Mohr-Tranebjærg Syndrome (Deafness-Dystonia-Optic Neuronopathy)

X-linked recessive neurodegenerative disorder caused by loss of function of TIMM8A, a small chaperone of the mitochondrial intermembrane space; deafness due to auditory neuropathy in early childhood, followed by dystonia, visual loss from optic and cortical neuronopathy, and cognitive and psychiatric decline; contiguous gene form with X-linked agammaglobulinaemia (XLA-MTS) due to a deletion that includes BTK.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. From «non-syndromic» X-linked deafness to a neurodegenerative disease

In 1960, Mohr and Mageroy described in a large Norwegian family a childhood-onset sensorineural deafness transmitted in an X-linked recessive manner, which they interpreted as isolated; the entity was indexed in McKusick's catalogue under number 304700 and named DFN-1, as the first form of X-linked deafness considered non-syndromic [1, 21]. Thirty-five years later, Tranebjærg and colleagues restudied the same family, updated the pedigree and characterised 16 affected males in five generations; they showed that the deafness, postlingual and progressive, was the first manifestation of a progressive syndrome that included visual impairment progressing to cortical blindness, dystonia, fractures and mental deficiency, and that some obligate carriers had signs of mild neuropathy and mild deafness [22]. In the original description, initial hearing had allowed normal speech development, and hearing loss became evident between 3 and 5 years of age; the first inferred carrier lived in a fishing village on an island in northern Norway [4]. A first linkage analysis, in 1992, gave a maximum lod score of 3.96 with marker DXS17, at Xq22, close to COL4A5, the gene for X-linked Alport syndrome; the family had no kidney disease and there was one recombinant with COL4A5 [4]. In 1995, linkage analysis placed the gene at Xq22, next to marker DXS101, with a lod score of 5.37 without recombination; the proteolipid protein gene (PLP1), located in the same region, was then proposed as a candidate and later excluded [5, 22]. The entity came to be called Mohr-Tranebjærg syndrome and, later, deafness-dystonia-optic neuronopathy syndrome, the name adopted by GeneReviews [1].

1.2. Identification of the gene and recognition as a mitochondrial disease

In 1996, Jin and colleagues started from a patient with a 21 kb deletion at Xq22, sensorineural deafness and dystonia to identify a new transcript within the deletion; they found small deletions in this gene in the original Norwegian family and in a second family with deafness, dystonia and mental deficiency without blindness, and named it DDP (deafness/dystonia peptide), reporting high expression in fetal and adult brain [23]. According to the review by Ventura and colleagues, the same work described the first case of a contiguous deletion that also included BTK, linking the syndrome to X-linked agammaglobulinaemia [5]. In 1999, Koehler and colleagues showed that the DDP protein is mitochondrial and belongs to the family of small Tim proteins of the intermembrane space described in yeast (Tim8p, Tim9p, Tim10p, Tim12p and Tim13p), being most similar to Tim8p, which forms a soluble 70 kDa complex with Tim13p and Tim9p; they therefore proposed that deafness-dystonia syndrome is a mitochondrial disease caused by a defect in the protein import system [24]. The gene later received the official name TIMM8A [7].

1.3. Entities grouped under the same name

Several independent clinical descriptions turned out to be the same disease. The opticoacoustic atrophy with dementia described by Jensen in 1981 and 1987, with central nervous system calcifications documented in 1988 (Jensen syndrome), and the familial syndrome of dystonia and neural deafness described by Scribanu and Kennedy in 1976 and by Hayes and colleagues in 1998 have TIMM8A variants and correspond to Mohr-Tranebjærg syndrome [1, 25, 26]. In the Jensen family, the nonsense variant E24X was identified in 1997, later also found in a nephew of the patient [5, 9]; it corresponds to NM_004085.4:c.70G>T p.(Glu24Ter) on the current reference transcript [8, 27]. For historical reasons, Orphanet keeps a separate entry for Jensen syndrome (ORPHA:3213) without its own definition, whereas OMIM groups all these descriptions under entry 304700 [1, 3]. The 2026 systematic review also notes that cases with variants in PLP1, MT-ND4, MT-ND6 or DNAJC19 were historically included in the spectrum of the syndrome and correspond to distinct entities [5].

