Basal Ganglia Calcification, Idiopathic, 6

A number sign (#) is used with this entry because of evidence that idiopathic basal ganglia calcification-6 (IBGC6) is caused by heterozygous mutation in the XPR1 gene (605237) on chromosome 1q25.

Description

Idiopathic basal ganglia calcification is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive neuropsychiatric and movement disorders, although some patients remain asymptomatic. Clinical features can include dystonia, parkinsonism, gait abnormalities, psychosis, dementia, and chorea. Brain imaging shows calcifications of the basal ganglia and other brain regions (summary by Legati et al., 2015).

For a detailed phenotypic description and a discussion of genetic heterogeneity of IBGC, see IBGC1 (213600).

Clinical Features

Boller et al. (1973) described palilalia, compulsive repetition of a phrase or word, in a mother and son with intracranial calcifications. Asymptomatic intracranial calcifications were present in other members of the family. In a later report, Boller et al. (1977) showed that 9 members of this family spanning 3 generations had bilateral calcifications of the basal ganglia. The family was of Swedish descent living in North America. The palilalia in the mother and son was accompanied by chorea and dementia beginning in the third or fourth decade. A third member was thought to show initial stages of a similar syndrome. Six members with calcifications but without neurologic signs were younger than 25 years. All 9 patients had normal calcium and phosphorus, and no evidence of endocrinologic or somatic abnormalities. Oliveira et al. (2004) excluded linkage to the IBGC1 locus on chromosome 14 in the family reported by Boller et al. (1977).

Legati et al. (2015) reported follow-up of the family reported by Boller et al. (1977). Features were variable, and included slurred speech, nervous affect, depression, concentration or memory complaints, and behavioral problems. One patient had sudden onset at age 44 and was severely affected and bedridden with speech impairment and seizures. At least 3 mutation carriers with a positive CT scan were asymptomatic, including 2 who were 16 and 20 years old. Four patients from 3 additional families with the disorder had similar features, including adult onset of depression, dysarthria, and cognitive impairment; 1 patient had a more severe course with visual hallucinations and parkinsonism. The disorder was progressive.

Inheritance

The transmission pattern of IBGC in the family reported by Boller et al. (1973, 1977) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 9 affected members of a large family of Swedish origin with IBGC6 originally reported by Boller et al. (1977), Legati et al. (2015) identified a heterozygous missense mutation in the XPR1 gene (L145P; 605237.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Further sequencing of XPR1 in 86 patients with a similar disorder identified heterozygous pathogenic missense mutations in 5 patients from 4 unrelated families (605237.0002-605237.0004). In vitro functional expression studies showed that all the mutations impaired phosphate efflux to various degrees. Legati et al. (2015) postulated that inhibition of phosphate export would lead to increased intracellular phosphate concentration and intracellular calcium/phosphate precipitation.