Last updated:
8/13/2025
Years published: 2025
NORD gratefully acknowledges Maheen Farooqi, MS, Amanda Mitchell, MS and Caitlin Silva, MS, Stanford University MS Program in Human Genetics and Genetic Counseling, Hetanshi Naik, PhD, MS, CGC, Associate Professor, Department of Genetics, Stanford University and Lisbeth Tranebjærg, MD, PhD, Professor of Medical Genetics and Genetic Audiology, Department of Clinical Genetics, The Kennedy Center and University of Copenhagen, for the preparation of this report.
Deafness-dystonia-optic neuronopathy (DDON) syndrome, also known as Mohr-Tranebjaerg syndrome, is a rare genetic and progressive disorder characterized by hearing loss, a movement disorder (dystonia) and eye nerve damage (optic neuronopathy).
DDON syndrome primarily affects the nervous system and the senses of vision and hearing. Early on, children may have hearing problems (sensorineural hearing loss) which usually appear before speech begins (prelingually). As children with DDON syndrome grow, they may develop movement problems or coordination issues (ataxia or dystonia) during their teenage years. Behavioral problems can also be common. Around age 20, individuals might start to have vision problems (optic atrophy) and by age 40, some may experience memory loss (dementia). Changes in mood or behavior (psychiatric symptoms or paranoia) can start in childhood and may get worse aspeople get older.2,3
DDON syndrome is caused by changes (pathogenic variants) in a specific gene on the X chromosome called TIMM8A or by a deletion of TIMM8A and nearby genes (contiguous gene deletion at Xq22.1).
Inheritance is X-linked recessive which means that it mostly affects males. Females may be affected and typically have less severe clinical symptoms.1
Hearing problems are a hallmark of DDON syndrome and other symptoms can vary in severity and how quickly they progress. Life expectancy is usually not affected, but can vary, even among affected family members. Treatment focuses on helping with symptoms rather than curing the condition. This includes educational support for learning and sensory issues, training in tactile sign language, physical and occupational therapy and help with behavioral challenges. Hearing aids and electronic devices that help people with severe hearing loss or deafness to hear sounds (cochlear implants) may be of benefit for some people. Support from social workers with special expertise in dual sensory impairment (deaf blindness) and coordination of care across different specialists are very important. The combination of hearing loss and severe vision problems can make communication difficult in later years, so care is focused on managing individual symptoms and providing ongoing support.2,4
The symptoms of DDON syndrome vary among individuals. Not every person will have all the symptoms or experience them in the same way. Symptoms can include:2,5–9
Hearing loss usually presenting in early childhood (around 18 months) that is rapidly progressive and very severe resulting in profound deafness by age 10.
Neurologic problems
Behavioral and psychiatric problems
Eye and vision problems
Other signs and symptoms may include:
Aspiration pneumonia (even though the heart and pulmonary function are usually normal)
Scans, including MRI, CT or PET scans frequently show loss of brain mass (general brain atrophy) with evidence of low energy consumption (hypometabolic areas), especially in specific brain areas (right striatum and parietal cortex), alongside prominent loss (atrophy) of the part of the brain responsible for vision (occipital lobes).
Tests usually show problems with the specific nerves in the eye (central auditory pathways) and ear (auditory neuropathy). Tiny calcium deposits (microcalcifications) and the death of nerve cells in different areas (neuronal cell death) can be observed.
Some females from families with affected males may have mild hearing impairment and involuntary muscle contractions (focal dystonia).
DDON syndrome is caused by changes (pathogenic variants) in the TIMM8A gene (also known as the DDP and DDP1 gene).10 The TIMM8A gene provides instructions for a protein that is found in the mitochondria–the tiny structures inside cells that help produce energy for the cell to work properly. The TIMM8A protein works together with a protein called TIMM13 to move and deliver proteins where they are needed in the mitochondria (protein transport).11 When TIMM8A is not working properly because of a change in the TIMM8A gene, it disrupts transport of proteins in the mitochondria. It is still unclear why this decreased protein transport causes the signs and symptoms of DDON syndrome.12
Some individuals with DDON syndrome do not have a pathogenic variant in the TIMM8A gene, but instead have a missing copy (deletion) of the whole TIMM8A gene.13 If there is a missing copy of TIMM8A, sometimes other genes nearby may be partly or fully missing (deleted), too.14 Changes in one gene nearby, the BTK gene, causes X-linked agammaglobulinemia (XLA). The BTK gene provides instructions for a protein (gamma globulin) involved in the development of cells in the body that help fight bacterial infections (B cells), so individuals with XLA are more likely to have recurrent bacterial infections. When an individual has a deletion that affects both TIMM8A and BTK, they will have signs and symptoms of both DDON syndrome and XLA.15
Because TIMM8A is on the X chromosome, DDON syndrome follows an X-linked pattern of inheritance. X-linked genetic disorders are caused by disease-causing gene variants on the X chromosome and mostly affect males. Females have two X chromosomes, so if only one of their X chromosomes has a disease-causing gene variant, a female might not have symptoms (because the other X chromosome without the disease-causing variant compensates), might have mild symptoms, or might have different symptoms than males. Males have one X chromosome that is inherited from their mother, and if a male inherits an X chromosome that contains a disease-causing gene variant, he will develop the disease.
