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Background Mohr-Tranebjaerg syndrome (MTS) is a rare X-linked recessive neurodegenerative disorder resulting in early-onset hearing impairment, gradual dystonia and optic atrophy. MTS is caused by variations in the nuclear TIMM8A gene, which is involved in mitochondrial transport of metabolites. This study aimed to identify the pathogenic gene variations in three Chinese families associated with predicted MTS with or without X-linked agammaglobulinaemia. Methods Otologic examinations, vestibular, neurological, optical and other clinical evaluations were conducted on the family members. Targeted genes capture combining next generation sequencing (NGS) was performed, and then Sanger sequencing was used to confirm the causative variation. Results A novel variation, c.232_233insCAAT, in TIMM8A was identified as the pathogenic variation in one Chinese family. This variation co-segregated with the most frequent phenotypic deafness and was absent in the 1000 Genomes Project, ExAC and 1751 ethnicity-matched controls. Clinically, otological examinations illustrated the typical postsynaptic auditory neuropathy for the proband without the symptoms of dystonia or optic atrophy. MRI demonstrated abnormal small cochlear symmetric nerves, while the vestibular function appeared to be less influenced. Furthermore, we found another two TIMM8A variations, the deletion c.133_135delGAG and a copy number variation (CNV) including the TIMM8A gene, in two independent case, when we performed NGS on an auditory neuropathy population. Conclusion We identified two novel variations in the TIMM8A gene (c.232_233insCAAT and c.133_135delGAG) and a CNV including the TIMM8A gene in three independent Chinese families with predicted MTS. To our knowledge, this is the first report of TIMM8A variations being identified in a Chinese population. Our results enrich the variation spectrum of TIMM8A and clinical heterogeneity of MTS. Genetic detection and diagnosis is a powerful tool for better understanding and managing syndromic hearing impairments, such as MTS, before they become full-blown. Electronic supplementary material The online version of this article (10.1186/s12881-018-0741-3) contains supplementary material, which is available to authorized users.

May-Thurner syndrome (MTS) is an unusual cause of deep venous thrombosis; even rarer is the spontaneous rupture of collaterals around the thrombosed common iliac vein due to MTS. We present a case of MTS which presented with left leg swelling and abdominal mass due to retroperitoneal haemorrhage.

Introduction A 28-year-old man presented with a history of sensorineural deafness since early childhood treated with bilateral cochlear implants (CIs). He showed signs of debilitating dystonia that had been present since puberty. Dystonic symptoms, especially a protrusion of the tongue and bilateral hand tremor, had not responded to botulinum toxin therapy. We diagnosed Mohr-Tranebjaerg syndrome (MTS). Methods and Material Deep brain stimulation (DBS) of the bilateral globus pallidus internus was performed predominantly with stereotaxic computed tomography angiography guidance under general anesthesia. Electrophysiology was used to identify the target regions and to guide DBS electrode placement. Results In the immediate postoperative course and stimulation, the patient showed marked improvement of facial, extremity, and cervical dystonia. More than 2 years after implantation, his dystonic symptoms had dramatically improved by 82%. Discussion MTS is a rare genetic disorder leading to sensorineural deafness, dystonia, and other symptoms. The use of DBS for the dystonia in MTS was previously described but not in the presence of bilateral CIs. Conclusion DBS in MTS may be a viable option to treat debilitating dystonic symptoms. We describe successful DBS surgery, despite the presence of bilateral CIs, and stimulation therapy over 2 years.

Atypical teratoid rhabdoid tumors (ATRTs) are fatal pediatric brain tumors that warrant improved therapies urgently. ATRTs are characterized by loss of INI1, a subunit of the SWI/SNF chromatin-remodeling complex. ATRTs grow aggressively despite majority of primary tumors expressing p53, suggesting inactivation of this tumor suppressor pathway. Reactivation of p53 could be a potential therapeutic strategy for inhibiting ATRT growth. Our laboratory specializes in researching mechanisms contributing to ATRT pathogenesis and potential therapies. In line with this, we investigated an anti-malarial drug called quinacrine that has been safely used in children for decades and can induce p53 in renal cell carcinoma. We used 5 patient-derived ATRT cell lines (BT-37, BT-12, CHLA-06, CHLA-266, CHLA-05) for our studies. We show that ATRT cell lines treated with quinacrine for 6 hours show increased expression of p53, suggesting its activation. Treatment of ATRT cell lines with increasing doses of quinacrine for 24 hours showed dose-dependent decrease in cell growth and proliferation (assessed by MTS assay and BrdU incorporation, P