OMIM groups other historical families under entry 304700 [4]. In the family described by Scribanu and Kennedy in 1976, two and possibly three males from three generations, linked through probable carriers, had dystonia and deafness: in the proband, deafness was recognised at 2 years and was progressive; at 8 years he had severe dysarthria, marked deterioration of handwriting, occasional abnormal head and neck postures and hyperactivity, and he died at 11 years; the maternal uncle became deaf at 6 years, stopped walking and speaking after 18 because of progressive dystonia and died at 20; a nephew had sensorineural deafness at 6 years without clear motor abnormality; neuropathology showed mainly neuronal loss and gliosis in the basal ganglia [4]. OMIM also includes a 1975 family (Pelletier and Tanguay) with eight males from four generations who became deaf in adolescence, without molecular confirmation in the sources consulted [4]. In the Jensen family, a 3-year-old boy and two maternal uncles aged 33 and 41 had profound sensorineural deafness from early childhood, progressive optic atrophy with visual loss from adolescence and progressive dementia in adulthood; both uncles died at around 40 years in general deterioration, and the autopsy of one of them showed extensive calcifications in all structures of the central nervous system, including meninges, vessels and neurons, interpreted as secondary to degeneration, and moderate diffuse atrophy of skeletal muscles [4, 25]. The nephew, re-evaluated at 21 years, had moderate cortical atrophy on computed tomography (CT) at 9 years, dysphagia and moderate ataxic gait at 19, no dystonia and mild dementia; positron emission tomography (PET) showed low uptake in the parietal and temporal lobes, especially in the medial and frontal regions of the temporal lobes, a pattern similar to that of Alzheimer disease; the optic discs were normal and there were no visual complaints, despite progressive changes in visual evoked potentials [4, 28]. On the basis of this comparison, Tranebjærg and colleagues considered the optic atrophy of the uncles to be the end-stage expression of a diffuse neuropathy and proposed, in 2001, merging Jensen syndrome and Mohr-Tranebjærg syndrome into a single deafness-dystonia-optic neuronopathy syndrome [4, 28]. The Australian family of Anglo-Saxon ancestry described by Hayes and colleagues in 1998 included two pairs of maternal half-brothers [4, 26]. In the Japanese family of 2001, the first non-Caucasian one, five males from four generations had early-onset deafness followed by dystonia with onset between 15 and 30 years; two had mild mental deterioration and none had visual impairment [4, 29].

1.4. Definition of the entities in this article

In the absence of formal diagnostic criteria, Mohr-Tranebjærg syndrome is defined by the presence of a pathogenic or likely pathogenic TIMM8A variant in the hemizygous state in a male (or in the heterozygous state in a symptomatic female), or of an Xq22.1 deletion that includes TIMM8A, in an individual with a compatible picture [1]. Two genetic forms are distinguished. In the classic form, the alteration is restricted to TIMM8A (point variant, small insertion or deletion, splicing alteration or deletion of one or both exons). In the contiguous gene form, called XLA-MTS in the recent literature, the deletion extends to BTK, located less than 1 kb away, and sometimes to TAF7L and DRP2; these patients have the neurological syndrome and, in addition, X-linked agammaglobulinaemia (XLA) [1, 5, 6]. Isolated XLA, non-syndromic deafness, Wolfram syndrome, Friedreich ataxia, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), Usher syndrome, dopa-responsive dystonias and X-linked dystonia-parkinsonism enter the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The TIMM8A gene and the TIMM8a protein

TIMM8A is located at Xq22.1, has only two exons and encodes a 97-amino-acid protein, TIMM8a (formerly DDP1, deafness-dystonia protein 1), resident in the mitochondrial intermembrane space [1, 7]. The MANE Select transcript is NM_004085.4, which encodes NP_004076.1 [8]; OMIM places the gene at X:101,345,661–101,348,742 (GRCh38), with an intron of about 2 kb, a protein of about 11 kDa and ubiquitous expression, highest in fetal and adult brain [9]. The first exon begins 770 bp downstream of the BTK polyadenylation signal; the gene had been identified in 1993 as DXS1274E, the 3' end of a BTK deletion, and was renamed DDP in 1996 [9]. There is a processed pseudogene, TIMM8AP1, with enough sequence differences for interference in TIMM8A analysis to be unlikely [1]. The protein contains a «twin CX3C» motif with four conserved cysteines that binds zinc and forms the zinc-finger domain of the Tim10/DDP family [30–32]. TIMM8a associates with TIMM13, encoded at 19p13.3 [33], in a 70 kDa hetero-hexameric complex (3:3 stoichiometry) in the intermembrane space, which protects hydrophobic precursors of inner membrane proteins from aggregation and guides them from the TOM complex of the outer membrane [7, 30, 34]. Humans have six small TIM proteins (hTim8a, hTim8b, hTim9, hTim10a, hTim10b and hTim13), and hTim8a is expressed mainly in the brain [35]. TIMM8a and TIMM13 are co-expressed at high levels in cerebellar Purkinje cells and not in glial cells [1].

