Basal Ganglia Calcification, Idiopathic, 1

A number sign (#) is used with this entry because of evidence that idiopathic basal ganglia calcification-1 (IBGC1) is caused by heterozygous mutation in the SLC20A2 gene (158378) on chromosome 8p11.

Description

Familial idiopathic basal ganglia calcification is an autosomal dominant condition characterized by symmetric calcification in the basal ganglia and other brain regions. Patients with calcifications can either be asymptomatic or show a wide spectrum of neuropsychiatric symptoms, including parkinsonism, dystonia, tremor, ataxia, dementia, psychosis, seizures, and chronic headache. Serum levels of calcium, phosphate, alkaline phosphatase, and parathyroid hormone are normal. The typical age at clinical onset is between 30 and 50 years (summary by Wang et al., 2012).

Calcification of the basal ganglia is a nonspecific finding in many medical conditions, including infectious, metabolic, and genetic syndromes. In addition, calcification of the basal ganglia is observed as an incidental finding in approximately 0.7 to 1.2% of CT scans (Koller et al., 1979; Harrington et al., 1981; Forstl et al., 1992). These incidental calcifications are usually benign and have no clear etiology, especially in patients over 60 years of age (Geschwind et al., 1999). Forstl et al. (1992) found no increased risk for dementia, cerebral infarction, seizures, alcoholism, vertigo, or headache in 166 patients with calcification of the basal ganglia compared to 622 individuals without calcification.

Genetic Heterogeneity of Idiopathic Basal Ganglia Calcification

IBGC2 (606656) has been mapped to chromosome 2q37. IBGC4 (615007) is caused by mutation in the PDGFRB gene (173410) on chromosome 5q32; IBGC5 (615483) is caused by mutation in the PDGFB gene (190040) on chromosome 22q13; IBGC6 (616413) is caused by mutation in the XPR1 gene (605237) on 1q25; and IBGC7 (618317) is caused by mutation in the MYORG gene (618255) on 9p13.

See 114100 for a childhood-onset form of idiopathic basal ganglia calcification.

The symbol IBGC3 previously referred to the locus on chromosome 8p11 that includes the SLC20A2 gene (Dai et al., 2010). However, the family that originally defined the putative IBGC1 locus on chromosome 14q (Geschwind et al., 1999) was later found to carry a pathogenic mutation in the SLC20A2 gene (Hsu et al., 2013), and the IBGC locus on chromosome 14q has not been replicated (Oliveira et al., 2004; Hsu et al., 2013). Thus, the symbol IBGC1 now refers to the disorder caused by mutation in the SLC20A2 gene on chromosome 8p11 and the symbol IBGC3 is no longer used.

Clinical Features

Foley (1951) reported a family in which calcification of the corpus striatum and dentate nuclei was inherited in an autosomal dominant pattern. Matthews (1957) and Schafroth (1958) reported affected families. Roberts (1959) reported a family with 6 affected persons in 2 generations, including an instance of male-to-male transmission. Two patients appeared refractory to the PTH-phosphaturic test, and 1 patient had low serum calcium, but the other patients had normal serum calcium. Roberts (1959) suggested a relation to PHP, but Moskowitz et al. (1971) concluded the family had familial idiopathic basal ganglia calcifications.

Pilleri (1966) reported clinicoanatomic studies of a 64-year-old man with nonarteriosclerotic, idiopathic intracerebral calcification of the blood vessels. The disorder was diagnosed radiologically in 3 generations of the family. Clinical features included fits, pyramidal symptoms, cerebellar dysarthria, and psychiatric changes. Calcification involved the media and adventitia of brain vessels of all sizes, and calcium concretions lay free in the tissues. Male-to-male transmission was not proven.