Human Tim8a and Tim8b are members of an intermembrane space chaperone network, known as the small TIM family. Mutations in TIMM8A cause a neurodegenerative disease, Mohr-Tranebjærg syndrome (MTS), which is characterised by sensorineural hearing loss, dystonia and blindness. Nothing is known about the function of hTim8a in neuronal cells or how mutation of this protein leads to a neurodegenerative disease. We show that hTim8a is required for the assembly of Complex IV in neurons, which is mediated through a transient interaction with Complex IV assembly factors, in particular the copper chaperone COX17. Complex IV assembly defects resulting from loss of hTim8a leads to oxidative stress and changes to key apoptotic regulators, including cytochrome c, which primes cells for death. Alleviation of oxidative stress with Vitamin E treatment rescues cells from apoptotic vulnerability. We hypothesise that enhanced sensitivity of neuronal cells to apoptosis is the underlying mechanism of MTS.

Human Tim8a is a member of an intermembrane space chaperone network, known as the small TIM family, which transport hydrophobic membrane proteins through this compartment. Mutations in TIMM8A cause a neurodegenerative disease, Mohr-Tranebjærg syndrome (MTS), which is characterised by sensorineural hearing loss, dystonia and blindness. Nothing is known about the function of hTim8a in neuronal cells and consequently how lack of hTim8a leads to a neurodegenerative disease. We identified a novel cell-specific function of hTim8a in the assembly of Complex IV, which is mediated through a transient interaction with the copper chaperone COX17. Complex IV assembly defects in cells lacking hTim8a leads to oxidative stress and changes to key apoptotic regulators, including cytochrome c and Bax, which primes cells for cell death. Alleviation of oxidative stress using Vitamin E rescues cells from apoptotic vulnerability. We hypothesis that enhanced sensitivity of neuronal cells to apoptosis is the underlying mechanism of MTS.

Diffuse intrinsic pontine glioma (DIPG) is driven by epigenetic dysregulation. The pan-HDAC inhibitor panobinostat showed pre-clinical efficacy against DIPG, but was limited by toxicity in clinical trials. RG2833 (RGFP109) is a selective HDAC1/3 inhibitor with established brain penetration. RG2833 reverses temozolomide-resistance in glioblastoma through downregulation of the NFĸB pathway. As this pathway is upregulated in DIPG and may contribute to tumorigenesis, we hypothesized that RG2833 would kill DIPG cells. We found that RG2833 treatment inhibits cell growth in the 4 to 9μM range in both autopsy and biopsy-derived DIPG cell lines (MTS assay for HSJD007 p=0.0004, JHH-DIPG1 p=0.001, SF-7761 p=0.04, SU-DIPG13 p=0.01 by t-test). Western blot confirmed on target activity by increased histone 3 acetylation at IC50 doses. RG2833 induces apoptosis (cPARP Western blot, cleaved caspase 3 immunofluorescence HSJD007 p