2.2. Disease mechanism

The mechanism is loss of function [1, 31]. The first pathogenic hypothesis derived from yeast, where the Tim8–Tim13 complex is required for the import of Tim23, a subunit of the TIM23 translocase of the inner membrane; human TIMM8a and TIMM13 restore Tim23p import in yeast mitochondria lacking their own complex and bind to the hTim23 import intermediate, which led to the proposal that the disease results from insufficient levels of Tim23 in the inner membrane of affected tissues [30, 36, 37]. The missense variant C66W, which affects one of the cysteines of the zinc-binding motif, gives rise to a protein that is imported into the intermembrane space but misfolded, unable to form the 70 kDa complex with hTim13 and to complement yeast Tim8; in fibroblasts from the patient with this variant TIMM8a is undetectable [30, 31]. The calcium-dependent aspartate and glutamate carriers citrin (SLC25A13) and aralar1 (SLC25A12), components of the malate-aspartate shuttle, were identified as substrates of the complex; co-expression of aralar1, TIMM8A and TIMM13 in cerebellar neurons, NADH depletion and defective hTim23 biogenesis were proposed as the basis of selective neuronal vulnerability [1, 5, 38]. In lymphoblasts from a patient with p.Gln34Ter, reduced ATP production attributed to aspartate/glutamate carrier dysfunction was observed [39].

Later studies in human cells and in mice qualified this model. In CRISPR-edited HEK293 and SH-SY5Y neuroblastoma cells, loss of hTim8a did not alter the TIM22 complex, the TIM23 complex or carrier biogenesis, and hTim23 import was normal; instead, hTim8a proved necessary for the assembly of complex IV (cytochrome c oxidase) in neuronal-type cells, through transient interaction with assembly factors, especially the copper chaperone COX17 [35]. The complex IV deficiency was associated with oxidative stress and changes in cytochrome c and other apoptosis regulators, with predisposition to intrinsic cell death, reversed in vitro by vitamin E [35]. In a mouse model with the Timm8a1 p.I23fs49X variant, import of Tim23 and Tom40 and the biogenesis of oxidative phosphorylation proteins and manganese superoxide dismutase were preserved, but there was abnormal mitochondrial structure in several brain regions, lower weight gain, hearing impairment and memory impairment [40]. In homozygous females of the same model, hearing impairment, anxiety-like behaviour, cognitive and coordination deficits, smaller hippocampal mitochondria with an increase in the fission protein Mtfp1/Mtp18 and reduced fertility were recorded [41]. In neurons derived from induced pluripotent stem cells (iPSC) from a patient with c.225_229del and from an edited isogenic control, neuronal differentiation was deficient (smaller somata, fewer branches, shorter neurites), with reduced complex IV and ATP synthesis, increased reactive oxygen species, mitochondrial fragmentation and greater susceptibility to apoptosis; the protein CHCHD2, also from the intermembrane space, was decreased, and its overexpression reversed the mitochondrial dysfunction and promoted neurite elongation [39]. Changes in the amount of DDP1 also modify mitochondrial morphology: patient fibroblasts and HeLa cells with reduced DDP1 have elongated mitochondrial tubules, and overexpression reduces the import of β-barrel proteins, an effect absent with the C66W variant [42, 43].