Moskowitz et al. (1971) reported a family in which 5 members spanning 2 generations had calcification of the basal ganglia. The proband was a 47-year-old man who presented with a 10-year history of progressive choreoathetosis, increasing clumsiness, progressive urinary incontinence, and difficulty with concentration and recent memory. Physical examination showed truncal and gait cerebellar ataxia, as well as dysarthria. Serum calcium and phosphorus were normal. Radiographic analysis showed symmetric calcifications of the basal ganglia and deep cerebellar nuclei. CSF was normal. A brother was similarly affected, but also had parkinsonism with bradykinesia, rigidity, and mental depression. Two asymptomatic daughters of the proband, aged 13 and 15 years, had calcification of the basal ganglia. Excretion of 3-prime, 5-prime-AMP, both basal and in response to PTH, was higher in the patients compared to controls. The findings clearly distinguished the disorder in this family from disorders of parathyroid hormone.

In 5 of 9 sibs born of related parents, Nyland and Skre (1977) found progressive encephalopathy with onset in middle life and massive calcification of the basal ganglia, dentate nuclei and cerebral sulci of the brain shown radiographically. Clinical features included mental deterioration, extrapyramidal motor deficits, cerebellar ataxia, and tremor. Serum calcium, phosphorus, and PTH were normal. Exogenous PTH induced a subnormal phosphate diuresis despite normal urinary excretion of cyclic AMP, and the authors suggested that the disorder was an unusual form of pseudo-pseudohypoparathyroidism. In this family, the disorder was consistent with autosomal recessive inheritance.

Francis (1979) described a family in which schizophreniform psychosis was associated with basal ganglia consistent with either autosomal or X-linked dominant inheritance. There were no skeletal or biochemical signs of pseudohypoparathyroidism. Calcification first became evident radiographically at puberty. Developmental delay occurred in 2 brothers whose mother was affected. One person had progressive parkinsonism, and 4 had extrapyramidal symptoms attributed to phenothiazine medication, suggesting increased sensitivity to these medications. Francis (1979) noted that a schizophrenia-like psychosis may be seen in other disorders of the basal ganglia, including Wilson disease (277900) and Huntington disease (143100).

Puvanendran and Wong (1980) reported 2 Japanese sisters who had idiopathic basal ganglia calcifications associated with severe hypertension in their teens. Follow-up of 14 years showed no neurologic deficits.

Smits et al. (1983) described 3 sibs, 2 men and a woman, with symmetric calcification in the striopallidodentate system. The eldest sib had onset in her late thirties of progressive speech and motor impairment. Neurologic examination at age 41 years showed choreic movements of the head, tongue, and limbs, as well as ataxic gait, dysarthria, and dysmetria. She also demonstrated mental deterioration. Serum calcium and phosphorus and response to PTH administration were all normal. CT scan showed dense symmetric calcifications in the striatum, globus pallidus, dentate nucleus, pons, and in the radiation of the corpus callosum. The patient's 2 younger brothers, aged 32 and 36 years, had normal neurologic exams, but showed calcifications on CT imaging. Smits et al. (1983) suggested autosomal recessive inheritance, and considered this to be the ninth reported family with autosomal recessive SPD calcinosis; others included those reported by Matthews (1957), Bruyn et al. (1964), and Nyland and Skre (1977).

Harati et al. (1984) reported a family in which 2 brothers were affected with a progressive adult-onset disorder characterized by gait impairment, parkinsonism, urinary incontinence, and cognitive decline. Serum calcium, phosphorus, and parathyroid hormone were all normal. Brain imaging in both brothers showed dense basal ganglia calcifications extending into the periventricular white matter and involvement of the dentate nucleus. A brother and mother reportedly had a similar clinical phenotype, suggesting autosomal dominant inheritance.

