Mohr-Tranebjaerg syndrome (MTS) is a rare X-linked recessive neurodegenerative disorder caused by pathogenic variants in the TIMM8A gene. TIMM8A, also known as Deafness-Dystonia Peptide-1 (DDP1) is a mitochondrial intermembrane space protein involved in the import and insertion of hydrophobic membrane proteins from the cytoplasm into the mitochondrial inner membrane. MTS typically presents early-onset progressive hearing loss, dystonia, visual impairment, and cognitive decline. Here, we report a case of a male adolescent with a previously undescribed variant in TIMM8A, associated with progressive dystonia but no hearing loss, highlighting the clinical variability of MTS. A 16-year-old male was referred for genetic evaluation due to a 6-year history of progressive dystonia, motor coordination difficulties, and iron deposits in the basal ganglia detected by brain MRI. Family history revealed mild motor abnormalities in his maternal uncle and recurrent muscle spasms in his mother. Whole-exome sequencing (WES) identified a c.98_101dupAGCA variant in TIMM8A in hemizygosity, classified as likely pathogenic. This variant causes a frameshift leading to a truncated protein. The patient inherited the variant from his mother, who is heterozygous for the mutation. Although the patient lacks the characteristic early-onset hearing loss seen in MTS, his neurological presentation and the imaging findings are consistent with the syndrome. This case underscores the phenotypic heterogeneity of Mohr-Tranebjaerg syndrome, where patients may present with prominent neurological symptoms such as dystonia without the hallmark auditory dysfunction. The identification of a novel TIMM8A variant expands the mutational spectrum of this rare disorder and provides insights into genotype-phenotype correlations. The absence of hearing loss in this patient raises important questions about the variability in the expression of the mutated TIMM8A. This report highlights a novel TIMM8A mutation associated with Mohr-Tranebjaerg syndrome, presenting primarily with dystonia and iron accumulation in the basal ganglia. The findings contribute to the understanding of the clinical spectrum of MTS and emphasize the importance of genetic testing in patients with unexplained progressive neurological symptoms.

Mohr-Tranebjaerg syndrome (MTS) is a rare X-linked recessive neurodegenerative disorder caused by mutations in the Translocase of Inner Mitochondrial Membrane 8A (TIMM8A) gene, which encodes TIMM8a, a protein localized to the mitochondrial intermembrane space (IMS). The pathophysiology of MTS remains poorly understood. To investigate the molecular mechanisms underlying MTS, we established induced pluripotent stem cells (iPSCs) from a male MTS patient carrying a novel TIMM8A mutation (c.225-229del, p.Q75fs95*), referred to as MTS-iPSCs. To generate an isogenic control, we introduced the same mutation into healthy control iPSCs (CTRL-iPSCs) using the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/Cas9), resulting in mutant iPSCs (MUT-iPSCs). We differentiated the three iPSC lines into neurons and evaluated their mitochondrial function and neuronal development. Both MTS- and MUT-iPSCs exhibited impaired neuronal differentiation, characterized by smaller somata, fewer branches, and shorter neurites in iPSC-derived neurons. Additionally, these neurons showed increased susceptibility to apoptosis under stress conditions, as indicated by elevated levels of cytochrome c and cleaved caspase-3. Mitochondrial function analysis revealed reduced protein levels and activity of complex IV, diminished ATP synthesis, and increased reactive oxygen species (ROS) generation in MTS- and MUT-neurons. Furthermore, transmission electron microscopy revealed mitochondrial fragmentation in MTS-neurons. RNA sequencing identified differentially expressed genes (DEGs) involved in axonogenesis, synaptic activity, and apoptosis-related pathways. Among these DEGs, coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2), which encodes a mitochondrial IMS protein essential for mitochondrial homeostasis, was significantly downregulated in MTS-neurons. Western blot analysis confirmed decreased CHCHD2 protein levels in both MTS- and MUT-neurons. Overexpression of CHCHD2 rescued mitochondrial dysfunction and promoted neurite elongation in MTS-neurons, suggesting that CHCHD2 acts as a downstream effector of TIMM8a in the pathogenesis of MTS. In summary, loss-of-function of TIMM8a leads to a downstream reduction in CHCHD2 levels, collectively impairing neurogenesis by disrupting mitochondrial homeostasis. TIMM8a mutation (p.Q75fs95*) leads to mitochondrial dysfunction and neuronal defects in iPSC-derived neurons from patient with Mohr-Tranebjaerg syndrome, which are rescued by overexpression of CHCHD2. TIMM8a translocase of inner mitochondrial membrane 8a, CHCHD2 coiled-coil-helix-coiled-coil-helix domain-containing protein 2, MTS Mohr-Tranebjaerg syndrome, I mitochondrial complex I, II mitochondrial complex II, III mitochondrial complex III, IV mitochondrial complex IV, Q coenzyme Q10, Cyt c cytochrome c.