The defect does not translate into an enzyme deficiency measurable on routine testing: muscle biopsy shows normal activity of the energy-producing systems, with no structural abnormalities or mitochondrial aggregates, and mild neurogenic atrophy on electron microscopy; only a mild complex IV deficiency has been described in the muscle of one patient with p.Gln38Ter, with normal fibroblasts [1, 44, 45]. In 1999, Wallace and Murdock interpreted the import defect as a defect of oxidative phosphorylation (OXPHOS) due to deficiency of inner membrane carrier proteins, which would bring the disease closer to the phenotypes of mitochondrial DNA variants with deafness and dystonia due to basal ganglia degeneration; the biochemical findings described do not consistently demonstrate this defect [1, 4]. In Saudubray, TIMM8A is listed among the mitochondrial protein import defects that can cause combined oxidative phosphorylation deficiency, alongside GFER, PAM16, PMPCA, TIMM22, TIMM50, TOMM70 and XPNPEP3 (autosomal recessive) and AIFM1 (X-linked) [46].

2.3. Tissue basis: neuronopathy

The word «neuronopathy» denotes destruction of neuronal cell bodies and is distinct from «neuropathy», which refers to a functional disturbance of the peripheral nervous system [1]. Neuropathological studies document global cerebral atrophy and gliosis, microcalcifications and neuronal death in the spiral ganglion cells of the cochlea, in Scarpa's ganglion, in the retinal ganglion cell layer, in the optic nerves and in the calcarine fissures (visual cortex), as well as focal neuronal loss in the striatum with astrocytosis and moderate frontal cortical atrophy [1, 28, 39]. The spinal cord is atrophic, with fibre loss in the dorsal roots and posterior columns, as in Friedreich ataxia [1]. In a man who lost his hearing at 4 years, his vision at 48 and developed dystonia at 57, the temporal bone studied after death, at 66 years, had only 1765 spiral ganglion cells (8.5% of the normal value for age), with preserved organ of Corti, hair cells, stria vascularis and spiral ligament, and severe loss of Scarpa's ganglion cells with intact vestibular hair cells [47]. In four members of the Norwegian family, who died between 49 and 67 years of age, loss of cochlear neurons was 90–95% and of vestibular neurons 75–85% compared with age-matched controls, which defines a postsynaptic auditory neuropathy due to postnatal, progressive neuronal degeneration [48].

2.4. Inheritance and expression in females

Transmission is X-linked recessive [1]. Hemizygous males develop the disease; the 2026 systematic review found no males carrying a pathogenic variant who did not manifest it at some point, although some, identified through severely affected relatives, had no detectable neurological dysfunction at 30–39 years [1, 5]. Heterozygous females are mostly asymptomatic or have mild deafness and focal dystonia, such as writer's cramp or torticollis [1, 12]. In carriers from a Norwegian family, X-inactivation patterns in leucocytes ranged from 50:50 to more than 95:5, with incomplete penetrance of the skewing; the responsible locus was mapped to Xq12-q22, a region that includes DDP and XIST, and data from several families indicate partial selection against cells with the mutated allele on the active X [49]. Skewed inactivation is the presumed explanation for manifestations in carriers, but it has not been measured in the families with the most severely affected heterozygotes [1]. Female probands and a woman with multiple disabling neurological complications have been described [1, 13], and the mother of an Italian patient with XLA-MTS, with skewed X inactivation, had dystonia [6].

2.5. Variant spectrum

The variants described include nonsense, frameshift, splicing and missense variants, small insertions and deletions, and partial or whole-gene deletions; contiguous deletions involving TIMM8A are an important fraction [5, 6]. In 2026, 39 published causal variants were counted, five of them splicing variants [32]. Table 2.1 presents, in Human Genome Variation Society (HGVS) nomenclature, the variants cited in this article normalised in VariantValidator on the MANE transcript and their ClinVar classification at the date of consultation; historical designations are kept alongside, and were only converted when OMIM points to a ClinVar record with the current description.

Table 2.1. TIMM8A variants described in the sources consulted (NM_004085.4; VariantValidator and ClinVar, 31 October 2026; historical OMIM designations were matched to ClinVar variants through the RCV identifiers cited in OMIM)

In ClinVar, among 91 records limited to TIMM8A, the following are also listed as pathogenic or likely pathogenic: c.28del, c.58C>T p.(Gln20Ter), c.66_67del, c.127T>C p.(Cys43Arg) (likely pathogenic, several submitters), c.132G>A p.(Trp44Ter), c.133-1G>A, c.133-1G>T, c.153_223dup, c.181del, c.217dup and c.223C>T p.(Gln75Ter), in addition to whole-gene deletions and several missense variants of uncertain significance [27]. Missense variants generally remain classified as of uncertain significance owing to the lack of functional evidence, unlike loss-of-function variants, which meet the PVS1 criterion [5]. Identification of a variant of uncertain significance in the hemizygous or heterozygous state neither establishes nor excludes the diagnosis [1]; transcript analysis from peripheral blood RNA made it possible to demonstrate, for c.132+5G>A, the absence of normal transcript and the loss of part of the zinc-finger domain in all aberrant transcripts [32].