Ellie et al. (1989) reported father and son with striopallidodentate calcifications in whom calcium and phosphorus metabolism was normal. The father showed a progressive disorder characterized predominantly by mental deterioration, cerebellar dysarthria, and clumsiness of fine movement. He later developed partial motor seizures. Skull radiograph showed dense, symmetric calcifications in the basal ganglia and dentate nuclei. One asymptomatic son had calcifications limited to the pallidum. In a review of the literature, Ellie et al. (1989) concluded that clinical symptoms begin between ages 30 and 50 years and are relentlessly progressive. Calcifications tend to begin within the basal ganglia, later affecting the cerebellum and deep white matter.

Manyam et al. (1992) reported a family with autosomal dominant inheritance of bilateral striopallidodentate calcinosis. Calcium deposits occurred before the onset of symptoms in the third decade of life. The proband showed progressive neurologic deterioration in the fifth decade. Manyam et al. (1992) found that CT scan was superior to MRI in the diagnosis. PET scan did not reveal any disturbance in the nigrostriatal dopaminergic pathway. Martinelli et al. (1993) found that 3 symptomatic members of an affected family had reduced 25-OH-vitamin D3 with normal levels of 1,25(OH)2-vitamin D3, suggesting an inborn error of vitamin D metabolism. Clinical features included late onset of parkinsonism, dysarthria, and depression.

Flint and Goldstein (1992) reported a mother and son with IBGC. The son developed paranoid schizophrenia and intellectual deterioration, while the mother had no psychiatric illness. After a review of the literature, the authors concluded that psychosis may be only coincidentally associated with familial IBGC. Callender (1995) reported intracranial calcifications in a mother and 2 sons who presented in middle age with schizophrenia.

Kobari et al. (1997) reported a Japanese family in which 5 members were affected with autosomal dominant idiopathic brain calcifications. The proband was a 48-year-old man who presented with memory impairment, gait disturbances, and parkinsonism beginning in his early thirties. Serum calcium and phosphorus were normal, CSF studies were normal. Upon PTH administration, he had a normal urinary cAMP response, but a slightly reduced phosphaturic response. Brain CT showed dense calcifications in the basal ganglia bilaterally, as well as in the thalamus, hippocampus, subcortical white matter, and cerebral cortex. The patient's parents and 2 sons, aged 21 and 15 years, had calcification of the lentiform nuclei without neurologic defects. In a review of the literature, Kobari et al. (1997) noted that clinical symptoms appeared between 30 and 50 years of age and included mental decline, parkinsonism, choreoathetosis, and cerebellar ataxia. Less common features included pyramidal signs, psychiatric symptoms, and urinary incontinence. Calcifications tended to be detected first in the basal ganglia, and later in the cerebellar dentate nucleus, thalamus, subcortical white matter, and cerebral cortex. Neurologic signs correlated with increased calcium load.

Manyam et al. (2001) reported 38 patients: 30 from 5 families with autosomal dominant inheritance and 8 sporadic cases. The authors also reviewed 20 publications comprising 61 patients. Inclusion criteria included radiographic evidence of calcifications, normal childhood growth and development, and absence of parathyroid disorders. In all, 67 patients were symptomatic and 32 were asymptomatic at the time of evaluation. The most common disease manifestation was movement disorders (55%), of which parkinsonism was the most common (57%), followed by chorea (19%), tremor (8%), dystonia (8%), athetosis (5%), and orofacial dyskinesia (3%). Other common features included cognitive defects (39% of patients), speech disorders (36%), cerebellar signs (36%), psychiatric manifestations (31%), pyramidal signs (22%), and sensory symptoms (16%). Symptomatic patients had a significantly greater amount of calcification compared to asymptomatic patients. Calcification was seen in the basal ganglia, thalamus, dentate nucleus, and centrum semiovale.

Lester et al. (2006) provided a case report of a 50-year-old man with Fahr disease. He presented with dysarthria and later developed wide-based gait, inability to write, dysphagia, emotional lability, supranuclear gaze palsies, dysmetria, and focal dystonia. He also had pyramidal and cerebellar signs. Brain imaging showed diffuse intracranial calcifications in multiple brain regions, which the authors noted was unusual for Fahr disease.

