Mohr–Tranebjærg syndrome

Overview

Mohr–Tranebjærg syndrome (MTS), also known as Deafness-Dystonia Syndrome, is a rare X-linked recessive neurodegenerative disorder that primarily affects males. The syndrome is characterized by early-onset sensorineural hearing loss, followed by progressive neurological decline, including dystonia (involuntary muscle contractions), spasticity, ataxia, and cognitive deterioration. Females who carry the mutation are typically asymptomatic or may have mild symptoms due to X-chromosome inactivation.

MTS was first described by Mohr and later expanded by Tranebjærg and colleagues. It is caused by mutations in the DDP1 gene, now referred to as TIMM8A, which plays a critical role in mitochondrial protein transport and neuronal function. The disorder progresses over time, often leading to severe disability or early death, though the clinical course can vary among individuals.

Causes

Mohr–Tranebjærg syndrome is caused by mutations in the TIMM8A gene, located on the X chromosome at position Xq22.1. This gene encodes a protein that is part of the mitochondrial intermembrane space import and assembly machinery. TIMM8A is essential for the proper transport of specific proteins into mitochondria, which are critical for neuronal energy production and survival.

Because MTS is inherited in an X-linked recessive manner, it predominantly affects males who inherit the defective gene from their mothers. Female carriers typically have one normal and one mutated copy of the gene and are usually asymptomatic or mildly affected due to the presence of one functioning allele.

Symptoms

Symptoms of Mohr–Tranebjærg syndrome typically begin in early childhood and progress over time. The clinical features are primarily neurological and can vary significantly in severity. Common symptoms include:

1. Hearing Loss

• Early-onset sensorineural deafness, usually beginning before the age of 10

• Progressive in nature and may lead to profound hearing loss

2. Neurological Deterioration

• Dystonia: Involuntary muscle contractions causing abnormal postures or movements

• Spasticity: Stiff or rigid muscles leading to difficulties with movement

• Ataxia: Impaired coordination and balance

• Myoclonus: Sudden, brief muscle jerks

• Cognitive decline: Progressive loss of intellectual abilities

• Behavioral problems: Including anxiety, aggression, or psychosis in later stages

3. Visual and Other Symptoms (in some cases)

• Optic atrophy and progressive visual impairment

• Seizures (rare)

• Feeding difficulties and poor weight gain due to motor dysfunction

Symptoms usually progress over time, with motor and cognitive issues becoming increasingly prominent in adolescence and early adulthood.

Diagnosis

Diagnosis of Mohr–Tranebjærg syndrome is based on clinical findings, family history, and confirmatory genetic testing. Because the initial symptom is often hearing loss, children are often first seen by audiologists or otolaryngologists before the neurological features emerge.

Diagnostic Steps

• Clinical evaluation: Detailed assessment of hearing, motor function, and neurodevelopmental history

• Audiological testing: Confirms sensorineural hearing loss

• Neurological examination: Identifies dystonia, spasticity, and cognitive changes

• Genetic testing: Sequencing of the TIMM8A gene confirms the diagnosis

• MRI of the brain: May reveal nonspecific signs of neurodegeneration or atrophy

• Family genetic analysis: Identifies female carriers and informs genetic counseling

Early diagnosis allows for anticipatory care, hearing management, and genetic counseling for affected families.

Treatment

There is currently no cure for Mohr–Tranebjærg syndrome. Treatment is supportive and aimed at managing symptoms, slowing progression, and improving quality of life. A multidisciplinary approach is essential and may involve audiologists, neurologists, physical therapists, occupational therapists, and speech-language pathologists.

1. Hearing Management

• Hearing aids: In early stages of hearing loss

• Cochlear implants: May be considered in cases of profound deafness

2. Neurological Symptom Management

• Antispasticity medications: Such as baclofen or tizanidine

• Antidystonic agents: Such as trihexyphenidyl or botulinum toxin injections

• Anti-seizure medications: If seizures occur

3. Rehabilitation and Supportive Care

• Physical therapy to improve mobility and manage spasticity

• Occupational therapy for daily living skills and assistive devices

• Speech and language therapy, especially for communication and swallowing difficulties

4. Psychological and Educational Support

• Behavioral therapy and mental health support as needed

• Special education services and accommodations

Genetic counseling is crucial for families to understand inheritance patterns, recurrence risk, and family planning options.

Prognosis

The prognosis for individuals with Mohr–Tranebjærg syndrome is generally poor due to the progressive nature of the neurological deterioration. Hearing loss typically begins in early childhood and is followed by motor and cognitive decline in adolescence or early adulthood.

Prognostic Considerations

• Progression is variable; some individuals maintain partial function into adulthood, while others experience rapid decline

• Most affected individuals eventually require full-time care due to severe motor and cognitive impairment

• Life expectancy may be reduced, especially in those with severe complications

Ongoing research is aimed at understanding the molecular mechanisms of TIMM8A mutations and developing potential therapies. Supportive care and early intervention remain key to maximizing function and quality of life in affected individuals.