A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness-dystonia-optic atrophy syndrome

We report the first de novo mutation in the DDP gene in a Dutch Ii-year-old boy with deafness and dystonia. Previously reported mutations in the DDP g ene have all been frameshifts/nonsense mutations or deletion of the entire gene as part of a larger deletion encompassing the BTK gene. The clinical p resentation was uniformly characterised by sensorineural hearing loss, dyst onia, mental deterioration, paranoid psychotic features, and optic atrophy, indicating progressive neurodegeneration. Our report illustrates that de n ovo mutations occur and that a missense mutation, C66W, may cause an equall y severe clinical picture. The diagnosis of sensorineural hearing impairmen t associated with neurologic and visual disability in a male, therefore, sh ould encourage the search for mutations in the DDP gene, even in sporadic c ases. The association of deafness-dystonia syndrome with a missense mutatio n provides valuable information for in vitro investigations of the function al properties of the deafness-dystonia peptide which was recently shown to be the human homolog of a yeast protein, Tim8p, belonging to a family of sm all Tim proteins involved in intermembrane protein transport in mitochondri a.