Weisman et al. (2007) reported a man with Fahr disease who died 10 years after symptom onset. At age 61 years, he developed slowly progressive memory difficulties, which progressed to fine motor dysfunction and changes in personality consistent with frontotemporal dementia (see 600274). CT scan showed diffuse calcification. The patient's condition deteriorated, with passivity, dysarthria, and upper and lower motor neuron signs. Postmortem analysis showed extensive capillary and parenchymal microcalcifications throughout the white matter and the cortical and subcortical gray matter.

Families With Identified SLC20A2 Mutations

Geschwind et al. (1999) reported a multigenerational family with dominantly inherited IBGC. A 39-year-old woman with a history of symptomatic basal ganglia calcification presented her 2 daughters for neurologic evaluation of a movement disorder. One demonstrated dystonia and chorea, whereas the other manifested a coarse tremor and motor delay. The mother had initially presented with writing tremor at age 18 years, which progressed to focal dystonia and mild generalized chorea by her mid-twenties. The age at onset appeared to be decreasing by an average of more than 20 years with each transmission, suggesting genetic anticipation.

Manyam et al. (2001) reported 3 patients from a large family with autosomal dominant bilateral striopallidodentate calcinosis. The proband was found to have bilateral calcium deposits in the basal ganglia at age 42 when a CT was taken after a fall. Three years later, he developed progressive and severe parkinsonism that was responsive to L-DOPA treatment. However, the movement disorder was progressive, he developed neuropsychiatric problems, and he died of cardiac disease. Neuropathologic examination showed significant calcium deposition in multiple brain regions, including the basal ganglia, thalamus, cerebellum, pons, and white matter. Sections of the substantia nigra showed neuronal loss, gliosis, Lewy bodies, and free neuromelanin within neurons. Eighteen of 27 family members available for study showed brain calcifications on imaging, although most were asymptomatic. Only 2 other family members had calcifications associated with mild or moderate parkinsonism. Neuropathologic studies of 1 of the relatives showed no Lewy bodies. Manyam et al. (2001) concluded that the family had autosomal dominant cerebral calcinosis, but that the parkinsonism in the proband may have been coincidental.

Brodaty et al. (2002) studied a multigenerational family ascertained through 2 sisters in their seventies with radiologic evidence of basal ganglia calcification, dementia, bipolar affective disorder, and parkinsonism. Of the 10 family members with radiologic intracranial calcification, none except the 2 index cases had dementia, bipolar affective disorder, or parkinsonism. Brodaty et al. (2002) suggested that this family had a form of IBGC in which calcification is inherited independently of neurologic, cognitive, and psychiatric symptoms.

Dai et al. (2010) reported a large 5-generation nonconsanguineous Chinese family in which 9 individuals had idiopathic basal ganglia calcification. The proband was a 36-year-old man with headache and discomfort in the head after drinking alcohol. Brain imaging showed symmetric calcium deposition in the caudate nucleus, lentiform nucleus, globus pallidus, inferior part of thalamus, and occipital lobes. Known disorders of parathyroid hormone, calcium regulation, phosphorus metabolism, ceruloplasmin, and other infectious etiologies were excluded. Brain imaging of other family members revealed 8 additional patients with basal ganglia calcifications. However, only 4 had clinical symptoms of headache, 1 also with depression; 5 were asymptomatic. All were adults, except for 1 asymptomatic 9-year-old boy, who had calcifications only in the globus pallidus.

