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Idiopathic basal ganglia calcification …
- Updated 03.06.2022
- Released 06.25.2007
- Expires For CME 03.06.2025
Idiopathic basal ganglia calcification
Introduction
Overview
Idiopathic basal ganglia calcification (IBGC), previously referred to as Fahr disease, is an inherited neuropsychiatric disorder, characterized by bilateral and usually symmetrical basal ganglia calcifications that may extend to the cerebellum, thalamus, and subcortical white matter. Parkinsonism and other movement disorders appear to be the most common clinical manifestation, followed by psychiatric symptoms, cognitive impairment, and ataxia. CT scan is considered more sensitive than MRI for finding calcifications. In this article, the authors discuss the etiology, pathogenesis, genetics, classification, and clinical manifestations of idiopathic basal ganglia calcification. A comprehensive list of disorders causing secondary brain calcification is provided (hypoparathyroidism being the most common).
Key points
Idiopathic basal ganglia calcification clinically presents as movement disorders such as parkinsonism, ataxia, chorea, tremor, dystonia, athetosis, or orofacial dyskinesia. | |
Idiopathic basal ganglia calcification is classically inherited in an autosomal dominant fashion, although it may occur de novo. | |
Head CT is the most sensitive imaging modality to assess for idiopathic basal ganglia calcification. |
Historical note and terminology
Basal ganglia calcifications involving the striatum, pallidum, with or without deposits in dentate nucleus, thalamus, and white matter have been reported in asymptomatic individuals and in a variety of neurologic conditions (61; 46; 72). Many terms are used in the literature to describe this imaging finding, which has added to the confusion regarding etiology and clinical manifestations of idiopathic basal ganglia calcification and other disorders with similar radiographic appearance.
When basal ganglia calcifications are thought to be idiopathic (after appropriate search for secondary causes), the term idiopathic basal ganglia calcification (IBGC) is used. This was previously referred to as Fahr disease, but this eponym went out of favor as Fahr was not the first to describe the disorder nor did he contribute significantly to its understanding (46). As genetic underpinnings of idiopathic basal ganglia calcification have been identified, many authors have started using term “primary familial” instead of “idiopathic” (75; 34; 76). Idiopathic basal ganglia calcification is typically inherited in an autosomal-dominant fashion, but if family history or genetic testing cannot be obtained, the term idiopathic may still be appropriate. Of note, incidental finding of basal ganglia calcification is present in 1% to 20% of healthy people (these calcifications are typically smaller, confined to pallidum, and increase with age) (89), so the term idiopathic basal ganglia calcification should only be used if there are appropriate accompanying clinical symptoms, or the calcifications are large (genetic forms have variable phenotype so affected individuals can be asymptomatic), or relevant genetic mutation has been identified. Secondary brain calcification has been reported in a variety of genetic, developmental, metabolic, infectious, and other conditions (see Table 1) (46). This was previously referred to as Fahr syndrome, but to avoid confusion the term “secondary” should be used to differentiate it from idiopathic basal ganglia calcification (71).
A historical description of basal ganglia calcification is provided by Manyam (46). Briefly, Delecour first described vascular calcifications of the basal ganglia in 1850 in a 56-year-old man who had stiffness and weakness of lower extremities with tremor. In 1855, Bamberger described the histopathologic entity of calcifications in a woman who had mental retardation and seizures (07). Later, in 1930, Fahr described an 81-year-old man with a long history of dementia, “immobility without paralysis,” with pathologic findings of “rough granular cortex and calcifications in centrum semiovale and striatum” (23). Fritzsche gave the first roentgenographic description of the condition in 1935 (46).
Because the hallmark is involvement of the basal ganglia, the term “idiopathic basal ganglia calcification” is well established in the literature, and idiopathic basal ganglia calcification is used in the OMIM registry, that will be the term used in this review.
