may limit the progression of calcification in the basal ganglia. A report of amelioration using Ca-chelators with antioxidant and Ca-antagonist has still to be confirmed [11]. Currently there is no cure for BSPDC nor is there a standard treatment. The available therapy is only symptomatic and corrections of known aetiology are admitted.
The prognosis is variable and unpredictable. There is no reliable correlation between age, extent of calcium deposits in the brain and neurological deficit. Progressive neurological deterioration generally results in disability and death.
Reduced 25-OH vitamin D3 with normal levels of 1.25(OH)2 vitamin D3, suggest an inborn error of vitamin D metabolism [47]. Further evaluation of this finding is needed so as to provide a therapeutic solution.
The treatment of BSPDC is directed to the identifiable causes [49]. Especially in HPT, an early treatment can prevent calcification and neurophysiological disorders [20,55,56].
Studies show that psychoses in BSPDC have variable and sometimes null responses to treatment [32].
The treatment targets include symptomatic support. The response to levodopa in those patients with parkinsonian features is reportedly poor. Atypical antipsychotics are preferred for psychiatric symptoms because of the coexistence of the extra pyramidal syndrome in this group of patients.
Treatment of underlying aetiology such as hypo­parathyroidism has led to neuropsychiatric impro­vement, but there are no specific treatments limiting the progression of calcification in the basal ganglia in BSPDC, except a theoretically unconfirmed report of Ca-chelators plus antioxidant and Ca-antagonist benefits [11]. Metal binding proteins and metal-chelating agents (like ammonium tetrathiomolybdate, which is a Cu-chelating agent) have been theoretically suggested as one of the treatment options [22].

Acknowledgements

The authors would like to thank the Santorso Hospital (Santorso, Italy).

Disclosure

Authors report no conflict of interest.

References

1. Asokan AG, D’Souza S, Jeganathan J, Pai S. Fahr’s Syndrome – An Interesting Case Presentation. J Clin Diagn Res 2013; 7: 532-533.
2. Avrahami E, Cohn DF, Feibel M, Tadmor R. MRI demonstration and CT correlation of the brain in patients with idiopathic intracerebral calcification. J Neurol 1994; 241: 381-384.
3. Baba Y, Broderick DF, Uitti RJ, Hutton ML, Wszolek ZK. Heredofamilial brain calcinosis syndrome. Mayo Clin Proc 2005; 80: 641-651.
4. Baker M, Strongosky AJ, Sanchez-Contreras MY, Yang S, Ferguson W, Calne DB, Calne S, Stoessl AJ, Allanson JE, Broderick DF, Hutton ML, Dickson DW, Ross OA, Wszolek ZK, Rademarkes R. SLC20A2 and THAP1 deletion in familial basal ganglia calcification with dystonia. Neurogenetics 2013; 15: 23-30.
5. Benke T, Karner E, Seppi K, Delazer M, Marksteiner J, Donnemiller E. Subacute dementia and imaging correlates in a case of Fahr’s disease. J Neurol Neurosurg Psychiatry 2004; 75: 1163-1165.
6. Bouras C, Giannakopoulos P, Good PF, Hsu A, Hof PR, Perl DP. A laser microprobe mass analysis of trace elements in brain mineralizations and capillaries in Fahr’ s disease. Acta Neuropathol (Berl) 1996; 92: 351-357.
7. Brodaty H, Mitchell P, Luscombe G, Kwok JBJ, Badenhop RF, McKenzie R, Schofield PR. Familial idiopathic basal ganglia calcification (Fahr’s disease) without neurological, cognitive and psychiatric symptoms is not linked to the IBGC1 locus on chromosome 14q. Hum Genet 2002; 110: 8-14.
8. Carecchio M, Varrasi C, Barzaghi C, Magistrelli L, Comi C, Gara­vaglia B, Cantello R. Phenotypic heterogeneity of movement disorders due to intracranial calcifications with or without SLC20A2 mutations. Mov Disord 2014; 29 (Suppl 1): S1-S571.
9. Chabot B, Roulland C, Dollfus S. Schizophrenia and familial idiopathic basal ganglia calcification: a case report. Psychol Med 2001; 31: 741-747.
10. Chen WJ, Yao XP, Zhang QJ, Ni W, He J, Li HF, Liu XY, Zhao GX, Munrong SX, Wang N, Wu ZY. Novel SLC20A2 mutations identified in southern Chinese patients with idiopathic basal ganglia calcification. Gene 2013; 529: 159-162.