Wang et al. (2012) reported a 4-generation Chinese family with autosomal dominant IBGC. Five patients were clinically asymptomatic and 1 had parkinsonism and cerebral infarction at age 73 years. However, the index case was a 12-year-old girl with epilepsy starting at age 1 year, followed by developmental delay and mental retardation after about age 4. Serum calcium, phosphate, and parathyroid hormone were normal. Brain MRI showed marked symmetric calcium deposition in the basal ganglia, inferior part of the thalamus, cerebellum, frontal, temporal, and occipital cortices, and subcortex. Her younger sister had a similarly severe phenotype, with mental retardation, epilepsy, dysarthria, and ataxia associated with marked calcium deposition throughout the brain. The images of these 2 patients with a severe clinical phenotype showed significantly more calcium deposition compared to the asymptomatic patients, who had calcium deposition primarily limited to the basal ganglia and inferior part of the thalamus.

Inheritance

The transmission pattern of IBGC in the family reported by Dai et al. (2010) was consistent with autosomal dominant inheritance.

Mapping

In a multigenerational family with dominantly inherited IBGC, Geschwind et al. (1999) performed a genomewide scan using polymorphic microsatellite markers. A maximum 2-point lod score of 3.37 was obtained at marker D14S1014, and a maximum multipoint lod score of 4.95 was obtained between D14S75 and D14S306. The locus was designated 'IBGC1.' However, Hsu et al. (2013) restudied the family reported by Geschwind et al. (1999) and found that affected individuals carried a heterozygous mutation in the SLC20A2 gene (508delC; 158378.0006) on chromosome 8p11. Two individuals who were originally reported as clinically affected and who were included in the original linkage studies by Geschwind et al. (1999) were found not to carry the mutation, which may have contributed to the previous erroneous linkage results.

By genomewide linkage analysis of a large Chinese family with IBGC, Dai et al. (2010) identified a locus, which they termed IBGC3, on chromosome 8p21.1-q11.23 (maximum 2-point lod score of 4.10 at D8S505). Haplotype analysis delineated a 25-Mb region between markers D8S1809 and D8S1833. IBGC mapping to chromosome 8p is now designated IBGC1, and the symbol IBGC3 is no loger used.

Genetic Heterogeneity

In a Spanish family in which 4 members were affected with parkinsonism, psychomotor slowing, seizures, behavioral changes, and basal ganglia calcifications, Oliveira et al. (2004) found evidence suggestive of linkage to the IBGC1 locus. Linkage to IBGC1 was excluded in 5 other families with autosomal dominant IBGC, including a family reported by Boller et al. (1977). See IBGC2 (606656).

Molecular Genetics

In affected members of 7 families with idiopathic basal ganglia calcification, Wang et al. (2012) identified 7 different heterozygous mutations in the SLC20A2 gene (see, e.g., 158378.0001-158378.0005) that segregated with the disorder. Three families were of Chinese origin, including the family reported by Dai et al. (2010), 3 were of Spanish origin, and 1 was Brazilian. In vitro functional expression studies in Xenopus oocytes showed that all the missense mutations resulted in substantially impaired transport of inorganic phosphate. However, expression of 2 mutant missense proteins with wildtype SLC20A2 did not result in diminished transport activity, suggesting haploinsufficiency as a pathogenic mechanism. Wang et al. (2012) postulated that functional loss of SLC20A2 in the brain may result in regional accumulation of inorganic phosphate in the extracellular matrix, causing calcium phosphate deposition. No genotype/phenotype correlations were observed. Two severely affected sisters in a Chinese family were found to carry a heterozygous S601W mutation (158378.0002) inherited from their affected father, as well as a ser121-to-cys (S121C) substitution in the SLC20A2 gene inherited from their unaffected mother. The S121C substitution did not show a significant impairment of SLC20A2 transport activity, and thus its contribution to the severe phenotype lacked clearly supportive evidence.