Clinical manifestations
Presentation and course
Idiopathic basal ganglia calcification is a rare, inherited disorder that typically presents in the third to fifth decade, but it can be seen in childhood and older age (55). Clinically, parkinsonism or other movement disorders (ataxia, chorea, tremor, dystonia, athetosis, orofacial dyskinesia) appear to be the most common presentation, followed by neuropsychiatric symptoms (cognitive impairment depression, psychosis, personality changes) and less commonly dysarthria, gait abnormalities, seizures, and migraines (49; 55). In 2001, Manyam and colleagues described clinical manifestations in 99 patients with idiopathic basal ganglia calcification from a registry (The Fahr’s Disease Registry) and 20 published studies (49). The inclusion criteria for the registry were: (1) radiological evidence of bilateral almost symmetric calcifications of one or more of the following areas: basal ganglia, dentate nuclei, thalamus, and cerebral white matter; (2) normal childhood growth and development; (3) absence of parathyroid disorder; (4) availability of details of family pedigree; and (5) documentation of detailed history and clinical examination. Of 99 subjects included, 73 belonged to 14 families with autosomal dominant inheritance, 12 were considered familial, and 14 were sporadic. Overall, 67 were symptomatic and 32 asymptomatic. Movement disorder was the most common manifestation, accounting for about 55% of the symptomatic patients. Parkinsonism was seen in 57%, chorea in 19%, tremor in 8%, dystonia in 8%, athetosis in 5%, and orofacial dyskinesia in 3%. Other neurologic manifestations included cognitive impairment, cerebellar signs, speech disorder, pyramidal signs, psychiatric features, gait disorders, sensory changes, and pain. In this study greater amount of calcification was seen in symptomatic patients compared to asymptomatic individuals (49).
Clinical manifestations of 57 genetically confirmed idiopathic basal ganglia calcification cases were reported (55). Mutations in the SLC20A2 gene were found in 24 patients (18 from seven families and six sporadic), the PDGFB gene in 19 (15 from three families and four sporadic), and the PDGFRB gene in 14 (13 from one family and one sporadic). In total, 58% of subjects were symptomatic, with median age of onset 31 years (range 6 to 77 years). The three most frequently observed categories of clinical features were psychiatric signs (75.8%), movement disorders (60.6%), and cognitive impairment (57.8%). Patients with early onset (< 18 years) showed primarily psychiatric or cognitive signs, whereas those with later onset (> 53 years) had mostly movement disorders. In patients with movement disorders, 85% had akinetic-rigid syndrome, and other features included tremor, chorea, dystonia, and orofacial dyskinesia. Additional less common symptoms were speech, gait, cerebellar, pyramidal, gastrointestinal symptoms, pain, urinary problems, and seizures. Migraines were reported in 14% of all subjects, and it was not clear if this finding was coincidental or related to idiopathic basal ganglia calcification (55).
Case reports describe additional clinical presentations, such as paroxysmal kinesigenic and nonkinesigenic dyskinesia responsive to carbamazepine (21; 14; 52), isolated schizophrenia-like psychosis (24; 56; 51), stroke (91), and impulse-control disorder (66).
The diagnosis of idiopathic basal ganglia calcification is supported by the following criteria (75):
1. Bilateral calcification of the basal ganglia visualized on neuroimaging. Other brain regions may also be affected. | |
2. Progressive neurologic dysfunction, generally including a movement disorder or neuropsychiatric manifestations. Age of onset is typically in the fourth or fifth decade, although this dysfunction may present in childhood or later in life. | |
3. Absence of biochemical abnormalities and somatic features suggestive of a mitochondrial or metabolic disease or other systemic disorder. | |
4. Absence of an infectious, toxic, or traumatic cause. | |
5. Family history consistent with autosomal dominant inheritance (although sporadic and other familial cases have been described). |
Prognosis and complications
Idiopathic basal ganglia calcification is characterized by usually progressive, but extremely variable course. Approximately 30% to 40% of individuals with large calcification burden or idiopathic basal ganglia calcification gene carriers are asymptomatic (49; 55). The neurodegenerative evolution of the disease was suggested by two studies where imaging demonstrated development of cerebral atrophy in several affected patients (48; 40).