11. Cummings JL, Gosenfeld LF, Houlihan JP, McCaffrey T. Neuropsychiatric disturbances associated with idiopathic calcification of the basal ganglia. Biol Psychiatry 1983; 18: 591-601.
12. Cummings JL. Clinical Neuropsychiatry. Grune and Stratton, Orlando 1985; pp. 154-155.
13. Duckett S, Galle P, Escourolle R, Poirier J, Hauw JJ. Presence of zinc, aluminum, magnesium in striopallidodentate (SPD) calcifications (Fahr’s disease): electron probe study. Acta Neuropathol (Berl) 1977; 38: 7-10.
14. Fénelon G, Gray F, Paillard F, Thibierge M, Mahieux F, Guillani A. Psychiatry. A prospective study of patients with CT detected pallidal calcifications. J Neurol Neurosurg 1993; 56: 622-625.
15. Fernández-Bouzas A, Ramírez H, Vásquez J, Alonso-Vanegas M, Mendizábal R. Brain calcification and dementia in children treated with radiotherapy and intrathecal metrotexate. J Neurosurg Sci 1992; 36: 2111-2114.
16. Forstl H, Krumm B, Eden S, Kohlmeyer K. Neurological disorders in 166 patients with basal ganglia calcification: a statistical evaluation. J Neurol 1992; 239: 36-38.
17. Geschwind DH, Loginov M, Stern JM. Identification of a locus on chromosome 14q for idiopathic basal ganglia calcification (Fahr disease). Am J Hum Genet 1999; 65: 764-772.
18. Gluck-Vanlaer N, Fallet A, Plas J, Chevalier JF. Depression and calcinosis of the basal ganglia: apropos of a case. Encephale 1996; 22: 127-131.
19. Gomille T, Meyer RA, Falkai P, Gaebel W, Konigshausen T, Christ F. Prevalence and clinical significance of computerized tomography verified idiopathic calcinosis of the basal ganglia. Radiologe 2001; 41: 205-210.
20. Goswami R, Sharma R, Sreenivas V, Gupta N, Ganapathy A, Das S. Prevalence and progression of basal ganglia calcification and its pathogenic mechanism in patients with idiopathic hypoparathyroidism. Clin Endocrinol (Oxf) 2012; 77: 200-206.
21. Hayashi T, Legati A, Nishikawa T, Coppola G. First Japanese family with primary familial brain calcification due to a mutation in the PDGFB gene: an exome analysis study. Clin Neurosci Psychiatry 2015; 69: 77-83.
22. Hozumi I, Kohmura A, Kimura A, Hasegawa T, Honda A, Hayashi Y, Hashimoto K, Yamada M, Sakurai T, Tanaka Y, Satoh M, Inuzuka T. High Levels of Copper, Zinc, Iron and Magnesium, but not Calcium, in the Cerebrospinal Fluid of Patients with Fahr’s Disease. Case Rep Neurol 2010; 2: 46-51.
23. Hsu SC, Sears RL, Lemos RR, Quintans B, Huang A, Spiteri E, Nevarez L, Mamah C, Zatz M, Pierce KD, Fullerton JM, Adair JC, Berner JE, Bower M, Brodaty H, Caermona O, Dobricić V, Fogel BL, García-Estevez D, Goldman J, Goudreau JL, Hopfer S, Jancović M, Jaumá S, Jen JC, Kirdlarp S, Klepper J, Kostić V, Lang AE, Linglart A, Maisenbacher MK, Manyam BV, Mazzoni P, Miedzbrodzka Z, Mitarun W, Mitchell PB, Mueller J, Novaković I, Paucar M, Paulson H, Simpson SA, Svenningsson P, Tuite P, Vitek J, Wetchaphanphesat S, Williams C, Yang M, Schofield PR, de Olivera JR, Sobrido MJ, Geschwind DH, Coppola G. Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification. Neurogenetics 2013; 14: 11-22.
24. Juppner H, Schipani E, Bastepe M, Cole DEC, Lawson ML, Mannstadt M, Hendy GN, Plotkin H, Koshiyama H, Koh T, Crawford JD, Olsen BR, Vikkula M. The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3. Proc Natl Acad Sci 1998; 95: 11798-11803.
25. Kao YC, Lin MI. Intramuscular hemangioma of the temporalis muscle with incidental finding of bilateral symmetric calcification of the basal ganglia: a case report. Pediatr Neonatol 2010; 51: 296-299.
26. Kasuga K, Konno T, Saito K, Ishihara A, Nishizawa M, Ikeuchi T. A Japanese family with idiopathic basal ganglia calcification with novel SLC20A2 mutation presenting with late-onset hallucination and delusion. J Neurol 2014; 261: 242-244.