BACKGROUND/OBJECTIVES Treatment of children with CNS NGGCT remains challenge: 5y OS is 60 – 80%; relapses are very aggressive. DESIGN/METHODS Between 2003 and 2019, 14 children (median age 10.5, range 4 – 16 years) with localized intracranial NGGCT were treated with RT after induction chemotherapy (focal – 4, WVI+boost – 6, WBI+boost – 3, CSI+boost – 1). Tumor markers were elevated in 13 patients: 6 – AFP, 5 – HCG, 2 – both. One patient with level of HCG 72049 IU/l in serum and 121451 IU/l in CSF received 4 cycles of PEI + CSI 30 Gy with boost 54Gy. RESULTS At a median follow-up of 4,7 years (range 1 – 16,25 years), 12 patients are alive. 5-year PFS and OS are 77,1% and 85,7%, respectively. Two patients (both AFP and HCG) progressed during RT (1 – focal, 1 – WBI+boost), both died. Two patients with high level of HCG recurred after therapy (WVI+boost – 1, focal – 1), both are alive. The first of them at recurrence (mts of lateral ventricle) received 4 cycles of PEI and RT (WBI+boost). The second patient had level of HCG 620IU/l and initially received focal irradiation 54Gy. At recurrence with distant spinal mts he received HD-CHT with auto-SCT, surgical resection of residual tumor and CSI with boost. CONCLUSIONS Good results of treatment of localized CNS NGGCT with CSI, WBI or WVI in compare with focal RT show advantages of extended irradiation field. CSI should be considered for patients with extremely high levels of tumor markers and respectively poor prognostic histology.

Introduction In this study we describe a patient with gross deletion containing the BTK and TIMM8A genes. Mutations in these genes are responsible for X-linked agammaglobulinemia and Mohr-Tranebjaerg syndrome, respectively. X linked agammaglobulinemia is a rare primary immunodeficiency characterized by low levels of B lymphocytes and recurrent microbial infections, whereas, Mohr-Tranebjaerg syndrome is a progressive neurodegenerative disorder with early onset of sensorineural deafness. Material and methods For neuroimaging, the magnetic resonance imaging and magnetic resonance spectroscopy of the brain were performed. Microarray analysis was performed to establish the extent of deletion. Results The first clinical symptoms observed in our patient at the age of 6 months were connected with primary humoral immunodeficiency, whereas clinical signs of MTS emerged in the third year of live. Interestingly, the loss of speech ability was not accompanied by hearing failure. Neuroimaging of the brain suggested leukodystrophy. Molecular tests revealed contiguous X-chromosome deletion syndrome encompassing BTK (from exons 6 through 19) and TIMM8A genes. The loss of the patient's DNA fragment was accurately localized from 100 601 727 to 100 617 576 bp on chromosome's loci Xq22.1. Conclusions We diagnosed XLA-MTS in the first Polish patient on the basis of particular molecular methods. We detected neurodegenerative changes in MRI and MR spectroscopy in this patient. Our results provide further insight into this rare syndrome.

Introduction In this study we describe a patient with gross deletion containing the BTK and TIMM8A genes. Mutations in these genes are responsible for X-linked agammaglobulinemia and Mohr-Tranebjaerg syndrome, respectively. X linked agammaglobulinemia is a rare primary immunodeficiency characterized by low levels of B lymphocytes and recurrent microbial infections, whereas, Mohr-Tranebjaerg syndrome is a progressive neurodegenerative disorder with early onset of sensorineural deafness. Material and methods For neuroimaging, the magnetic resonance imaging and magnetic resonance spectroscopy of the brain were performed. Microarray analysis was performed to establish the extent of deletion. Results The first clinical symptoms observed in our patient at the age of 6 months were connected with primary humoral immunodeficiency, whereas clinical signs of MTS emerged in the third year of live. Interestingly, the loss of speech ability was not accompanied by hearing failure. Neuroimaging of the brain suggested leukodystrophy. Molecular tests revealed contiguous X-chromosome deletion syndrome encompassing BTK (from exons 6 through 19) and TIMM8A genes. The loss of the patient’s DNA fragment was accurately localized from 100 601 727 to 100 617 576 bp on chromosome’s loci Xq22.1. Conclusions We diagnosed XLA-MTS in the first Polish patient on the basis of particular molecular methods. We detected neurodegenerative changes in MRI and MR spectroscopy in this patient. Our results provide further insight into this rare syndrome.