Female breast cancer has become the world's most common malignant tumor, displacing lung malignancy, and the incidence of malignant tumors has increased continuously in recent decades. However, the underlying molecular mechanisms of breast tumorigenesis have not been fully elucidated. By consulting the literature, we discovered that the TIMM8A gene could affect oxidative stress and apoptosis in patients with Mohr-Tranebjærg syndrome. However, the biological function of TIMM8A has yet to be explored. We investigated the expression level of TIMM8A via bioinformatic analysis and performed immunohistochemistry, diagnostic value, immune infiltration, functional enrichment, and survival analyses. Nonetheless, in vitro, additional experiments were performed. We explored whether TIMM8A expression was greater in breast tumors than in nearby normal tissues through qRT‒PCR. The expression of TIMM8A was knocked down by siRNA. Then, we conducted proliferation tests (CCK-8 experiment and colony formation) and Transwell assays (migration and invasion assays) to determine the specific biological functions of TIMM8A in the MDA-MB-231 and BT-549 cell lines. Tumor samples exhibited higher TIMM8A expression and exon expression, whereas normal tissues had higher TIMM8A methylation. The expression level of TIMM8A was linked to immune infiltration and survival, making it a valuable prognostic indicator and effective diagnostic tool. Functional enrichment analysis of TIMM8A indicated potential pathways through which it may play a role. In vitro experiments demonstrated that suppressing TIMM8A significantly inhibited the viability, colony formation, migration, and invasion of breast carcinoma cell lines. This study revealed that TIMM8A is an oncogene and is critical for the tumorigenesis of breast carcinoma.

Mohr-Tranebjaerg syndrome (MTS) is an X-linked recessive disorder caused by TIMM8A loss of function. It is characterized by sensorineural hearing loss in childhood, progressive optic atrophy in early adulthood, early onset dementia and psychiatric symptoms of variable expressivity. We present a family with 4 affected males, explore age-related and interfamilial variability and review the literature. A 31 years-old male developed psychiatric symptoms at age 18 and presented early onset dementia. Sensorineural hearing loss had been diagnosed in childhood. At 28yo, he developed dysarthria, dysphonia, dysmetria, limb hyperreflexia, dystonia, and spasticity following an acute encephalopathic crisis. WES revealed a hemizygous novel likely pathogenic variant in TIMM8A, c.45_61dup p.(His21Argfs*11), establishing the diagnosis of MTS. Genetic counseling of the family allowed the diagnosis of three other symptomatic relatives -3 nephews (11yo and two 6yo twins), children of a carrier sister. The oldest nephew had been followed since 4yo due to speech delay. Sensorineural hearing loss was diagnosed at 9yo, and hearing aids were prescribed. The two other nephews were monozygotic twins, and both had unilateral strabismus. One of the twins had macrocephaly and hypoplasia of the anterior temporal lobe, as disclosed by an MRI performed due to febrile seizures. Both had developmental delays, with the language being the most affected area. Their audiograms confirmed hearing loss. All three nephews were hemizygous for the familial TIMM8A variant. Hearing loss, an early sign of MTS due to auditory neuropathy, can often be overlooked until more severe features of the disorder manifest. Recurrence risk is high for female carriers, and reproductive options should be offered. Early monitoring of hearing and vision loss and neurological impairment in MTS patients is mandatory since early interventions may positively impact their development. This family showcases the importance of performing a timely etiological investigation of hearing loss and its impact on genetic counseling.

We report a Dystonia-Deafness syndrome patient treated by pallidal Deep Brain Stimulation with significant long-term benefits. Our study expands and confirms the complex phenotypic spectrum of ACTB gene-related disorders and supports the effectiveness of pallidal stimulation on motor outcomes and quality of life in dystonia due to ACTB p.Arg183Trp heterozygosity.