Overview
Mohr-Tranebjaerg syndrome (MTS), also known as deafness-dystonia-optic neuronopathy (DDON), is a rare X-linked recessive neurodegenerative disorder characterized by early-onset progressive auditory neuropathy, followed by the development of dystonia and optic atrophy typically in adolescence or adulthood. Additional psychiatric manifestations such as dementia, irritability, and mental retardation are frequently observed. First described in 1960 1, MTS is caused by mutations in the TIMM8A gene located on the X chromosome (Xq22) 23. Given its rarity and variable phenotypic expression, early diagnosis can be challenging, but advancements in next-generation sequencing (NGS) have significantly improved the ability to identify the condition before full manifestation of symptoms. Early recognition is crucial for timely intervention and management, particularly in addressing auditory and neurological symptoms 18.Pathophysiology
MTS arises from mutations in the TIMM8A gene, which encodes a protein crucial for the import of metabolite transporters into the mitochondrial inner membrane 56. The TIMM8A protein forms a complex with TIMM13, facilitating the transport of essential proteins necessary for mitochondrial function and integrity 45. Mutations in TIMM8A disrupt this complex, leading to impaired mitochondrial protein import and subsequent mitochondrial dysfunction 56. This dysfunction affects multiple organ systems, particularly neurons and muscle cells, explaining the progressive neurological and muscular symptoms observed in MTS patients 7. The resultant cellular energy deficits and oxidative stress contribute to neurodegeneration, manifesting as auditory neuropathy, dystonia, and optic atrophy 57.Epidemiology
MTS is exceedingly rare, with only approximately 69 cases reported since its initial description in 1960 1. The condition predominantly affects males due to its X-linked recessive inheritance pattern, although female carriers can exhibit milder symptoms, as seen in some reported cases 6. There is no clear geographic or ethnic predilection noted in the literature, suggesting a global distribution but with underreporting likely due to the condition's rarity and diagnostic challenges 12. Trends over time indicate an increasing recognition of MTS with advancements in genetic testing, particularly NGS, which has facilitated earlier and more accurate diagnoses 8.Clinical Presentation
The clinical presentation of MTS typically begins with early-onset sensorineural hearing loss, often diagnosed in childhood 17. This auditory neuropathy is usually progressive and can be detected through audiometric testing showing abnormal distortion product otoacoustic emissions (DPOAEs) and absent auditory brainstem responses (ABRs) 13. Subsequently, patients develop dystonia, characterized by involuntary muscle contractions and spasms, usually emerging in adolescence or early adulthood 12. Optic atrophy leading to visual impairment often becomes apparent later in the disease course, typically in the fourth to sixth decade of life 7. Psychiatric symptoms such as cognitive decline, irritability, and dementia can also occur, complicating the clinical picture 1. Red-flag features include rapid progression of neurological symptoms and the presence of optic atrophy, which should prompt genetic testing for MTS 17.Diagnosis
Diagnosis of MTS involves a combination of clinical evaluation and genetic testing. The diagnostic approach typically includes:Specific Criteria and Tests:
Management
First-Line Management
Second-Line Management
Refractory Cases / Specialist Referral
Contraindications:
Complications
Prognosis & Follow-Up
The prognosis for MTS is generally poor, with progressive neurological decline leading to significant disability over time. Key prognostic indicators include early onset of symptoms and severity of initial manifestations. Regular follow-up intervals should include:Special Populations
Key Recommendations
References
1 Wang H, Wang L, Yang J, Yin L, Lan L, Li J et al.. Phenotype prediction of Mohr-Tranebjaerg syndrome (MTS) by genetic analysis and initial auditory neuropathy. BMC medical genetics 2019. link 2 Aguirre LA, Pérez-Bas M, Villamar M, López-Ariztegui MA, Moreno-Pelayo MA, Moreno F et al.. A Spanish sporadic case of deafness-dystonia (Mohr-Tranebjaerg) syndrome with a novel mutation in the gene encoding TIMM8a, a component of the mitochondrial protein translocase complexes. Neuromuscular disorders : NMD 2008. link 3 Blesa JR, Solano A, Briones P, Prieto-Ruiz JA, Hernández-Yago J, Coria F. Molecular genetics of a patient with Mohr-Tranebjaerg Syndrome due to a new mutation in the DDP1 gene. Neuromolecular medicine 2007. link 4 Roesch K, Hynds PJ, Varga R, Tranebjaerg L, Koehler CM. The calcium-binding aspartate/glutamate carriers, citrin and aralar1, are new substrates for the DDP1/TIMM8a-TIMM13 complex. Human molecular genetics 2004. link 5 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. Human molecular genetics 2002. link 6 Swerdlow RH, Wooten GF. A novel deafness/dystonia peptide gene mutation that causes dystonia in female carriers of Mohr-Tranebjaerg syndrome. Annals of neurology 2001. link 7 Merchant SN, McKenna MJ, Nadol JB, Kristiansen AG, Tropitzsch A, Lindal S et al.. Temporal bone histopathologic and genetic studies in Mohr-Tranebjaerg syndrome (DFN-1). Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 2001. link