Deafness, dystonia and optic neuronopathy syndrome; DDON syndrome; Mohr-Tranebjærg syndrome - TIMM8A gene

The syndrome of deafness, dystonia, optic neuropathy (DDON), also known as Mohr-Tranebjærg syndrome or DDON syndrome, is characterized by sensorineural hearing loss accompanied by problems of movement, vision and behavior.

Signs related to this process begin in early childhood with a sensorineural hearing loss due to optic atrophy, usually followed by the development of progressive problems with movement during adolescence, such as dystonia and / or ataxia. Behavioral problems may include changes in personality and aggressive or paranoid behavior. In addition, some affected individuals have developed dementia.

This process is due to mutations in the TIMM8A gene (translocase of inner mitochondrial membrane 8A), located on the long arm of chromosome X (Xq22.1), which encodes a protein found inside mitochondria. Specifically, the TIMM8A protein is found in the intermembrane space, where it forms a complex with the TIMM13 protein. This complex transports other proteins through the intermembrane space to the inner mitochondrial membrane.

At least 20 mutations in the TIMM8A gene responsible for the development of deafness, dystonia, optic neuropathy (DDON) syndrome have been identified. The majority of these mutations give rise to the absence of functional TIMM8A protein inside the mitochondria, which prevents the formation of the TIMM8A / TIMM13 complex. Although it is believed that the absence of this complex leads to an abnormal transport of proteins through the intermembrane space, it is not clear how the abnormal transport of proteins affects the function of the mitochondria and causes the signs and symptoms of the syndrome.

Some people with DDON syndrome have large DNA deletions that kill the entire TIMM8A gene and one end of the BTK gene (Bruton tyrosine kinase). Mutations in the BTK gene lead to the development of X-linked agammaglobulinemia (XLA), a process characterized by an increased susceptibility to infections. People with large DNA deletions that include the TIMM8A gene and the BTK gene have the signs and symptoms of both DDON syndrome and X-linked agammaglobulinemia.

The syndrome of deafness, dystonia and optic neuropathy (DDON) is inherited with a recessive pattern linked to X. In males, an altered copy of the gene in each cell is sufficient to express the process. In women, a mutation would have to occur in both copies of the gene to express the DDON syndrome. Because women are unlikely to have two altered copies of this gene, males are affected by recessive processes linked to the X chromosome much more frequently than women. Women who carry an altered copy of the TIMM8A gene are generally not affected; however, they may develop mild hearing loss and dystonia. A feature of X-linked inheritance is that parents cannot pass traits linked to X to their children.

Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with deafness syndrome, dystonia, optic neuropathy (DDON), by complete PCR amplification of the TIMM8A gene exons, and subsequent sequencing.

Recommended samples: blood drawn with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).