A number sign (#) is used with this entry because idiopathic basal ganglia calcification-5 (IBGC5) is caused by heterozygous mutation in the PDGFB gene (190040) on chromosome 22q13.

Idiopathic basal ganglia calcification-5 (IBGC5) is an autosomal dominant disorder characterized by progressive neurologic symptoms that are associated with brain calcifications mainly affecting the basal ganglia. Calcifications may also occur in the thalamus, cerebellum, or white matter. Affected individuals have motor symptoms, such as dyskinesias or parkinsonism, headache, cognitive impairment, and psychiatric manifestations, including apathy and depression. Some patients are asymptomatic. The age at symptom onset ranges from late childhood to adulthood; the disorder is progressive (summary by Keller et al., 2013).

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

Kostic et al. (2011) reported a 4-generation Serbian family in which 6 individuals had symmetric brain calcifications ascertained by CT scan. Two individuals with brain calcifications were asymptomatic. The 4 other individuals developed neurologic symptoms between ages 22 and 55.4 years. The main clinical findings included parkinsonism, severe gait disturbances with freezing of gait, dyskinesia, and psychiatric manifestations. Brain perfusion single photon emission CT showed predominant hypoperfusion in the frontal cortex and the basal ganglia.

Keller et al. (2013) reported 6 unrelated families with IBGC, including the Serbian family described by Kostic et al. (2011). The mean age at symptom onset was 23.9 years (range 10 to 55 years), although at least 5 individuals with calcifications were asymptomatic, the oldest being 57 years of age. Twelve patients had motor signs, including dystonia/dyskinesias in 8, parkinsonism in 3, and chorea in 3, and 9 patients had cognitive impairment or psychiatric disease, such as psychosis, apathy, and depression. The most common symptom was migraine or headache, present in 13 patients. Brain imaging in all 31 mutation carriers showed calcification in the basal ganglia. Some patients also had calcification in other brain regions, including the thalamus, cerebellum, and cerebral and subcortical white matter.

Hayashi et al. (2015) reported a 26-year-old Japanese man and his 71-year-old father with IBGC5. The phenotype was characterized by auditory hallucinations with onset at 16 years of age and a diagnosis of schizophrenia in the son. The son also had seizures at 3 years of age. His father had progressive memory and gait disturbances in his late 60s. The father also had poor attention and extrapyramidal symptoms, including slight tremor of fingers and rigidity of upper extremities. A symmetrical area of calcification over the basal ganglia on CT scan was seen in both father and son, with calcification extending to the thalamus, frontal cortex, and cerebellum on the father's scan.

Keogh et al. (2015) reported a grandmother, 2 daughters, and a granddaughter with IBGC5. The grandmother had episodic psychosis and depression for more than 20 years and a severe midline ataxia with jerky ocular pursuit. Her MRI showed calcium deposition in the globus pallidus and dentate. Her daughter, aged 31 years, had acute psychosis, with recurrent episodes of psychosis and depression, and at age 36 years, a CT scan showed basal ganglia calcification. On examination, she had jerky ocular pursuit, generalized chorea, and midline ataxia. Her sister, aged 40 years, had a 2-year history of gait disturbance, with midline ataxia. A CT scan showed bilateral calcification of the globus pallidus. At age 43 years, she developed a complex motor tic and dystonic posturing of both feet. The 20-year-old granddaughter was referred for a gait disturbance, but her neurologic examination was normal. A brain MRI showed small frontal noncalcified white matter changes, but no evidence of calcium in the basal ganglia, leading the authors to note that absence of calcifications does not rule out the diagnosis.

Yektay Farahmand et al. (2024) reported 2 Swedish families with IBGC5. All 6 affected family members (3 in each family) had white matter hyperintensities and bilateral brain calcifications on imaging. In family A, the 87-year-old grandmother had moderate cognitive decline. At age 57, she was noted to have recurrent episodes of right-sided weakness and paresthesias, consistent with transient ischemic attacks, and was later noted to have a permanent right central facial palsy, consistent with a previous stroke. Her 68-year-old son had a gait disturbance, blepharospasm, cervical dystonia, and vocal tics. The 46-year-old grandson had no signs or symptoms of disease, despite the presence of intracranial calcifications. In family B, the 78-year-old grandmother had seizures and expressive aphasia consistent with a stroke, with hundreds of supratentorial microbleeds on MRI. Her daughter, aged 56 years, had depression, anxiety, bipolar disorder, and psychosis and had ischemic brain lesions, which were clinically silent. The granddaughter, aged 29 years, had depression, anxiety, bipolar disorder, vertigo, headaches, aphasia with limb weakness, involuntary muscle jerks, and vocal tics. These findings led the authors to propose that IBGC5 could predispose patients to stroke, transient ischemic attacks, silent brain infarcts, and cerebral microbleeds, caused by cerebral small vessel disease. Skin biopsies done on 3 affected family members showed normal skin microvasculature, which does not suggest systemic vasculopathy.

The transmission pattern of IBGC5 in the families reported by Keller et al. (2013) was consistent with autosomal dominant inheritance.

Keller et al. (2013) identified 6 different heterozygous putative loss-of-function mutations in the PDGFB gene (see, e.g., 190040.0003-190040.0007) in 6 (18.8%) of 13 families with idiopathic basal ganglia calcification-5. The initial mutations were found by genome or exome sequencing.

In a 36-year-old Japanese man and his 71-year-old father with IBGC5, Hayashi et al. (2015) identified one of the mutations in the PDGFB gene (R149X; 190040.0006) that was previously reported by Keller et al. (2013). The mutation was found by Sanger sequencing.

In 4 members of a family with IBGC5, Keogh et al. (2015) identified a heterozygous missense mutation (c.3657C-T, P122L) in the PDGFB gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family. The variant was not present in the 1000 Genomes Project and ESP6500 databases.

In 2 Swedish families with IBGC5, Yektay Farahmand et al. (2024) identified heterozygous nonsense mutations in the PDGFB gene: Q140X (c.418C-T, NM_002608.4) in family A and R191X (c.571C-T, NM_002608.4) in family B. The mutations were found by whole-exome or whole-genome sequencing, followed by targeted investigation of all known genes related to IBGC. Sanger sequencing confirmed segregation of the mutation with disease in the families. The variants were not present in the gnomAD database (v2.1).

Keller et al. (2013) found that 4-month-old mice homozygous for a hypomorphic Pdgfb allele developed clusters of calcified nodules in the midbrain and thalamus. At age 1 year, mutant mice had more extensive calcification involving the basal forebrain, midbrain, and pons. The lesions were punctate and composed of calcium phosphate. Transgenic reexpression of 2 copies of wildtype endothelial Pdgfb in Pdgfb-null mice prevented the development of brain calcification, whereas reexpression of 1 copy of the rescue allele did not prevent calcification. The findings suggested that it is endothelial Pdgfb, rather than neuronal Pdgfb, that drives the pathology. Keller et al. (2013) postulated that the brain calcification may result from defects in pericytes and the blood-brain barrier.