TIMM8A – deafness-dystonia syndrome

Mohr-Tranebjaerg syndrome (deafness-dystonia syndrome; MONDO:0010578) is an X-linked recessive neurodegenerative disorder characterized by early childhood sensorineural hearing loss followed by progressive dystonia and other neurological features (PMID:11338284). Pathogenic variants in TIMM8A (HGNC:11817), encoding a mitochondrial intermembrane space chaperone, underlie the majority of cases.

Multiple hemizygous male probands across at least nine unrelated families have been reported harboring TIMM8A loss-of-function variants (PMID:37325222, PMID:30634948). Segregation of the familial frameshift c.45_61dup (p.His21ArgfsTer11) in three affected nephews confirms X-linked recessive inheritance and high penetrance (PMID:37325222).

The variant spectrum is dominated by truncating alleles—e.g., c.45_61dup (p.His21ArgfsTer11), c.232_233insCAAT (p.Leu78SerfsTer21), c.133_135del (p.Glu45del)—and the only reported missense C66W (c.197G>T (p.Cys66Trp)) affecting the conserved Cys₄ metal-binding motif (PMID:11956200).

Functional studies demonstrate that both truncating and missense mutants fail to assemble into the DDP1–TIM13 hetero-hexamer, impair zinc binding, reduce TIMM8A transcript and protein abundance, and induce abnormal mitochondrial morphology in patient fibroblasts (PMID:11956200, PMID:31903733). A Timm8a1 frameshift mouse model recapitulates hearing impairment, cognitive deficits, and abnormal brain mitochondrial structure (PMID:32820032).

A single case of deafness-dystonia syndrome negative for TIMM8A mutations underscores genetic heterogeneity within this clinical spectrum (PMID:27100856).

Collectively, the robust genetic, segregation, functional, and animal-model evidence supports a definitive gene–disease relationship. Early molecular diagnosis of TIMM8A variants enables timely audiological, neurological, and genetic counseling interventions.

References

• Pediatric allergy and immunology • 2001 • A contiguous deletion syndrome of X-linked agammaglobulinemia and sensorineural deafness. PMID:11338284
• Frontiers in neurology • 2023 • Case report: Mohr-Tranebjaerg syndrome: hearing impairment as the onset of an insidious disorder with high recurrence risk. PMID:37325222
• BMC medical genetics • 2019 • Phenotype prediction of Mohr-Tranebjaerg syndrome (MTS) by genetic analysis and initial auditory neuropathy. PMID:30634948
• The Journal of biological chemistry • 2002 • The C66W mutation in the deafness dystonia peptide 1 (DDP1) affects the formation of functional DDP1.TIM13 complexes in the mitochondrial intermembrane space. PMID:11956200
• Molecular genetics & genomic medicine • 2020 • Functional analysis of a novel mutation in the TIMM8A gene that causes deafness-dystonia-optic neuronopathy syndrome. PMID:31903733
• Journal of medical genetics • 2021 • Frameshift mutation of Timm8a1 gene in mouse leads to an abnormal mitochondrial structure in the brain, correlating with hearing and memory impairment. PMID:32820032
• Stereotactic and functional neurosurgery • 2016 • Long-Term Follow-Up with Video of a Patient with Deafness-Dystonia Syndrome Treated with DBS-GPi. PMID:27100856

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