2.6. Contiguous Xq22.1 deletions

BTK lies less than 1 kb downstream of TIMM8A; the region contains, in order, DRP2 and TAF7L (transcribed in the 5'→3' direction) and TIMM8A and BTK (transcribed in the opposite direction) [5, 6]. Gross deletions account for 7–8% of BTK variants in the Leiden Open Variation Database (LOVD), and some of them include TIMM8A [57]. In GeneReviews, about half of affected males and females have a contiguous Xq22.1 deletion involving TIMM8A, and most deletions not detectable by sequencing are large and include BTK [1]. In the contiguous deletions with BTK characterised in the sources consulted, sizes range from about 16 kb to 196 kb [52, 58, 59]. In deletions smaller than 10 kb, breakpoints preferentially involve Alu elements; in larger ones, endogenous retroviruses or absence of transposable elements are also found [58]. Nucleotide-level characterisation of four deletions by mate-pair library sequencing showed deletions of 63.5 kb (with breakpoints in Alu), 39.9 kb (with an inverted 59 bp insertion and at least four breakpoints), 27.2 kb and 2.1 kb (the latter limited to TIMM8A exon 2), with microhomologies of 2 to 38 nucleotides compatible with homologous recombination in the larger ones [6]. A single intragenic deletion of exon 2 was described in GeneReviews, since characterised at nucleotide level [1, 6]. Severity did not correlate with deletion size in a series of six boys from four families [59]. Regarding the contribution of neighbouring genes, the 2026 systematic review proposes that loss of DRP2 and TAF7L modifies the phenotype, a hypothesis without experimental demonstration [5].

2.7. Genotype–phenotype correlations, penetrance and allelic disorders

The limited number of patients, the variable course and the private nature of the variants prevented the detection of genotype–phenotype correlations until 2019, and the neurological phenotype of contiguous deletions was described as indistinguishable from that of point variants, apart from XLA [1]. The three 1996 families already showed overlapping but not identical phenotypes: the picture was more severe in the original Norwegian family, with mental deterioration and blindness in almost all affected individuals, and milder in the family with the 21 kb deletion, limited to deafness and dystonia; however, no male in this family had passed the age of 9 years, because of the morbidity of XLA, and mental deterioration and blindness usually appear later, so the difference reflects age and not a more benign genotype [4, 23]. The 2026 systematic review, with 75 published patients, found differences in frequency between the classic form and XLA-MTS that are presented in section 3 and that the authors themselves consider subject to publication bias and to bias from age at diagnosis [5]. Within each family there is relative homogeneity, with variation between families [13], although there are exceptions: in the Spanish family with c.133-23A>C, one patient presented at 4 years with complete deafness, severe generalised dystonia and visual loss, and the other at 11 years with mild deafness, mild focal dystonia and behavioural changes [9, 53]. The authors of the Japanese family with p.(Arg80Ter), whose truncated protein has 79 amino acids, suggested that the milder and more slowly progressive picture might be related to the late truncation, and Pizzuti and colleagues suggested that complete absence of the protein might be less harmful than truncated peptides; neither hypothesis has been confirmed [9, 29, 60]. Expressivity is highly variable: there are patients with isolated auditory neuropathy in childhood, who may or may not develop the remaining signs, and a Spanish boy with progressive dystonia and iron deposits in the globus pallidus without deafness [34, 52]. GeneReviews does not recognise other allelic phenotypes of TIMM8A and records that isolated deafness had not been described without other manifestations [1]; the patients with isolated auditory neuropathy in the Chinese series were 7 years old or younger at the time of the study, which does not allow conclusions about their course [52]. Overexpression of TIMM8A has been studied as a prognostic factor in cancers, unrelated to the hereditary disease [34].