Complications of idiopathic basal ganglia calcification include movement disorders, psychiatric symptoms, cognitive impairment, speech disorder, cerebellar impairment, and less commonly pyramidal signs, gait disorders, sensory changes, pain, seizures, and migraines (49; 15; 55).
Clinical vignette
A 57-year-old, previously healthy man presented with memory loss, speech difficulty, and involuntary movements. The patient had no history of alcohol or any recreational drug usage. His childhood was uneventful, and he graduated from college at 23 years of age. He was working in an office until a year prior, when he began to experience memory problems and difficulty with calculations. He later began to have speech difficulty and involuntary movements. His neurologic examination revealed moderate dementia with a score of 17/30 on Mini-Mental Status Examination. Although he had moderate memory loss, other cognitive functions, including praxis, were intact. His speech was dysarthric. He had normal cranial nerve examination. He exhibited increased tone in his upper and lower extremities and choreoathetotic movements.
His complete blood count, serum electrolytes, vitamin B12, and hepatic and thyroid function tests were normal. Serum calcium was 9.4 mg/dL (normal values: 8.4 to 10.2 mg/dL) and phosphate was 4.0 mg/dL (normal values: 2.5 to 4.7 mg/dL). His parathyroid levels were normal, as were his CSF studies. Brain CT revealed symmetrical calcification of the basal ganglia, thalami, and dentate nuclei of the cerebellum. Twelve months later his cognitive functions declined further. The most striking deficits were found on tasks measuring executive functions. His behavior was now characterized by apathy, disinhibition, and increasing antisocial behavior.
Biological basis
Etiology and pathogenesis
The precise mechanisms for calcification formation in idiopathic basal ganglia calcification are still unknown, but genetic studies have implicated phosphate homeostasis as being central to the disease process. Four autosomal dominant genes were identified as causative in idiopathic basal ganglia calcification. Two (SLC20A2, XPR1) have been linked to phosphate metabolism, whereas the other two (PDGFB, PDGFRB) are associated with blood-brain barrier integrity and pericyte maintenance (94; 33; 58; 41; 60). Phosphate transport appears to be crucial because the gene most commonly associated with the disease (SLC20A2) encodes inorganic phosphate transporter PiT2 (94).
Calcium is the major element present in idiopathic basal ganglia calcifications and it accounts for the radiological appearance of the disease. Other elements include mucopolysaccharides, traces of aluminum, arsenic, cobalt, copper, molybdenum, iron, lead, manganese, magnesium, phosphorus, silver, and zinc (54; 74).
Predilection for basal ganglia is not clear, although basal ganglia is a target for many other deposits, such as bilirubin in the newborn leading to kernicterus, and carbon monoxide poisoning leading to parkinsonism (46). It was shown that although SLC20A2 is expressed in most tissues, it is relatively high in the globus pallidus, thalamus, and cerebellum (17). Calcium and other mineral deposits were found in the walls of capillaries, arterioles, and small veins and in perivascular spaces (48; 35).
The SLC20A2 gene encodes a phosphate importer (PiT-2) and the XPR1 gene encodes phosphate exporter. SLC20A2 mutation leads to loss of function, and as a result, PiT-2 expression in the astrocytes is also decreased in idiopathic basal ganglia calcification (35). Inhibition of phosphate uptake may lead to deposition of calcium phosphate in the vascular extracellular matrix. In contrast, inhibition of phosphate export, associated with the XPR1 mutations, is expected to increase intracellular phosphate concentration and may induce intracellular calcium phosphate precipitation (41). Two studies showed that mice deficient in SLC20A2 had high phosphate level in CSF, predisposing to vascular brain calcification (32; 84). It is possible that PiT2 and XPR1 participate in phosphate directional transport from CSF to the blood in epithelial cells of the choroid plexus or ependyma, known for regulating ion concentrations in CSF (04).