Pediatric low-grade glioma (pLGG) is the most common brain tumor in children. We and others have identified constitutive activation of the mTOR and MEK-pathway in pLGG. This led us to investigate TAK228, a mTORC1/2-inhibitor, and the FDA approved MEK-inhibitor, trametinib, in mono- and combination therapy in pLGG. We examined antitumor activity in five patient-derived pLGG cell models treated with TAK228, trametinib, and combination: JHH_NF1_PA1(NF1mut), BT66_SV40(BRAF:KIAA1549), BT40(BRAFV600E), Res186(PTEN-/-) and Res259(CDKN2A-/-). In all cell lines, trametinib treatment led to suppression of phospho-ERK at low levels (1-5nM; Western Blot). TAK228 treatment led to inhibition of mTORC1/2 in low nanomolar range. Treatment with TAK228 or trametinib reduced cell proliferation in a dose and time dependent manner (MTS-assay). The combination treatment exerted a synergistic effect at 5-20nM in JHH_NF1_PA1, Res186, and Res259 cells (Chou-Talay method). We tested trametinib and TAK228 against the mutant BT40(BRAFV600E) patient-derived xenograft cells in immunodeficient mice. Combination of TAK228 with trametinib showed greater antitumor activity than that of either mono-treatment in vivo. BT40 tumor growth was significantly decreased in combination compared to vehicle or either agent alone (p Our study provides evidence that pLGG-derived cell lines in vitro and in vivo are sensitive to mTORC1/2 kinase inhibition and MEK inhibition. Combination treatment with TAK228 and trametinib had a significant anti-tumor activity in vivo shown in survival rate, decreased tumor size, and reduced vascularity. These results provide a strong rationale for combination therapy with TAK228 and trametinib for clinical consideration in pLGG.

Atypical teratoid rhabdoid tumors (AT/RT) are deadly tumors of infancy in need of new, targeted therapies to reduce morbidity and improve survival. Molecular analyses have revealed considerable molecular heterogeneity dividing AT/RT into three distinct subgroups. MYC expression is identified in a particularly aggressive subgroup of AT/RT. MYC is challenging to target directly given large, flat, featureless protein-protein binding sites. To identify anomalies that can be targeted in high MYC-expressing AT/RT, we performed unbiased metabolic profiling of each of our 8 AT/RT cell lines using high pressure liquid chromatography mass spectrometry (HPLC-MS). Partial Least Squares-Discriminant Analysis (PLS-DA) identified a distinct metabolic profile in high MYC-expressing cell lines. Further pathway analysis highlighted unique patterns of glutamine utilization in these cell lines. In fact, high-MYC expressing cell lines were more dependent on glutamine for growth and survival (MTS assay, glutamine-free media vs normal media). Due to this dependence on glutamine metabolism, we hypothesized that high-MYC expressing AT/RT would be especially sensitive to glutamine metabolic inhibitors. We showed that the glutamine analogue, 6-diazo-5-oxo-L-norleucine (DON) slowed high-MYC expressing AT/RT cell growth (MTS assay, p

Background: The prevalence of deafness-dystonia syndrome (DDS) is relatively low. To our knowledge, only 2 cases of this syndrome treated with deep brain stimulation (DBS) have been reported. Objectives: We present a patient with DDS of unknown cause, refractory to medical treatment, who has been successfully treated with DBS of the internal globus pallidus (DBS-GPi) and followed up for 4 years. Methods: A 21-year-old male, with progressive bilateral sensorineural hearing loss since the age of 3, developed dystonic movements at the age of 12. The patient presented with progressive segmental craniocervical dystonia with jaw-opening, tongue protrusion, retrocollis and gradual overflow including upper limb dystonia. Pharmacological therapy was ineffective. At the age of 17, the patient's condition deteriorated with the risk of developing a dystonic state. Results: DBS-GPi implantation resulted in a striking improvement. The Burke-Marsden-Fahn Dystonia Rating Scale (BMFDRS) score improved from 75 points before the surgery to 10 points at 3 months after DBS-GPi implantation. Neurological examination at the age of 21 showed mild dystonic movements, mainly oromandibular dystonia (BMFDRS: 15 points). The clinical phenotype of our patient was consistent with Mohr-Tranebjaerg syndrome (MTS). We performed genetic analysis of the TIMM8A gene (the only gene in which mutations are known to cause MTS), but the result was negative; however, other potentially new mutations have to be considered. Conclusions: Based on our case with the longest reported follow-up of 4 years and 2 earlier reports, we advise to consider DBS-GPi in patients with DDS with unsatisfactory effect of pharmacological treatment.