27. Kazis AD. Contribution of CT scan to the diagnosis of Fahr’s syndrome. Acta Neurol Scand 1985; 71: 206-211.
28. Keller A, Westenberger A, Sobrido MJ, Garcìa-Murias M, Domingo A, Sears RL, Lemos RR, Ordońez-Ugalde A, Nicolas G, da Cunha JE, Rushing EJ, Hugelshofer M, Wurnig MC, Kaech A, Reimann R, Lohmann K, Dobričić V, Carracedo A, Petrović I, Miyasaki JM, Abakumova I, Mäe MA, Raschperger E, Zatz M, Zschiedrich K, Klepper J, Spiteri E, Prieto JM, Navas I, Preuss M, Dering C, Janković M, Paucar M, Svenningsson P, Saliminejad K, Khorshid HR, Novaković I, Aguzzi A, Boss A, Le Ber I, Defer G, Hannequin D, Kostić VS, Campion D, Geschwind DH, Coppola G, Betsholtz C, Klein C, Oliveira JR. Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet 2013; 45: 1077-1082.
29. Kobari M, Nogawa S, Sugimoto Y, Fukuuchi Y. Familial idiopathic brain calcification with autosomal dominant inheritance. Neurology 1997; 48: 645-649.
30. Kobayashi S, Yamadori I, Miki H, Ohmori M. Idiopathic nonarteriosclerotic cerebral calcification (Fahr’s disease): an electron microscopic study. Acta Neuropathol (Berl) 1987; 73: 62-66.
31. Koller WC, Cochran JW, Klawans HL. Calcification of the basal ganglia: computerized tomography and clinical correlation. Neurology 1979; 29: 328-333.
32. König P. Psychopathological alterations in cases of symmetrical basal ganglia sclerosis. Biol Psychiatry 1989; 25: 459-468.
33. Kozik M, Kulczycki J. Laser-spectrographic analysis of the cation content in Fahr’s syndrome. Arch Psychiatr Nervenkr (1970) 1978; 225: 135-142.
34. Lauterbach EC, Cummings JL, Duffy J, Coffey CE, Kaufer D, Lovell M, Malloy P, Reeve A, Royall DR, Rummans TA, Salloway SP. Neuropsychiatric correlates and treatment of lenticulostriatal diseases: a review of the literature and overview of research opportunities in Huntington’s, Wilson’s and Fahr’s diseases. A report of the ANPA Committee on Research. American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci 1998; 10: 249-266.
35. Lawrence AD, Watkins LHA, Sahakian BJ, Hodges JR, Robbins TW. Visual object and visuospatial cognition in Huntington s disease: implications for information processing in corticostriatal circuits. Brain 2000; 123: 1349-1364.
36. Lazar M, Ion DA, Streinu-Cercel A, Badarau AI. Fahr’s syndrome: diagnosis issues in patients with unknown family history of disease. Rom J Morphol Embryol 2009; 50: 425-428.
37. Lebo RV, Cheung M-C, Bruce BD, Riccardi VM, Kao F-T, Kan YW. Mapping parathyroid hormone, beta-globin, insulin, and LDH-A genes within the human chromosome 11 short arm by spot blotting sorted chromosomes. Hum Genet 1985; 69: 316-320.
38. Legati A, Giovannini D, Nicolas G, López-Sánchez U, Quintáns B, Oliveira JR, Sears RL, Ramos EM, Spiteri E, Sobrido MJ, Carracedo Á, Castro-Fernández C, Cubizolle S, Fogel BL, Goizet C, Jen JC, Kirdlarp S, Lang AE, Miedzybrodzka Z, Mitarnun W, Paucar M, Paulson H, Pariente J, Richard AC, Salins NS, Simpson SA, Striano P, Svenningsson P, Tison F, Unni VK, Vanakker O, Wessels MW, Wetchaphanphesat S, Yang M, Boller F, Campion D, Hannequin D, Sitbon M, Geschwind DH, Battini JL, Coppola G. Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat Genet 2015; 47: 579-581.
39. Lemos R, Oliveira M, Oliveira J. Reporting a new mutation at the SLC20A2 gene in familial idiopathic basal ganglia calcification. Eur J Neurol 2013; 20: e43-44.
40. Lombardi WJ, Gross RE, Trepanier LL, Lang AE, Lozano AM, Saint-Cyr JA. Relationship of lesion location to cognitive outcome following microelectrode-guided pallidotomy for Parkinson’s disease. Support for the existence of cognitive circuits in the human pallidum. Brain 2000; 123: 746-758.
