Deafness-Dystonia-Optic Neuronopathy Syndrome

In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
[updated ].


Clinical characteristics: Males with deafness-dystonia-optic neuronopathy (DDON) syndrome have prelingual or postlingual sensorineural hearing impairment in early childhood, slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from optic atrophy beginning at approximately age 20 years, and dementia beginning at approximately age 40 years. Psychiatric symptoms such as personality change and paranoia may appear in childhood and progress. The hearing impairment appears to be consistent in age of onset and progression, whereas the neurologic, visual, and neuropsychiatric signs vary in degree of severity and rate of progression. Females may have mild hearing impairment and focal dystonia.

Diagnosis/testing: The diagnosis of DDON syndrome is established in either a male proband who has a hemizygous TIMM8A pathogenic variant (~50% of affected males) or a female proband who has a heterozygous TIMM8A pathogenic variant (~50% of affected females) or a contiguous gene deletion of Xq22.1 involving TIMM8A (~50% of affected males and females).

Management: Treatment of manifestations: Educational programs for developmental and sensory deficits, including training in tactile sign language. Because auditory neuronopathy is the cause of the hearing loss, hearing aids have only variable success. Physical medicine and rehabilitation, physical and occupational therapy to improve fine and gross motor skills and mobility, to prevent contractures, and to provide adaptive devices to improve activities of daily living. Standard treatment of behavioral issues / psychiatric disorders. Ensure appropriate social work involvement to connect families with local resources, respite, and support, especially care coordination with multiple subspecialty appointments, equipment, medications, and supplies.

Surveillance: Regular neurologic evaluation and assessment for dementia and/or psychiatric manifestations; annual developmental, speech-language, and vision assessments in childhood; regular physical therapy and occupational therapy for review of activities of daily living, gross motor and fine motor needs; routine follow up of the social support and social services needs of the family/caregivers.

Genetic counseling: DDON syndrome is inherited in an X-linked manner. If the mother of a proband with DDON syndrome has the causative genetic alteration (i.e., a TIMM8A pathogenic variant or a contiguous gene deletion of Xq22.1 involving TIMM8A), the chance of transmitting the genetic alteration in each pregnancy is 50%. Males who inherit the genetic alteration will be affected; females who inherit the genetic alteration will be heterozygotes and may have mild hearing impairment and focal dystonia. Males who reproduce pass the genetic alteration to all of their daughters and none of their sons.

Prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic testing are possible if the DDON-causing genetic alteration in the family is known.

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