3. Clinical Spectrum and Manifestations by System

3.1. Overview and temporal sequence

Mohr-Tranebjærg syndrome is a progressive neurodegenerative disease whose initial manifestation is, in the vast majority of patients, a prelingual or postlingual sensorineural deafness of early childhood [1]. This is typically followed by slowly progressive dystonia or ataxia in adolescence, a slowly progressive decrease in visual acuity from 20 years of age and dementia from 40 years; psychiatric manifestations, such as personality change and paranoia, may appear in childhood and progress [1]. Deafness is more constant in age at onset and progression than the neurological, visual and neuropsychiatric manifestations, which vary in severity and pace [1]. In late adulthood, the combination of deafness and severe visual impairment profoundly compromises communication [1]. Table 3.1 summarises the chronology described in GeneReviews and in published series, and Table 3.2 the frequencies from the 2026 systematic review.

Table 3.1. Typical chronology in males (natural history)

3.2. Hearing

The mean age at onset of deafness is about 18 months; some patients have apparently congenital prelingual deafness [1]. Deafness progresses quickly and is usually profound before 10 years; in the Norwegian family, the four patients studied after death developed language before becoming deaf, at least one used amplification at first, and the audiometry of two showed losses of 80–100 dB at 10 years [1, 48]. This is a postsynaptic auditory neuropathy: otoacoustic emissions (OAE) and cochlear microphonics are present, at least in the early stages, whereas auditory brainstem responses (ABR) are absent or markedly abnormal and the stapedial reflex is absent [1, 52]. In a 7-year-old Chinese boy with deafness since the age of 3, OAE were normal, ABR were absent bilaterally with cochlear microphonics present, speech recognition was 16% and 12%, and magnetic resonance imaging (MRI) showed symmetrically small cochlear nerves [52]. Vestibular function is clinically normal, despite the loss of vestibular neurons; in the same patient, vestibular evoked myogenic potentials were normal and caloric testing showed reduced function of the horizontal semicircular canal [1, 48, 52]. Because outer hair cells are preserved, OAE-based newborn hearing screening may be normal in children who go on to develop deafness, as happened in three boys from a Portuguese family [50]. In XLA-MTS, speech delay and deafness are often initially attributed to recurrent otitis [6, 61].

3.3. Movement and the motor system

The first neurological sign may be gegenhalten, a diffuse resistance to passive movement of a limb [1]. The movement disorder manifests as dystonia or as ataxia, with onset from childhood to much later ages; it is progressive, gait becomes unsteady, tendon reflexes are brisk, with ankle clonus and Babinski sign, and patients come to use a cane and then a wheelchair, with dystonic contractures [1]. Analysis of six patients from three Australian families and from the literature showed that profound deafness always precedes dystonia, that dystonia begins from the first to the sixth decade with a peak in the second and third, that onset is focal, segmental or multifocal with a predilection for the upper body (head, neck and upper limbs), and that most progress or generalise regardless of age at onset; the median time to disabling moderate to severe dystonia was 11 years [13]. In the series of 20 patients with deafness-dystonia syndrome seen between 1994 and 2011, deafness always preceded dystonia; childhood onset was associated with generalised dystonia with frequent bulbar involvement and adult onset with segmental dystonia with laryngeal dystonia [62]. The phenotypes described include blepharospasm and limb dystonia with marked arm tremor in a 42-year-old man, tongue protrusion and bilateral hand tremor in a 28-year-old man, and dystonia with onset at 12 years (foot dragging, equinovarus, writer's cramp) that became severe and generalised at 17 [16, 54, 63]. Pyramidal signs and spasticity may dominate the picture, and freezing of gait and postural instability have been described [13, 50]. Some males identified through severely affected relatives had no detectable neurological dysfunction at 30–39 years [1]. There may be mild peripheral sensory neuropathy, and spinal cord dysfunction with prolonged somatosensory evoked potentials and abnormal central motor conduction to the lower limbs has been described [1, 44]. Seizures are not characteristic; one patient from the Portuguese family had generalised epilepsy from 10 years, interpreted by the authors as possibly concomitant [1, 50].