Mohr-Tranebjaerg syndrome (MTS) is an X-liked recessive rare syndrome also known as deafness-dystonia syndrome. The severity of the symptoms may vary, but they progress usually to severe deafness and dystonia and sometimes they are accompanied by cortical deterioration of vision and mental deterioration. The purpose of this paper is to illustrate a very interesting case of Mohr-Tranebjaerg syndrome. A 24-year-old italian man with Mohr-Tranebjaerg syndrome underwent full field electroretinography (ERG) and visual evoked potentials (VEPs). Fundus examination showed apparently normal retina with pallor of the optic disc. Pattern reversal VEP and flash VEP responses were non-recordable. ERG showed amplitude reduction of the fotopic, scotopic and 30 Hz flicker responses revealing generalized retinal dysfunction with reduction of cone and rod responses. The progressive neurodegeneration in Mohr-Tranebjaerg syndrome can be also associated with a retinal degeneration.

The clinical evaluation of a patient with dystonia is a stepwise process, beginning with classification of the phenomenology of the movement disorder(s), then formulation of the dystonia syndrome, which, in turn, leads to a targeted etiological differential diagnosis. In recent years, there have been significant advances in our understanding of the etiological basis of dystonia, aided especially by discoveries in imaging and genetics. In this review, we provide an update on the assessment of a patient with dystonia, including the phenomenology of dystonia and highlighting how to integrate clinical, imaging, blood, and neurophysiological investigations in order to formulate a dystonia syndrome. Evolving or emerging dystonia syndromes are reviewed, and potential etiologies of these as well as established dystonia syndromes listed to guide diagnostic testing. © 2013 Movement Disorder Society.

The syndrome of deafness-dystonia is rare and refers to the association of hearing impairment and dystonia when these are dominant features of a disease. Known genetic causes include Mohr-Tranebjaerg syndrome, Woodhouse-Sakati syndrome, and mitochondrial disorders, but the cause frequently remains unidentified. The aim of the current study was to better characterize etiological and clinical aspects of deafness-dystonia syndrome. We evaluated 20 patients with deafness-dystonia syndrome who were seen during the period between 1994 and 2011. The cause was identified in only 7 patients and included methylmalonic aciduria, meningoencephalitis, perinatal hypoxic-ischemic injury, large genomic deletion on chromosome 7q21, translocase of inner mitochondrial membrane 8 homolog A (TIMM8A) mutation (Mohr-Tranebjaerg syndrome), and chromosome 2 open reading frame 37 (C2orf37) mutation (Woodhouse-Sakati syndrome). The age of onset and clinical characteristics in these patients varied, depending on the etiology. In 13 patients, the cause remained unexplained despite extensive work-up. In the group of patients who had unknown etiology, a family history for deafness and/or dystonia was present the majority of patients, suggesting a strong genetic component. Sensory-neural deafness always preceded dystonia. Two clinical patterns of deafness-dystonia syndrome were observed: patients who had an onset in childhood had generalized dystonia (10 of 13 patients) with frequent bulbar involvement, whereas patients who had a dystonia onset in adulthood had segmental dystonia (3 of 13 patients) with the invariable presence of laryngeal dystonia. Deafness-dystonia syndrome is etiologically and clinically heterogeneous, and most patients have an unknown cause. The different age at onset and variable family history suggest a heterogeneous genetic background, possibly including currently unidentified genetic conditions.

Muir–Torre syndrome (MTS) is a rare inherited cancer syndrome with variable penetrance. MTS follows an autosomal-dominant pattern of inheritance, and is a subtype of Lynch syndrome [formally known as hereditary non-polyposis colorectal cancer (HNPCC)]. MTS is caused by mutations in one of several mismatch repair genes. Patients typically present with sebaceous neoplasms (sebaceous adenoma, sebaceous epithelioma, or sebaceous carcinoma) or with multiple keratoacanthomas. These patients also have an increased lifetime risk of visceral malignancies, typically affecting the colon, ovary, endometrium, genitourinary tract and small bowel. We describe a case of MTS in a haemodialysis patient and implications for transplant listing.