Platelet-derived growth factors bind to two receptor tyrosine kinases, and PDGFRB mutations impair receptor kinase signaling (05). In animal models, PDGFRB is an essential mediator in the development of pericytes in brain vessels, which have a key role in the maintenance of the blood-brain barrier, thought to be defective in idiopathic basal ganglia calcification (58). PDGFB pathway may be involved in phosphate-induced calcifications in vascular smooth muscle cells by downregulating SLC20A2 (82). Another group has observed that PDGFB increases the expression of SLC20A2 in mesenchymal cell cultures, suggesting a link between the two genes (19).
Even though our understanding of calcification formation was expanded, it is not clear how calcifications lead to neuronal dysfunction and clinical symptoms. Interestingly, the calcification itself does not always cause neuronal degeneration around the affected vessels (87; 35). This may help explain why clinical manifestations in idiopathic basal ganglia calcification show a wide range, from asymptomatic to variably symptomatic. Reduced focal cerebral blood flow and glucose metabolism were found in several case studies in patients with basal ganglia calcification (81; 28; 10; 67). Perfusion studies such as SPECT may not demonstrate perfusion abnormalities in all calcified lesions visualized on CT scan, but they correlate more specifically with those exhibiting clinical findings (62). Therefore, calcifications may not always be pathogenic, but when they are they may lead to hypometabolism and local neuronal dysfunction.
Genetics. Idiopathic basal ganglia calcification is inherited in mostly autosomal dominant fashion, although it may occur sporadically, and in some families the pattern of inheritance may not be apparent. The age of onset, clinical presentation, and severity vary both between and within families (12; 61; 20).
Four autosomal dominant causative genes have been identified. Early study on a large, multigenerational family with an autosomal dominant inheritance was found to have significant linkage to the long arm of chromosome 14 (26). Three loci were then linked to the disorder (IBGC1-3) (83; 16), and SLC20A2 was the first gene identified (94). Eventually, all three idiopathic basal ganglia calcification loci were found to map to the SLC20A2 gene (30; 27). Additional genes that have been described include platelet-derived growth factor receptor beta (PDGFRB) (58), polypeptide of platelet-derived growth factor beta (PDGFB) (33; 57; 34; 93), and xenotropic and polytropic retrovirus receptor 1 (XPR1) (41; 04), but a large number of familial cases still do not have a known gene (08). There is one report of autosomal recessive inheritance involving ISG15 protein (95). A dual mutation in SLC2042 and THAP1 genes has been reported in a large Canadian idiopathic basal ganglia calcification family with dystonia plus syndrome (06). MYORG gene was identified as a novel causative gene for autosomal-recessive primary familial brain calcification (92). Previously described in patients with Chinese and Middle Eastern origin, this report describes the disorder in a patient of European descent caused by homozygous MYORG mutation (p.N511Tfs*243).
Over 40 pathogenic variants of SLC20A2 have been reported, and of the known families with idiopathic basal ganglia calcification, 40% to 50% have SLC20A2 mutations. To date, more than 40 families with SLC20A2 mutations have been identified worldwide, but the same mutations have also been linked to sporadic cases (30; 85; 90). SLC20A2 is the most common genetic abnormality in idiopathic basal ganglia calcification followed by PDGFB, whereas PDGFRB seems rare and XPR1 was only recently identified (27). Batla and colleagues reported that the three most commonly associated genes are SLC20A2 (55%), PDGFB (31%), and PDGFRB (11%) (09). Of note, a report of familial idiopathic basal ganglia calcification (FIBGC) demonstrated a novel heterozygous missense pathologic variant in SLC20A1 (c.920C> T/p.P307L), which is a variant in the large intracytoplasmic loop of the PiT-2 protein, suggesting that aberrant clearance of inorganic phosphate from the brain could contribute to the pathogenesis of familial idiopathic basal ganglia calcification (70).
Finally, X-linked juvenile parkinsonism and basal ganglia calcification have been reported to be caused by a RAB39B mutation (73).
Grutz and colleagues proposed an algorithm based on neuroimaging findings to predict the chances of positive genetic finding based on sites of calcification and an individual’s age (27). Based on their kindred of 24 subjects, individuals less than 40 years of age with at least one site of bilateral calcification, and 41 to 70 years of age with two bilateral calcified sites, will likely have a positive genetic finding with a sensitivity of 100% and a specificity of 92.3%. Individuals more than 70 years of age and without calcification will likely test negative (27). If further validated, this approach could help determine utility of genetic testing, as brain calcifications are common in people older than 60 years (89).
