Mohr–Tranebjærg syndrome

Alternate names

MTS; Deafness dystonia syndrome; DDS; Deafness syndrome, progressive, with blindness, dystonia, fractures, and mental deficiency; Deafness-dystonia-optic atrophy syndrome; DDP; Deafness-dystonia-optic neuronopathy (DDON) syndrome; DDON syndrome; Deafness - dystonia - optic neuronopathy syndrome; Deafness-dystonia-optic neuronopathy syndrome

Definition

Deafness-dystonia-optic neuronopathy (DDON) syndrome, also known as Mohr-Tranebjærg syndrome, is characterized by hearing loss that begins early in life, problems with movement, impaired vision, and behavior problems. This condition occurs almost exclusively in males.

Epidemiology

DDON syndrome is a rare disorder; it has been reported in fewer than 70 people worldwide.

Cause

Mutations in the TIMM8A gene cause DDON syndrome. The protein produced from this gene is found inside the energy-producing centers of cells (mitochondria). The TIMM8A protein forms a complex (a group of proteins that work together) with a very similar protein called TIMM13. This complex functions by transporting other proteins within the mitochondria.

Most mutations in the TIMM8A gene result in the absence of functional TIMM8A protein inside the mitochondria, which prevents the formation of the TIMM8A/TIMM13 complex. Researchers believe that the lack of this complex leads to abnormal protein transport, although it is unclear how abnormal protein transport affects the function of the mitochondria and causes the signs and symptoms of DDON syndrome.

Inheritance

X-linked recessive inheritance

• DDON syndrome is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition.
• In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause DDON syndrome. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females.
• Females who carry one altered copy of the TIMM8A gene are typically unaffected; however, they may develop mild hearing loss and dystonia. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Signs and symptoms

• The first symptom of DDON syndrome is hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss), which begins in early childhood. The hearing impairment worsens over time, and most affected individuals have profound hearing loss by age 10.
• People with DDON syndrome typically begin to develop problems with movement during their teens, although the onset of these symptoms varies among affected individuals. Some people experience involuntary tensing of the muscles (dystonia), while others have difficulty coordinating movements (ataxia). The problems with movement usually worsen over time.
• Individuals with DDON syndrome have normal vision during childhood, but they may develop vision problems due to breakdown of the nerves that carry information from the eyes to the brain (optic atrophy). Affected individuals can develop an increased sensitivity to light (photophobia) or other vision problems beginning in adolescence. Their sharpness of vision (visual acuity) slowly worsens, often leading to legal blindness in mid-adulthood.
• People with this condition may also have behavior problems, including changes in personality and aggressive or paranoid behaviors. They also usually develop a gradual decline in thinking and reasoning abilities (dementia) in their forties. The lifespan of individuals with DDON syndrome depends on the severity of the disorder. People with severe cases have survived into their teenage years, while those with milder cases have lived into their sixties.

Diagnosis

Formal diagnostic criteria for deafness-dystonia-optic neuronopathy (DDON) syndrome have not been established.[1].

Deafness-dystonia-optic neuronopathy (DDON) syndrome is suspected in males with the following:

• Progressive sensorineural hearing impairment with prelingual or postlingual onset:
• Absent stapedius reflex
• Abnormal findings on auditory brain stem response testing
• Normal evoked otoacoustic emissions, indicating normal outer hair cells [Richter et al 2001]
• Normal findings on CT scan of the inner ear [Mohr & Mageroy 1960, Tranebjaerg et al 1995]
• Movement disorder (dystonia/ataxia)
• Gradual onset and slow progression of personality changes, paranoia, dementia
• Gradual decrease in visual acuity associated with optic atrophy
• Gradual onset and slow progression of dysphagia

• A family history consistent with X-linked inheritance

Establishing the DiagnosisThe diagnosis of deafness-dystonia-optic neuronopathy (DDON) syndrome is established in a proband who has one of the following on molecular genetic testing.

Treatment

• 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.[2].

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NIH genetic and rare disease info

• NIH info on Mohr–Tranebjærg syndrome

Mohr–Tranebjærg syndrome is a rare disease.

Mohr–Tranebjærg syndrome Resources
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