Basal Ganglia Calcification, Idiopathic, Childhood-Onset

Description

Bilateral striopallidodentate calcinosis, also known as idiopathic basal ganglia calcification (IBGC), is characterized by the accumulation of calcium deposits in different brain regions and is associated with a neurodegenerative clinical phenotype. The changes seen in IBGC occur in the absence of calcium or parathyroid hormone (PTH; 168450) metabolic disorders, such as hypoparathyroidism (see 146200) or pseudohypoparathyroidism (PHP; see 103580).

See also the adult-onset form (213600), which is sometimes erroneously referred to as 'Fahr disease.'

Hallervorden (1950) observed 2 sibs with infantile onset of mental retardation, extrapyramidal signs, and diffuse, symmetric intracerebral calcium deposits in the basal ganglia, dentate nucleus, cortex, and subcortical white matter. The findings were associated with microcephaly and pathologic changes consistent with meningoencephalitis. Melchior et al. (1960) argued against an infectious etiology of the calcifications.

Jervis (1954) described the pathologic findings in 2 cases with microcephaly, muscular hypertonicity, and choreoathetosis. Calcification was found in the basal ganglia, cerebellum, and cerebral cortex, and the centrum ovale showed extensive demyelination. Manyam (2005) considered the patients reported by Jervis (1954) to have a secondary form of calcinosis due to developmental defects.

Bowman (1954) described 2 affected male sibs; one died at age 33 months and the other at age 31 months. Calcification of the cerebral capillaries was demonstrated at autopsy, but not by x-ray during life.

Melchior et al. (1960) described 2 affected families in which 5 members had onset in infancy of a severe neurodegenerative disorder characterized by intracerebral calcifications. Three sibs in 1 family had onset at 13 to 24 months of age of severe spastic tetraplegia, contractures of all 4 limbs, and mental retardation. They all had short stature and a poorly developed small body habitus. Two of the sibs had dolichocephaly; 1 had pigmentary retinopathy, and another had calcifications in the retina. Neuropathologic examination showed calcium deposition in the basal ganglia and cerebellar dentate nucleus, spotty calcifications in the cortex and subcortical white matter, and calcium deposition in brain vessels. Although the patients lived until the third or fourth decade, they were helpless and bedridden. Two sibs of a second family had a similar disorder. Melchior et al. (1960) suggested a metabolic etiology.

Babbitt et al. (1969) described this disorder, which they called 'familial cerebrovascular ferrocalcinosis,' in 2 sisters and a brother. Symptoms appeared before age 10 years and consisted of mental deterioration, seizures, extrapyramidal signs, abnormal EEG, and retinitis pigmentosa. Calcifications were seen in the basal ganglia, dentate nucleus, and white matter (Smits et al., 1983). Harati et al. (1984) suggested that the family reported by Babbitt et al. (1969) had Cockayne syndrome (216400). An apparently recessive form of basal ganglia calcification was associated with steatorrhea and mental retardation in 4 of 16 sibs in a family reported by Cockel et al. (1973). Autopsy showed normal parathyroid glands.

Kousseff (1980) described 2 sisters with infantile 'Fahr disease.' Bilateral glaucoma was a pleiotropic feature in both.

Jensen (1983) described 2 sisters who died soon after birth and showed at necropsy extensive calcifications of several parts of the brain, including cortex and white matter of the cerebrum, basal ganglia, brainstem, and cerebellum. The calcification affected neurons and was also seen around small vessels. The neurons were severely reduced in number and in some areas, e.g., the thalamus, were almost absent. The areas of calcification also gave a positive histochemical reaction for iron; note the designation 'ferrocalcinosis' used by Babbitt et al. (1969). Glial cell proliferation and small cystic changes were seen in various parts of the brain. Significantly, no signs of inflammation, no perivascular cellular infiltrations, no toxoplasma or other infectious agents, no kernicterus, and no intracellular accumulation of metabolic products were observed. The brain weight was significantly reduced in each case.

Burn et al. (1986) described 2 sibs, born of second-cousin parents, with intracranial calcification and microcephaly. The findings in the first child suggested intrauterine infection. The authors urged that phenotype alone should not be relied on in such cases, and that definite serologic evidence of infection be required before a negligible genetic risk is counseled. The patients died at 30 days and 50 days of age. At least 1 had corneal clouding. The brain showed lissencephaly and polymicrogyria. Many of the features were consistent with Miller-Dieker syndrome (247200), except for the calcification and normal chromosome 17. Burn et al. (1986) concluded that the Norman-Roberts syndrome (257320) and the disorders in the patients described by Aicardi and Goutieres (1984) and Baraitser et al. (1983) were different. On the other hand, Reardon et al. (1994) concluded that the disorder in the family of Burn et al. (1986) was the same as pseudo-TORCH syndrome (251290).

Billard et al. (1989) reported 14 cases of childhood-onset encephalopathy with calcification of the basal ganglia and proposed a 4-group classification based on a review of the literature. Group 1 represented a slowly progressive encephalopathy of presumably autosomal recessive inheritance associated with microcephaly, dwarfism, retinal degeneration or optic atrophy, and symmetrical patchy demyelinization (see 225755). Group 2 comprised patients with a sporadic, stationary encephalopathy resulting from an unknown prenatal insult. Group 3 was characterized by progressive encephalopathy with chronic spinal fluid lymphocytosis, originally described by Aicardi and Goutieres (1984) (225750). Group 4 was an autosomal dominant disorder with mild neurologic symptoms in the oldest family members only (213600).