Epidemiology
Idiopathic basal ganglia calcification is a rare condition, but precise incidence is difficult to establish given the varied nomenclature in the literature and wide spectrum of clinical manifestations including asymptomatic carriers.
Earlier studies have suggested slightly higher incidence in men than in women (1.3-2:1), but a study showed no sex bias, although men had higher calcification burden (48; 85; 55). It has also been noted that older age and lower body mass index (BMI) have been associated with greater risk of developing basal ganglia calcifications (18).
Idiopathic basal ganglia calcification is thought to have onset between ages 30 and 50; however, onset in childhood or older age is not uncommon (75; 85; 55).
Prevention
There are no known methods to prevent idiopathic basal ganglia calcification.
Differential diagnosis
The main differential diagnosis is hypoparathyroidism and other endocrine disorders of calcium metabolism. Before idiopathic basal ganglia calcification diagnosis can be made, disorders causing secondary brain calcifications, listed in Table 1, should be considered.
Confusing conditions
To some degree, basal ganglia calcifications can be associated with normal aging, are considered “physiological” over the age of 50, and are noted as an incidental finding in up to 20% of head CTs (89; 71). As previously noted, metabolic disorders such as pseudohypoparathyroidism, Aicardi-Goutieres syndrome, mitochondrial diseases, and neuroferritinopathies are associated with basal ganglia calcification; therefore, the patient history and metabolic work-up must be considered prior to making a diagnosis of idiopathic basal ganglia calcification (22).
Diagnostic workup
Diagnosis of idiopathic basal ganglia calcification is made by presence of brain calcification on imaging, appropriate clinical manifestation, and after secondary causes have been ruled out (Table 1). CT is more sensitive than MRI for finding deposits, although susceptibility-weighted imaging (SWI) can improve MRI sensitivity (47; 66). In idiopathic basal ganglia calcification, calcifications are usually symmetrical and seen in the basal ganglia and frequently also in the dentate nucleus, thalamus, or centrum semiovale.
Healthy older people may have incidental bilateral basal ganglia calcification of unknown pathologic significance and this is not considered idiopathic basal ganglia calcification (calcifications are typically smaller than in idiopathic basal ganglia calcification and confined to pallidum) (89).
When basal ganglia calcifications are identified on imaging of symptomatic patients, laboratory workup should include serum calcium, phosphate, and parathyroid hormone to exclude hypoparathyroidism and other disorders of calcium metabolism. Serum calcium, phosphate, and parathyroid hormone are normal in idiopathic basal ganglia calcification. Additional workup for secondary causes should be guided by other associated symptoms, but may include routine hematologic and biochemical investigations, workup for metabolic, inflammatory, and infectious conditions, and blood and urine heavy metal. CSF analysis may be indicated to rule out infectious or autoimmune disease, but isolated CSF protein elevation has been reported in idiopathic basal ganglia calcification (11; 75).
Genetic testing can confirm the diagnosis of idiopathic basal ganglia calcification. Four autosomal dominant genes (SLC20A2, PDGFB, PDGFRB, and XPR1) have been identified (65). However, availability of commercial testing may vary. The levels of inorganic phosphorus in CSF were found to be higher in patients with idiopathic basal ganglia calcification with SLC20A2 mutations compared to other patients with idiopathic basal ganglia calcification (including those with PDGFB mutations) and controls (29).
Testing of asymptomatic family members may include brain CT scan to evaluate calcium deposits; however, predictive clinical value is unclear given wide phenotypic variability within families.
Additional imaging studies that may be considered in idiopathic basal ganglia calcification workup include brain perfusion SPECT, transcranial sonography, and fluoro-L-dopa PET studies (62; 37; 68; 78).
