Linkage studies in familial idiopathic basal ganglia calcification: separating the wheat from the chaff

Idiopathic Basal Ganglia Calcification (IBGC) is a neuropsychiatric condition characterized by brain calcinosis, heterogeneous motor impairment and behavioral symptoms. The IBGC1 locus was the first region linked to this phenotype in an American family, but another kindred from Spain was also reported as possibly associated with this locus. Our group excluded this locus in additional families together with an independent study of an Australian pedigree with IBGC, but without clinical symptoms. Recently, a large Italian family from a population isolate was excluded from IBGC1. However, there are unusual aspects concerning this Tyrolean family, especially if we consider that almost all the clinically affected subjects manifested symptoms and signs suggestive of a dysmorphic syndrome, associated with neuropsychiatric symptoms. Curiously, some of the clinical features in this kindred match with the autosomal dominant chromosomal instability syndrome reported in Japan. Previous studies show that the definition of an autosomal dominant pattern of inheritance is an assumption that might be considered cautiously in familial IBGC, due to the limited clinical penetrance for the brain calcifications and especially when there is no access to all the parents neuroimaging data. Families from an Italian isolate, such as Tyrol, with high inbreeding rates, are more likely to manifest recessive syndromes. Nevertheless, the current debate regarding the nosology of this heterogeneous phenotype demands the establishment of standard diagnostic criteria. The current identification of loci or mutations responsible for FIBGC might help to elucidate this intriguing neuropsychiatric condition.