In 13 (41%) of 29 families with IGBC, Hsu et al. (2013) identified 13 different heterozygous mutations in the SLC20A2 gene (see, e.g., 158378.0003 and 158378.0006-158378.0008). Several of the families had previously been reported (Geschwind et al., 1999; Manyam et al., 2001; Brodaty et al., 2002). Variants predicted to be deleterious cosegregated with the disease in 5 families. No carriers of SLC20A2 variants were unaffected, suggesting 100% sensitivity of the clinical or CT evaluation. In contrast, several individuals in 3 large families who received an affected disease status based on clinical examination or CT scan did not carry mutations. Hsu et al. (2013) noted that CT calcifications may be found in up to 1% of the general population, and that a wide range of neuropsychiatric manifestations can be considered part of the disorder. The findings established SLC20A2 as a key gene for familial IBGC.

Population Genetics

Yamada et al. (2014) identified 6 different heterozygous mutations in the SLC20A2 gene in 5 (50%) of 10 Japanese families with IBGC and in 2 (4.3%) of 46 Japanese patients with sporadic occurrence of IBGC. The symptoms and neurologic findings varied widely and included gait instability, dysarthria, cognitive impairment, dementia, behavioral abnormalities, and psychosis; several mutation-carrying family members were asymptomatic. There were 4 missense mutations, 1 nonsense mutation, and 1 frameshift mutation; 2 families shared a missense mutation. Functional studies of the mutations were not performed.

Nomenclature

Idiopathic calcinosis of the basal ganglia is frequently referred to as 'Fahr disease' or 'Fahr syndrome,' which is a misnomer (Moskowitz et al., 1971; Klein and Vieregge, 1998; Manyam, 2005). Fahr (1930) reported a sporadic case of an 81-year-old man with a long history of dementia who may have died from tetanic seizures secondary to hypoparathyroidism (Klein and Vieregge, 1998). Although some cite the postmortem examination of Fahr (1930) as showing calcifications in the basal ganglia, dentate nucleus, and cerebral cortex (Moskowitz et al., 1971; Manyam, 2005), Klein and Vieregge (1998) stated that the patient had little calcification of the basal ganglia, and that calcification was primarily seen in brain vessels of the white matter. Nevertheless, Fahr's name has become associated with all forms of bilateral calcifications in the basal ganglia and other parts of the brain, including those resulting from disorders of calcium homeostasis. Moskowitz et al. (1971), Klein and Vieregge (1998), and Manyam (2005) commented that the term 'Fahr disease' is overly broad and vague, and should not be used; better terms include 'familial idiopathic basal ganglia calcifications,' 'bilateral striopallidodentate calcinosis,' and 'idiopathic nonarteriosclerotic intracerebral calcifications.' Klein and Vieregge (1998) stated that Delacour (1850) should be credited with the first pathologic description of basal ganglia calcinosis.

History

Delacour (1850) first described vascular calcifications of the basal ganglia in a 56-year-old man with stiffness and weakness of the lower extremities and tremor (Klein and Vieregge, 1998; Manyam, 2005). Bamberger (1855) described the histopathologic finding of calcifications of the small cerebral vessels. Fritzsche (1935) is also credited with one of the first reports.

Early descriptions of 'Fahr disease' or intracerebral calcifications are difficult to classify accurately, and authors have argued over precise diagnoses of historical cases (see, e.g., Moskowitz et al., 1971; Harati et al., 1984; Ellie et al., 1989; Manyam, 2005).

Lowenthal (1948) reviewed 32 cases of nonarteriosclerotic vascular intracerebral calcification in the literature, of which 3 were familial, and discussed the possible relationship to hypoparathyroidism. The disorder was referred to as 'Fahr' syndrome. Beyme (1945) reported a familial disorder characterized by basal ganglia deposits.

Nichols et al. (1961) reported a family in 3 generations of which members had a syndrome of calcification of the basal ganglia and hypocalcemia. Short stature and mental retardation were also features. The authors reported that 2 of the patients responded to PTH administration. Nigra (1970) restudied the family of Nichols et al. (1961) and found no evidence of parathormone unresponsiveness. However, Moskowitz et al. (1971) questioned the PTH responsiveness in the patients reported by Nichols et al. (1961) and concluded that they indeed had PHP.