Management
Scant anecdotal evidence describes use of bisphosphonates to treat brain calcifications. In one case report, a patient with idiopathic basal ganglia calcification-related parkinsonism improved on etidronate disodium (43). In a small case series, patients with idiopathic basal ganglia calcification were administered weekly alendronate; no change in imaging of calcifications was observed and several patients maintained clinical stability (60). Two patients with secondary calcifications treated with etidronate disodium showed improvement in seizures and headaches (44).
The management focuses on symptomatic relief using antidepressants, mood stabilizers, antipsychotics, dopaminergics, anticonvulsants, and analgesics (61). Parkinsonism may respond to levodopa (48; 38).
Based on genetic studies, regulation of phosphate transport may have future therapeutic implications (31).
Classification. Manyam proposed classification based on the anatomical sites, namely bilateral striopallidodentate calcinosis, striopallido (basal ganglia) calcinosis, and dentate (cerebellar) calcinosis (46). Each classification is divided into subgroups according to etiology: autosomal dominant, familial, sporadic, and secondary. The table is modified from 46, with additional disorders and references provided.
Table 1. Anatomical Classification of Calcification
Basal ganglia and dentate nucleus | |
Primary | Autosomal dominant |
Secondary | |
Endocrinologic | Hypoparathyroidism |
Developmental | Cockayne syndrome |
Renal | Membranoproliferative glomerulonephritis (79) |
Degenerative | Multiple system atrophy (64) |
Connective tissue disorders | Systemic lupus erythematosus |
Toxic | Lead |
Bilateral basal ganglia | |
Physiological | Aging: older than 50 years of age |
Developmental | Angiomatous malformation with vein of Galen aneurysm |
Degenerative | Aicardi-Goutieres syndrome |
Genetic | Biotinidase deficiency |
Infectious | AIDS |
Metabolic | Dihydropteridine reductase deficiency |
Neoplastic | Acute lymphocytic leukemia |
Physical agents | Radiation therapy |
Toxic | Carbon monoxide poisoning |
Dermatologic | Generalized pustular psoriasis (63) |
Bilateral cerebellar | |
Primary | Idiopathic |
Secondary | |
Infection | Syphilis |
Vascular | Hematoma |
Cerebellopontine | |
Primary | Idiopathic (69) |
Secondary | Aicardi-Goutieres syndrome (80) |
| |
Outcomes
Clinical presentation and disease course in idiopathic basal ganglia calcification are very heterogeneous, and outcomes have not been systematically studied.
Media
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Sarah O’Shea MD MS
Dr. O’Shea of Boston University has no relevant financial relationships to disclose.
See Profile
Editor
-
Robert Fekete MD
Dr. Fekete of New York Medical College received consultation fees from Acadia, Acorda, Adamas, Amneal/Impax, Kyowa Kirin, Lundbeck, Neurocrine, and Teva.
See Profile
Former Authors
- Shaheda N Azher MD (original author), Svjetlana Miocinovic MD PhD, and Shilpa Chitnis MD PhD
Patient Profile
- Age range of presentation
-
- 6 to 65+ years
- Sex preponderance
-
- male>female
- Heredity
-
- heredity may be a factor
- autosomal dominant
- autosomal recessive
- familial
- sporadic
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-9
-
- Other degenerative diseases of the basal ganglia: 333.0
- ICD-10
-
- Other specified degenerative diseases of basal ganglia: G23.8
- OMIM
-
- Solute carrier family 20 (phosphate transporter), member 2; SLC20A2: *158378
- Platelet-derived growth factor, beta polypeptide; PDGFB: *190040
- Platelet-derived growth factor receptor, beta; PDGFRB: *173410
- Xenotropic and polytropic retrovirus receptor; XPR1: *605237
- Basal ganglia calcification, idiopathic, 1: IBGC1: #213600
- Basal ganglia calcification, idiopathic, 2: %606656
- Basal ganglia calcification, idiopathic, 4: IBGC4: #615007
- Basal ganglia calcification, idiopathic, 5: IBGC5: #615483
- Basal ganglia calcification, idiopathic, childhood-onset: %114100
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