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An X-linked syndromic intellectual disability characterized by clinical manifestations commencing with early childhood onset hearing loss, followed by adolescent onset progressive dystonia or ataxia, visual impairment from early adulthood onwards and dementia from the 4th decade onwards.
ORPHA:52368Classification level: Disorder
Mohr-Tranebjaerg syndrome (MTS) prevalence is unknown. More than 90 cases (37 families) are known, but not all cases have been reported in the literature.
The onset of rapidly progressive prelingual or postlingual sensorineural hearing loss, the only typical symptom, occurs in early childhood (18 months). The audiological phenotype is characterized by auditory neuropathy, characterized by preserved OAE (oto- acoustic emissions,) abnormal ABR (Auditory brain stem response), very poor speech discrimination, worsening in noisy environment and questionable benefit of treatment with cochlear implants (very few cases reported). Neuropsychologic manifestations, such as personality changes, paranoia, and mild intellectual deficit may emerge at the same time. A slowly progressive movement disorder, appearing as gegenhalten (diffuse resistance to limb movement), dystonia (mostly generalized or focal) or ataxia develops from early adolescence and is associated with brisk tendon reflexes, ankle clonus and extensor plantar responses. Patients experience reduced visual acuity, photophobia, acquired color vision defect and central scotomas starting from about 20 years of age and leading to legal blindness at around age 30 to 40. Slowly progressive dementia develops from the 4th decade onwards. In those with a contiguous gene deletion syndrome (CGS), recurrent infections may be present. Carrier females may be mildly affected with mild hearing impairment and focal dystonia. Despite the X linked recessive inheritance of the disease, there are a few cases where the proband was a female with dystonia.
MTS is caused by either a mutation in the TIMM8A gene (located to Xq22) or by a CGS at Xq22, resulting in a deafness-dystonia peptide 1 (DDP1) deficiency. If the CGS includes the Bruton agammaglobulinemia tyrosine kinase (BTK) gene, recurrent infections secondary to this X-linked agammaglobulinemia (XLA) are present.
A combination of hearing impairment and recurrent infections due to XLA in a male patient should elicit sequencing of the TIMM8A gene. Neuroimaging is employed to verify the presence of cerebral atrophy. In cases of suspected CGS; testing for XLA is possible.
Differential diagnosis includes MELAS syndrome; mitochondrial DNA depletion syndrome (encephalomyopathic form with methylmalonic aciduria); Arts syndrome; X-linked spinocerebellar ataxia type 3 and 4; McLeod neuroacanthocytosis syndrome; Usher syndrome type 1 and 2; Wolfram syndrome; autosomal recessive nonsyndromic sensorineural deafness type DFNB; Pendred syndrome; and other forms of dystonia or rarely Friedreich ataxia.
Prenatal diagnosis may be proposed to affected couples or parents for further pregnancies.
The pattern of inheritance is X-linked recessive and gentic counselling should be offerend to affected families. Where the female is a carrier, the risk to male offspring inheriting the disease is 50%, female offspring have a 50% risk of being carriers. Where a male is affected, female offspring are obligate carriers, and male offspring do not inherit the pathogenic mutation.
Management and treatment
Treatment of MTS is symptomatic and evolves over time. Hearing aids are used with variable success. For mild hearing loss, a hearing device and cochlear implants are an option whereas hearing aids with visual clues are used in cases with more severe hearing loss. The management of the hearing impairment is challenged by the fact that it is an auditory neuropathy. Management of dystonia and ataxia includes treatment with GABA-agonists together with psycho-motor re-education and physical therapy. Other supportive measures include therapies for the deaf-blind, addressing progressive sensory deficits, such as tactile sign language. In those with secondary complications, intravenous immunoglobulin may prevent infections in XLA. Furthermore, live viral vaccines should be avoided in cases of XLA. In adulthood, regular neurological evaluation (assessment for dementia and/or psychiatric manifestations) should be maintained.
Prognosis is poor. The combination of deafness and blindness severely affects communication, while the ongoing movement disorder results in an increasingly unstable gait. Life expectancy is highly variable and can range from death in the teenage years (after a rapidly progressive dystonia) to those that live into their 60's.