3.4. Vision

Optic neuronopathy may remain subclinical for many years and be detected only by prolonged P100 wave latency on visual evoked potentials (VEP) [1]. In childhood, colour vision and visual fields are normal; in late adolescence, photophobia, decreased visual acuity, acquired dyschromatopsia and central scotomas appear [1]. The optic nerves look normal in children and become pale in adults; the retina, night vision and electroretinogram are usually normal [1, 64]. The decline leads to legal blindness at around 30–40 years [1]. Visual loss results mainly from degeneration of the visual cortex, with a contribution from the retina and optic nerve, as shown by PET and MRI of a patient with marked occipital atrophy [28, 44]. The patients with isolated auditory neuropathy in the Chinese series and the four Portuguese patients had no visual impairment at the ages at which they were studied [50, 52], and the Japanese family described in 2001 had no visual disturbances [29].

3.5. Cognition, behaviour and psychiatry

From childhood there may be mild intellectual disability, personality changes, restlessness, anxiety, reduced impulse control, aggressive outbursts and poor concentration [1]. Later, paranoid symptoms may appear, such as fear of poisoned food, imaginary skin sensations and imaginary foreign bodies in the eyes leading to self-injury, and dementia gradually sets in [1]. In the Portuguese family, all four patients had developmental delay with speech or language disorder and behavioural problems; the index case had severe behavioural changes and progressive cognitive decline from late adolescence, with psychiatric admissions [50]. An Australian patient with XLA-MTS was diagnosed at 16 years with level 3 autism spectrum disorder, attention deficit and dysgraphia, with socio-emotional regression [6]. Behaviours may resemble those of autism without being autism, and may be aggravated by sensory processing difficulties [1].

3.6. Other manifestations

Dysphagia appears late and frequently causes aspiration pneumonia [1]. Male fertility is normal [1]. Hip fractures are frequent in males and are attributed to poor neuromuscular coordination and falls, not to changes in calcium metabolism or intrinsic bone disease [1, 22]. There is no cardiomyopathy, and respiratory capacity only decreases as a consequence of aspiration pneumonia [1]. Worsening during systemic illnesses has been described: the Portuguese index case was left with permanent neurological deficits (dysarthria, dysphagia requiring temporary gastrostomy, spasticity) after a prolonged encephalopathy with hospital-acquired pneumonia at 27 years, and deteriorated with each systemic illness [50].

3.7. Neuroimaging and neurophysiology

Computed tomography (CT), MRI or positron emission tomography (PET) show global cerebral atrophy in most males from 40 years, sometimes earlier [1]. PET and MRI show hypometabolic areas mainly in the right striatum and parietal cortex and marked atrophy of the occipital lobes [1, 44]. MRI may be normal in young adults, as in the Portuguese index case at 27–31 years [50]. A pattern suggestive of leukodystrophy on MRI and spectroscopy in a Polish boy with XLA-MTS and bilateral globus pallidus hypointensities due to iron deposition in a Spanish adolescent without deafness have also been described [34, 57]. CT of the inner ear is normal [1]. Muscle biopsy and respiratory chain enzymology are normal or nearly normal and have no diagnostic value [1, 7].

3.8. Heterozygous females

The older women of the original family possibly had mild involvement, and carriers identified through families with affected males may have mild deafness and focal dystonia, including writer's cramp and torticollis [1, 12, 22]. In 2012, a woman with multiple disabling neurological complications was described, and there are published female probands [1, 13]. The mother of a Spanish boy with dystonia, a heterozygous carrier, had episodic muscle spasms and finger stiffness [34]. In the Chinese family studied in 2019, the carrier mother had normal ABR and OAE [52].

