MYORG Mutations: a Major Cause of Recessive Primary Familial Brain Calcification

Until recently, the gene associated with the recessive form of familial brain calcification (PFBC, Fahr disease) was unknown. MYORG, a gene that causes recessive PFBC was only recently discovered and is currently the only gene associated with a recessive form of this disease. Here, we review the radiological and clinical findings in adult MYORG mutation homozygous and heterozygous individuals.

MYORG was shown to be the cause of a large fraction of recessive cases of PFBC in patients of different ethnic populations. Pathogenic mutations include inframe insertions and deletions in addition to nonsense and missense mutations that are distributed throughout the entire MYORG coding region. Homozygotes have extensive brain calcification in all known cases, whereas in some carriers of heterozygous mutation, punctuated calcification of the globus pallidus is demonstrated. The clinical spectrum in homozygotes ranges from the lack of neurological symptoms to severe progressive neurological syndrome with bulbar and cerebellar signs, parkinsonism and other movement disorders, and cognitive impairments. Heterozygotes are clinically asymptomatic. MYORG is a transmembrane protein localized to the endoplasmic reticulum and is mainly expressed in astrocytes. While the biochemical pathways of the protein are still unknown, information from its evolution profile across hundreds of species (phylogenetic profiling) suggests a role for MYORG in regulating ion homeostasis via its glycosidase domain. MYORG mutations are a major cause for recessive PFBC in different world populations. Future studies are required in order to reveal the cellular role of the MYORG protein.