Admission blood films from 72 patients who died of severe falciparum malaria (50 Thai adults, 22 Gambian children) were matched retrospectively for parasitaemia with equal numbers of survivors. The peripheral blood parasites from fatal cases were more mature than those from survivors. Tiny rings (TR) comprised > 50% of parasites in 47/72 (65%) survivors but only 12/72 (17%) of fatal cases (P < 0.001). Parasites containing visible pigment (MTS: mature trophozoites and schizonts) comprised < 20% of the total parasite count in 10/72 (14%) survivors compared with 31/72 (43%) fatal cases (P < 0.001). Of the 39 patients with > 10(4) MTS/microL, 30 (81%) died. These findings were confirmed in a prospective study of 279 adult Thai patients admitted sequentially with acute falciparum malaria. Only 4 of the 19 fatal cases (21%) had > 50% TR, compared with 130 of 260 (50%) survivors, whereas > 20% MTS were found in 10/19 (53%) fatal cases, compared with 28/108 (27%) severe malaria survivors, and 26/155 (17%) patients with moderately severe malaria (P = 0.001). As a predictor of fatal outcome, the finding of either > 10(4) MTS/microL or > 5 x 10(5) parasites/microL in severe malaria had a sensitivity of 90% (95% confidence interval [CI] = 75-97%) and a specificity of 72% (95% CI = 59-86%). These observations are consistent with the hypothesis that a predominance of mature parasites in the peripheral blood reflects a greater sequestered biomass, and thus more severe disease. Simple microscopical assessment of parasite maturity on an admission blood slide provides important pathophysiological and prognostic information in severe falciparum malaria.

Atypical teratoid rhabdoid tumors (AT/RT) are deadly infantile brain tumors in dire need of new, targeted therapies. Recent molecular analyses revealed considerable tumor heterogeneity subdividing AT/RT into 3 distinct sub-groups - TYR, SHH, and MYC. The MYC subgroup is especially aggressive with a dismal survival. Directly targeting MYC has proven to be challenging, but MYC is known to drive reliance on glutamine for cellular metabolism. We hypothesize that high MYC expressing AT/RT can be targeted with glutamine antagonists to improve survival. 6-diazo-5-oxo L-norleucine (DON) is a glutamine analogue that has been well tolerated in phase I clinical trials in children but never tested against MYC-driven pediatric brain tumors. We find that DON slows cell growth in high MYC expressing AT/RT while it has no effect on low MYC expressing AT/RT cell lines (MTS assay; p< 0.01 DON 10uM compared to DMSO control) or normal neural stem cells. DON also causes G2/M cell cycle arrest in high MYC expressing cell lines (MUSE cell cycle analysis) and induces DNA damage and apoptosis (Western blot for pH2A.X and c-PARP respectively). DON treatment of MYC-expressing AT/RT orthotopic xenografts nearly doubles median survival (p

Patients with X-linked agammaglobulinemia (XLA) can present with sensorineural deafness. This can result from a gross deletion that not only involved the Bruton's tyrosine kinase (BTK) gene, but also TIMM8A, mutations in which underlie the Mohr-Tranebjaerg syndrome (MTS). We analyzed the genomic break points observed in three XLA-MTS patients and compared these with deletions break points from XLA patients. Patient 1 had a 63-kb deletion with break points in intron 15 of BTK and 4 kb upstream of TAF7L. Patients 2 and 3 had 149.7 and 196 kb deletions comprising BTK, TIMM8A, TAF7L and DRP2. The break points in patients 1 and 3 were located in Alu and endogenous retrovirus (ERV) repeats, whereas the break points in patient 2 did not show involvement of transposable elements. Comparison of gross deletion sizes and involvement of transposable elements in XLA and XLA-MTS patients from the literature showed preferential involvement of Alu elements in smaller deletions (< 10 kb). These results show further insights into the molecular mechanisms underlying gross deletions in patients with primary immunodeficiency. Journal of Human Genetics (2011) 56, 577-582; doi:10.1038/jhg.2011.61; published online 14 July 2011