41. López-Villegas D, Kulisevsky J, Deus J, Junque C, Pujol J, Guardia E, Grau JM. Neuropsychological alterationsin patients with computed tomography detected basal ganglia calcification. Arch Neurol 1996; 53: 251-256.
42. Lowenthal A, Bruyn GW. Calcification of the striopallidodentate system. In: Handbook of Clinical Neurology. Vol. 6. Diseases of the Basal Ganglia. Vinkin PJ, Bruyn GW (eds.). North-Holland, Amsterdam 1968; p.703-725; Chapter 27.
43. Manyam BV. Bilateral striopallidodentate calcinosis: a proposed classification of genetic and secondary causes. Mov Disord 1990; 5 (Suppl. 1): 94.
44. Manyam BV, Bhatt MH, Moore WD, Develschoward AB, Anderson DR, Caline DB. Bilateral striopallidodentate calcinosis: cerebrospinal fluid, imaging, and electrophysiological studies. Ann Neurol 1992; 31: 379-384.
45. Manyam BV. What is and what is not ‘Fahr’s disease’. Parkinsonism Relat Disord 2005; 11: 73-80.
46. Malik R, Pandya V, Naik D. Fahr disease – a rare neurodegenerative disorder. Indian J Radiol Imaging 2004; 14: 383-384.
47. Martinelli P, Giuliani S, Ippoliti M, Martinelli A, Sforza A, Ferrari S. Familial idiopathic strio-pallido-dentate calcifications with late onset extrapyramidal syndrome. Mov Disord 1993; 8: 220-222.
48. McCormick M, Schinzel A, Petersen M, Stetten G, Driscoll D, Cantu E, Tranebjaerg L, Mikkelsen M, Watkins P, Antonarakis S. Molecular genetic approach to the characterization of the Down syndrome region of chromosome 21. Genomics 1989; 5: 325-331.
49. Mitchell DM, Regan S, Cooley MR, Lauter KB, Vrla MC, Becker CB, Burnett-Bowie SA, Mannstadt M. Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab 2012; 97: 4507-4514.
50. Morita M, Tsuge I, Matsuoka H, Ito J, Iotsu T, Yamamoto M, Mori­shima T. Calcification in the basal ganglia with chronic active Epstein-Barr virus infection. Neurology 1998; 50: 1485-1488.
51. Neumann MA. Iron and calcium dysmetabolism in the brain with special predilection for globus pallidus and cerebellum. J Neuropath Exp Neurol 1963; 22: 148-168.
52. Nicolas G, Pottier C, Charbonnier C, Guyant-Maréchal L, Le Ber I, Pariente J, Labauge P, Ayrignac X, Defebvre L, Maltęte D, Martinaud O, Lefaucheur R, Guillin O, Wallon D, Chaumette B, Rondepierre P, Derache N, Fromager G, Schaeffer S, Krystkowiak P, Verny C, Jurici S, Sauvée M, Vérin M, Lebouvier T, Rouaud O, Thauvin-Robinet C, Rousseau S, Rovelet-Lecrux A, Frebourg T, Campion D, Hannequin D. French IBGC Study Group Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification. Brain 2013; 136 (Pt 11): 3395-3407.
53. Nicolas G, Pottier C, Maltete D, Coutant S, Rovelet-Lecrux A, Legallic S, Rousseau S, Vaschalde Y, Guyant-Maréchal L, Augustin J, Martinaud O, Defebvre L, Krystkowiak P, Pariente J, Clanet M, Labauge P, Ayrignac X, Lefaucheur R, Le Ber I, Frébourg T, Hannequin D, Campion D. Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology 2013; 80: 181-187.
54. Nicolas G, Rovelet-Lecrux A, Pottier C, Martinaud O, Wallon D, Vernier L, Landemore G, Chapon F, Prieto-Morin C, Tournier- Lasserve E, Frébourg T, Campion D, Hannequin D. PDGFB partial deletion: a new, rare mechanism causing brain calcification with leukoencephalopathy. J Mol Neurosci 2014; 53: 171-175.
55. Nicolau Ramis J, Espino Ibáńez A, Rivera Irigoín R, Artigas CF, Masmiquel Comas L. Extrapyramidal symptoms due to calcinosis cerebri in a patient with unknown primary hypoparathyroidism. Endocrinol Nutr 2012; 59: 69-71.
56. Rastogi R, Singh AK, Rastogi UC, Mohan C, Rastogi V. Fahr’s syndrome: a rare clinico-radiologic entity. Med J Armed Forces India 2011; 67: 159-161.