If a male with an X-linked disorder can reproduce, he will pass the gene variant to all his daughters (female children of an affected male are obligatory carriers of the X-linked disorder). Since females have a second X chromosome, they may or may not develop symptoms depending on which X chromosome is active in their cells. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome to their sons.
Females with an X-linked disorder have a 50% chance with each pregnancy to pass the X chromosome with the disease-causing variant to their daughters and sons. Sons that inherit the X chromosome without the disease-causing variant will be unaffected, and sons that inherit the X chromosome with the disease-causing variant will develop DDON syndrome. Daughters that inherit the X chromosome without the disease-causing variant will be unaffected, and daughters that inherit the X chromosome with the disease-causing variant may or may not develop symptoms.
The authors wanted to flag a change they made to the templated language for X-linked inheritance in the “Causes” section. While NORD provides standard wording, both Hetanshi (our genetic counseling mentor) and Dr. Tranebjærg (our medical reviewer) recommended significant edits to more accurately reflect the potential for females to exhibit symptoms. Their recommendations were incorporated into the report, but they wanted to bring this to NORD’s attention in case consistency with templated language is preferred.
The exact number of individuals with DDON syndrome is unknown. In 2012, it was reported that 91 individuals from 37 families had been identified to have DDON syndrome both in published and unpublished studies.16 It predominantly affects males due to its X-linked inheritance pattern, and it has been identified in people from all over the world.
To date, there is not any formal diagnostic criteria for DDON syndrome. A diagnosis of DDON syndrome can be suspected based on clinical features (congenital profound hearing impairment possibly combined with recurrent bacterial infections in boys). A diagnosis of DDON is established by genetic testing:16
Depending on the clinical features and the family history, a whole genome sequencing test or a sequencing test of the TIMM8A gene may be ordered.2
Currently, there are no treatments for DDON syndrome that address the underlying cause of the condition, so individuals are treated for the specific symptoms they have.2 Treating symptoms may include support from many different medical specialists.
After an individual has been diagnosed with DDON syndrome, a formal audiologic and speech-language assessment should be performed to determine the extent and type of hearing impairment and speech language needs. Audiologic and speech-language assessments should then be completed annually, with auditory and speech training, sign language and other hearing services provided as needed.
Because of the auditory neuropathy type of hearing disorder, hearing aids are not useful in many people and a cochlear implant may be considered to help regain a sense of sound.
After diagnosis, an evaluation is also recommended to assess the clarity of vision (visual acuity). Standard treatment with corrective lenses and other visual support is recommended, with regular follow-up with eye specialists according to the progression of vision impairment.
In addition, a developmental assessment can assist access to early intervention and special education resources. Working with a pediatrician specializing in development can ensure access to these resources, such as individualized education plan (IEP) services and a 504 plan (Section 504: a US federal law that was created to ensure that students with disabilities have access to education and there is not discrimination based on disability), both of which provide access to accommodations and specialized services for education.25
Orthopedic doctors, physical and occupational therapists can assess and provide support for improving motor skills that are impacted by dystonia and/or ataxia, with regular follow-up depending on symptoms. A neurologic exam can monitor the progression of dystonia and/or ataxia over time and neurologists can provide guidance on medication options.
A neuropsychiatric evaluation is recommended for individuals with psychiatric or behavioral concerns, with psychiatric support provided as needed.
Genetic counseling is recommended for families affected by DDON syndrome.
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1. Swerdlow RH, Wooten GF. A novel deafness/dystonia peptide gene mutation that causes dystonia in female carriers of Mohr-Tranebjaerg syndrome. Ann Neurol. 2001;50(4):537-540. doi:10.1002/ana.1160
2. Deafness-Dystonia-Optic Neuronopathy Syndrome. Updated November 21, 2019. In: Adam MP, Feldman J, Mirzaa GM, et al., eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2025. Published February 6, 2003. Accessed February 4, 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1216/ Accessed July 29, 2025.
3. Tranebjaerg L, Schwartz C, Eriksen H, et al. A new X linked recessive deafness syndrome with blindness, dystonia, fractures, and mental deficiency is linked to Xq22. J Med Genet. 1995;32(4):257-263. doi:10.1136/jmg.32.4.257
4. Binder J, Hofmann S, Kreisel S, et al. Clinical and molecular findings in a patient with a novel mutation in the deafness-dystonia peptide (DDP1) gene. Brain J Neurol. 2003;126(Pt 8):1814-1820. doi:10.1093/brain/awg174
5. Scribanu N, Kennedy C. Familial syndrome with dystonia, neural deafness, and possible intellectual impairment: clinical course and pathological findings. Adv Neurol. 1976;14:235-243.