Mutations in GJB2, which encodes Cx26, are one of the most common causes of inherited deafness in humans. More than 100 mutations have been identified scattered throughout the Cx26 protein, most of which cause nonsyndromic sensorineural deafness. In a subset of mutations, deafness is accompanied by hyperkeratotic skin disorders, which are typically severe and sometimes fatal. Many of these syndromic deafness mutations localize to the amino-terminal and first extracellular loop (E1) domains. Here, we examined two such mutations, A40V and G45E, which are positioned near the TM1/E1 boundary and are associated with keratitis ichthyosis deafness (KID) syndrome. Both of these mutants have been reported to form hemichannels that open aberrantly, leading to “leaky” cell membranes. Here, we quantified the Ca2+ sensitivities and examined the biophysical properties of these mutants at macroscopic and single-channel levels. We find that A40V hemichannels show significantly impaired regulation by extracellular Ca2+, increasing the likelihood of aberrant hemichannel opening as previously suggested. However, G45E hemichannels show only modest impairment in regulation by Ca2+ and instead exhibit a substantial increase in permeability to Ca2+. Using cysteine substitution and examination of accessibility to thiol-modifying reagents, we demonstrate that G45, but not A40, is a pore-lining residue. Both mutants function as cell–cell channels. The data suggest that G45E and A40V are hemichannel gain-of-function mutants that produce similar phenotypes, but by different underlying mechanisms. A40V produces leaky hemichannels, whereas G45E provides a route for excessive entry of Ca2+. These aberrant properties, alone or in combination, can severely compromise cell integrity and lead to increased cell death.

The deafness-dystonia syndrome (DDS) or Mohr-Tranebjaerg syndrome (MTS, MIM 304700) is a rare X-linked recessive neurological disorder resulting from loss-of-function mutations in the nuclear DDP1/TIMM8A gene, involved in the transport and sorting of proteins to the mitochondrial inner membrane. A Mohr-Tranebjaerg patient and his mother were subjected to clinical and molecular studies. Screening of mutations were performed in TIMM8A, TIMM13, and other mitochondrial protein transport genes by conformation sensitive gel electrophoresis (CSGE), followed by direct DNA sequencing of tissue samples from the patient. Mitochondrial DNA of the patient was also sequenced at the genes for COX subunits and some mitochondrial tRNAs. Respiratory chain activities in a muscle biopsy and cultured fibroblasts from the patient were assessed using biochemical methods. mRNA expression of TIMM8A and TIMM13 was determined by RT-PCR in cultured fibroblasts. We identified a new case of Mohr-Tranebjaerg syndrome and report the characteristics of a new pathogenic de novo mutation (c.112C>T, pGln38X) in the TIMM8A gene. Biochemical measures of respiratory chain complex activities in muscle biopsy and fibroblasts did not show a major deficiency or alteration. mRNA expression studies demonstrated increased TIMM8A mRNA levels in cultured fibroblasts from the patient. Phenotypic differences among published cases seem not to be related with the mutation location or type. Our results support the idea that dysfunctions of mitochondrial protein transport, in addition to OXPHOS deficiency, can be the basis of important mitochondrial pathologies.

Background: Mohr-Tranebjaerg syndrome (MTS) is an X-linked, recessive, syndromic sensorineural hearing loss (HL) characterized by onset of deafness in childhood followed later in adult life by progressive neural degeneration affecting the brain and optic nerves. MTS is caused by mutations in the DDP/TIMM8A gene, which encodes for a 97 amino acid polypeptide; this polypeptide is a translocase of the inner mitochondrial membrane. Objectives: To describe the otologic presentation and temporal bone histopathology in four affected individuals with MTS. Material and Methods: All four subjects belonged to a large, multigenerational Norwegian family and were known to carry a frame shift mutation in the TIMM8A gene. Temporal bones were removed at autopsy and studied by light microscopy. Cytocochleograms were constructed for hair cells, stria vascularis, and cochlear neuronal cells. Vestibular neurons were also counted. Results: All four subjects developed progressive HL in early childhood, becoming profoundly deaf by the age of 10 years. All four developed language, and at least one subject used amplification in early life. Audiometric evaluation in two subjects showed 80- to 100-dB HL by the age of 10 years. The subjects died between the ages of 49 and 67. The otopathology was strikingly similar in that all bones examined showed near-total loss of cochlear neuronal cells and severe loss of vestibular neurons. When compared with age-matched controls, there was 90% to 95% loss of cochlear neurons and 75% to 85% loss of vestibular neurons. Conclusions: We infer that the HL in MTS is likely to be the result of a postnatal and progressive degeneration of cochlear neurons and that MTS constitutes a true auditory neuropathy. Our findings have implications for clinical diagnosis of patients with MTS and management of the HL.