57. Raymond AA, Zariah AA, Samad SA, Chin CN, Kong NC. Brain calcification in patients with cerebral lupus. Lupus 1996; 5: 123-128.
58. Rodríguez MJ, Ursu G, Bernal F, Cusì V, Mahy N. Perinatal human hypoxia-ischemia vulnerability correlates with brain calcification. Neurobiol Dis 2001; 8: 59-68.
59. Saleem S, Aslam HM, Anwar M, Anwar S, Saleem M, Saleem A, Rehmani MA. Fahr’s syndrome: literature review of current evidence. Orphanet J Rare Dis 2013; 8: 156.
60. Senoglu M, Tuncel D, Orhan FO, Yuksel Z, Gokçe M. Fahr’s syndrome: a report of two cases. Firat Tip Dergisi 2007; 12: 70-72.
61. Shakibai SV, Johnson JP, Bourgeois JA. Paranoid delusions and cognitive impairment suggesting Fahr’s disease. Psychosomatics 2005; 46: 569-572.
62. Simoni M, Pantoni L, Pracucci G, Palmetz B, Guo X, Gustafson D, Skoog J. Prevalence of CT-detected cerebral abnormalities in an elderly Swedish population sample. Acta Neurol Scand 2008; 118: 260-267.
63. Skvortsov IA, Rudenskaia GE, Karaseva AN, Vel’tishchev IuE. Effectiveness of therapeutic use of complexones in various diseases of the extrapyramidal system in children. Zh Nevropatol Psikhiatr Im S S Korsakova 1987; 87: 1457-1462.
64. Smeyers-Verbeke J, Michotte Y, Pelsmaeckers J, Lowenthal A, Massart DL, Dekegel D, Karcher D. The chemical composition of idiopathic nonarteriosclerotic cerebral calcifications. Neurology 1975; 25: 48-57.
65. Srivastava S, Bhatia MS, Sharma V, Mahajan S, Rajender G. Fahr’s Disease: An Incidental Finding in a Case Presenting with Psychosis. German Journal of Psychiatry 2010; 13: 86-90.
66. Swami A, Kar G. Intracranial hemorrhage revealing pseudohypoparathyroidism as a cause of Fahr syndrome. Case Rep Neurol Med 2011; 2011: 407567.
67. Taglia I, Mignarri A, Olgiati S, Menci E, Petrocelli PL, Breed- veld GJ, Scaglione C, Martinelli P, Federico A, Bonifati V, Dotti MT. Primary Familial Brain Calcification: Genetic Analysis and Clinical Spectrum. Mov Disord 2014; 29: 1691-1695.
68. Trautner RJ, Cummings JL, Read SL, Benson DF. Idiopathic basal ganglia calcification and organic mood disorder. Am J Psychiatry 1988; 145: 350-353.
69. Wang C, Li Y, Shi L, Ren J, Patti M, Wang T, de Oliveira JR, Sobrido MJ, Quintáns B, Baquero M, Cui X, Zhang XY, Wang L, Xu H, Wang J, Yao J, Dai X, Liu J, Zhang L, Ma H, Gao Y, Ma X, Feng S, Liu M, Wang QK, Forster IC, Zhang X, Liu JY. Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet 2012; 44: 254-256.
70. Wider C, Dickson DW, Schweitzer KJ, Broderick DK, Wszoleck ZK. Familial idiopathic basal ganglia calcification: a challenging clinical-pathological correlation. J Neurol 2009; 256: 839-842.
71. Yamada M, Asano T, Okamoto K, Hayashi Y, Kanematsu M, Hoshi H, Akaiwa Y, Shimohata T, Nishizawa M, Inuzuka T, Hozumi I. High frequency of calcification in basal ganglia on brain computed tomography images in Japanese older adults. Geriatr Gerontol Int 2013; 13: 706-710.
72. Yamada N, Hayashi T. Asymptomatic familial basal ganglia calcification with autosomal dominant inheritance: a family report. No To Hattatsu 2000; 32: 515-519.
73. Yamada M, Masaki T, Mari T, Kobayashi S, Taguchi J, Takashima S, Tanaka K, Touge T, Hatsuta H, Murayama S, Hayashi Y, Kaneko M, Ishiura H, Mitsui J, Atsuta N, Sobue G, Shimozawa N, Inuzuka T, Tsuji S, Hozumi I. Evaluation of SLC20A2 mutations that cause idiopathic basal ganglia calcification in Japan. Neuro­logy 2014; 82: 705-712.
74. Zhang Y, Guo X, Wu A. Association between a novel mutation in SLC20A2 and familial idiopathic basal ganglia calcification. PLoS One 2013; 8: e57060.