6. Ujike H, Tanabe Y, Takehisa Y, Hayabara T, Kuroda S. A Family With X-linked Dystonia-Deafness Syndrome With a Novel Mutation of the DDP Gene. Arch Neurol. 2001;58(6):1004. doi:10.1001/archneur.58.6.1004
7. Sousa E, Abreu M, Tkachenko N, Rocha J, Falcão Reis C. Case report: Mohr-Tranebjaerg syndrome: hearing impairment as the onset of an insidious disorder with high recurrence risk. Front Neurol. 2023;14:1161940. doi:10.3389/fneur.2023.1161940
8. Ha AD, Parratt KL, Rendtorff ND, et al. The phenotypic spectrum of dystonia in Mohr-Tranebjaerg syndrome. Mov Disord Off J Mov Disord Soc. 2012;27(8):1034-1040. doi:10.1002/mds.25033
9. Olusanya BO, Davis AC, Hoffman HJ. Hearing loss grades and the International classification of functioning, disability and health. Bull World Health Organ. 2019;97(10):725-728. doi:10.2471/BLT.19.230367
10. Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University, Baltimore, MD. MIM Number: 300356, Date Last Edited:8/14/2023. https://omim.org/entry/304700 Accessed July 29, 2025.
11. Jin H, May M, Tranebjærg L, et al. A novel X–linked gene, DDP, shows mutations in families with deafness (DFN–1), dystonia, mental deficiency and blindness. Nat Genet.1996;14(2):177-180. doi:10.1038/ng1096-177
12. Roesch K, Curran SP, Tranebjaerg L, Koehler CM. Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a–TIMM13 complex. Hum Mol Genet. 2002;11(5):477-486. doi:10.1093/hmg/11.5.477
13. Rendtorff ND, Karstensen HG, Lodahl M, et al. Identification and analysis of deletion breakpoints in four Mohr-Tranebjærg syndrome (MTS) patients. Scientific Reports. 2022;12(1). doi:10.1038/s41598-022-18040-y
14. Šedivá A, Smith CIE, Asplund AC, et al. Contiguous X-chromosome Deletion Syndrome Encompassing the BTK, TIMM8A, TAF7L, and DRP2 Genes. J Clin Immunol. 2007;27(6):640-646. doi:10.1007/s10875-007-9123-x
15. Ochs HD, Edvard Smith CI. X-Linked Agammaglobulinemia A Clinical and Molecular Analysis. Medicine (Baltimore). 1996;75(6):287.
16. Tranebjærg L. Mitochondrial Diseases Caused by Mutations in Inner Membrane Chaperone Proteins. In: Wong LJC, ed. Mitochondrial Disorders Caused by Nuclear Genes. Springer; 2013:337-366. doi:10.1007/978-1-4614-3722-2_21
17. MELAS Syndrome. NORD. Updated 2025. https://rarediseases.org/rare-diseases/melas-syndrome/#complete-report Accessed July 29, 2025.
18. Finsterer J, Scorza FA, Fiorini AC, Scorza CA. MEGDEL Syndrome. Pediatr Neurol. 2020;110:25-29. doi:10.1016/j.pediatrneurol.2020.03.009
19. El-Hattab AW, Scaglia F. SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria. 2009 May 26 [Updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6803/ Accessed July 29, 2025.
20. de Brouwer APM, Christodoulou J. Phosphoribosylpyrophosphate Synthetase Deficiency. 2008 Oct 21 [Updated 2023 Jun 8]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK2591/ Accessed July 29, 2025.
21. Jung HH, Danek A, Walker RH, et al. McLeod Neuroacanthocytosis Syndrome. 2004 Dec 3 [Updated 2021 Sep 16]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1354/ Accessed July 29, 2025.
22. Usher Syndrome. NORD. Updated 2023. https://rarediseases.org/rare-diseases/usher-syndrome/#complete-report Accessed July 29, 2025.
23. Wolfram Syndrome. NORD. Updated 2025. https://rarediseases.org/rare-diseases/wolfram-syndrome/#complete-report Accessed July 29, 2025.
24. Friedreich’s Ataxia. NORD. Updated 2023. https://rarediseases.org/rare-diseases/friedreichs-ataxia/#complete-report Accessed July 29, 2025.
25. IEPs vs. 504 Plans. National Center for Learning Disabilities. January 6, 2024. https://ncld.org/ieps-vs-504-plans/ Accessed July 29, 2025.
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