Mohr-Tranebjaerg syndrome (NITS) is an X-linked disorder characterized by childhood-onset progressive deafness, dystonia, spasticity, mental deterioration, and blindness. It is due to mutations in the deafness/dystonia peptide (DDP1) gene. We describe a sporadic 42-year-old man with MTS presenting with postlingual deafness, adult-onset progressive dystonia with marked arm tremor, mild spasticity of the legs, and visual disturbance due to a novel mutation (g to a transition at the invariant gt of the 5' splice donor site of exon 1) in the DDP1 gene. This case, and a review of previously reported cases, highlights a variety of potential diagnostic pitfalls in this condition. (c) 2007 Movement Disorder Society

Mohr-Tranebjærg syndrome (MTS) is an X-liked recessive rare syndrome also known as deafness-dystonia syndrome. The severity of the symptoms may vary, but they progress usually to severe deafness and dystonia and sometimes they are accompanied by cortical deterioration of vision and mental deterioration. The purpose of this paper is to illustrate a very interesting case of Mohr-Tranebjærg syndrome. A 24-year-old italian man with Mohr-Tranebjærg syndrome underwent full field electroretinography (ERG) and visual evoked potentials (VEPs). Fundus examination showed apparently normal retina with pallor of the optic disc. Pattern reversal VEP and flash VEP responses were non-recordable. ERG showed amplitude reduction of the fotopic, scotopic and 30 Hz flicker responses revealing generalized retinal dysfunction with reduction of cone and rod responses. The progressive neurodegeneration in Mohr-Tranebjærg syndrome can be also associated with a retinal degeneration. A síndrome de Mohr-Tranebjærg é rara, com herança recessiva ligada ao X, conhecida também como síndrome da surdez-distonia. A intensidade dos sintomas pode variar e normalmente, evoluem para uma surdez profunda e a distonia, algumas vezes, vem acompanhados por deterioração visual e mental. O objetivo deste trabalho é ilustrar um caso muito interessante dessa doença. Um homem, italiano, de 24 anos, com a síndrome de Mohr-Tranebjærg, foi submetido ao exame de eletrorretinografia de campo total (ERG) e ao exame de potencial evocado visual (PEV) (padrão e flash). No exame do fundo do olho era presente uma palidez do nervo óptico com retina, aparentemente, sem alterações. No exame do eletrorretinografia de campo total ERG detectou-se redução das amplitudes das respostas fotópicas, escotópicas e ao flicker de 30 Hz, demonstrando uma disfunção generalizada da retina, com redução da função dos cones e bastonetes. A progressiva neurodegeneração da síndrome de Mohr-Tranebjærg pode ser também associada à degeneração da retina.

Mohr-Tranebjærg syndrome (MTS) is an X-liked recessive rare syndrome also known as deafness-dystonia syndrome. The severity of the symptoms may vary, but they progress usually to severe deafness and dystonia and sometimes they are accompanied by cortical deterioration of vision and mental deterioration. The purpose of this paper is to illustrate a very interesting case of Mohr-Tranebjærg syndrome. A 24-year-old italian man with Mohr-Tranebjærg syndrome underwent full field electroretinography (ERG) and visual evoked potentials (VEPs). Fundus examination showed apparently normal retina with pallor of the optic disc. Pattern reversal VEP and flash VEP responses were non-recordable. ERG showed amplitude reduction of the fotopic, scotopic and 30 Hz flicker responses revealing generalized retinal dysfunction with reduction of cone and rod responses. The progressive neurodegeneration in Mohr-Tranebjærg syndrome can be also associated with a retinal degeneration.