3.9. Classic MTS and XLA-MTS

The systematic review by Ventura and colleagues included 47 studies published between February 1995 and May 2025 with 75 molecularly confirmed patients: 51 with an alteration restricted to TIMM8A (45 with point variants and 3 with intragenic deletions) and 24 with contiguous deletions of TIMM8A and BTK [5]. Patients with XLA-MTS had agammaglobulinaemia in all cases, a lower frequency of neurodegenerative signs and a higher frequency of language delay (Table 3.2) [5]. The review is based on case reports, with bias towards severe phenotypes and heterogeneity of methods, and the XLA-MTS group is small; the article presents discordant values between the abstract, the table and the discussion for language delay (52.4%, 54.2% and 9.6% in one or the other group) and for cortical blindness (12.3% and 12.5%) [5]. The comparison was not adjusted for age at observation; since XLA usually leads to diagnosis in childhood, part of the difference in late manifestations may reflect follow-up time, a possibility that the review did not analyse; the authors propose a modifying effect of the neighbouring genes [5]. A 24-year-old Italian man with complete deletion of TIMM8A and partial deletion of BTK, diagnosed at 2 years with agammaglobulinaemia and bilateral deafness, developed progressive visual loss at 15 years and progressive difficulty writing due to task-specific focal dystonia at 19, with mild cognitive impairment [9, 60]. In the series of four deletions characterised in 2022, two boys with XLA-MTS aged 16 and 21 years had neither dystonia nor visual impairment, one had bronchiectasis at 21 years, and a third, Italian, had severe deafness from 2 years, markedly reduced visual acuity and late-onset dystonia [6].

Table 3.2. Frequency of manifestations in classic MTS and XLA-MTS (systematic review of 75 patients published between 1995 and 2025)

Source: [5]. Frequencies from published reports, with publication bias and without adjustment for age at observation; they are not estimates of lifetime risk.

3.10. Immunological manifestations in XLA-MTS

In the contiguous form, XLA dominates the first years. A Polish boy had skin abscesses at 5 months, generalised skin infection with fever and neutropenia (600 cells/µL) at 6 months and pneumonia at 7 months; he had IgG of 0.09 g/L, IgA <0.06 g/L, IgM <0.04 g/L and absent B lymphocytes, and neurological signs appeared in the third year of life with loss of speech [57]. In a boy described in 2008, the deletion was only identified after cochlear implantation at 4 years, in a child initially diagnosed with XLA because of recurrent infections [65].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

In infants and young children, suspicion arises from sensorineural deafness with an auditory neuropathy pattern, that is, OAE present or recordable cochlear microphonics with absent or markedly abnormal ABR and absent stapedial reflex, with normal inner ear CT [1, 52]. In a child with deafness and no other findings, GeneReviews considers that suspicion of DDON should be strong when the auditory phenotype is auditory neuropathy [1]. Suspicion is reinforced in a boy with a family history compatible with X-linked transmission (maternal uncles, maternal cousins or brothers with deafness) and when the most frequent genetic causes of prelingual deafness, such as DFNB1 or Pendred syndrome, have been excluded [1]. Physiological OAE-based newborn hearing screening may be normal in these children, and later-onset deafness may go unnoticed until there is language delay or behavioural problems: in the Portuguese family, the 70 dB deafness of the oldest nephew was only diagnosed at 9 years, after follow-up for language delay since the age of 4 [14, 50].

In adolescence and adulthood, the combination of early-childhood deafness with focal or segmental dystonia of the neck, face or upper limbs, with pyramidal signs or ataxia, suggests the diagnosis; sensorineural deafness always precedes dystonia in deafness-dystonia series [13, 62]. Visual loss with photophobia, dyschromatopsia and central scotomas, with normal fundus or optic pallor and normal electroretinogram, points to optic neuronopathy and not to retinal dystrophy [1]. Cognitive decline, paranoid psychosis and early dementia in a man deaf since childhood should also prompt consideration of the syndrome [1, 50]. In a woman with focal dystonia and a family history of male deafness, a TIMM8A variant should be sought [12].

4.2. Warning signs for the contiguous gene form

The presence of immunodeficiency and deafness in a boy should raise the hypothesis of a contiguous Xq22 deletion involving TIMM8A and BTK [1]. The rule applies in both directions: a boy with XLA and sensorineural deafness, speech delay not explained by otitis or behavioural changes should be investigated for Mohr-Tranebjærg syndrome, and a boy with DDON should have immunoglobulin levels and a B lymphocyte count measured, because XLA is treatable and potentially fatal if not recognised [7, 61, 65].

4.3. Situations requiring urgent assessment

GeneReviews does not define disease-specific emergencies. The sources describe as risk situations aspiration pneumonia in patients with dysphagia, severe bacterial infections in patients with XLA-MTS and neurological worsening during systemic illnesses, such as the prolonged encephalopathy with hospital-acquired pneumonia that left permanent deficits in the Portuguese index case [1, 50, 57]. Rapidly worsening dystonia, with a risk of status dystonicus, was the reason for deep brain stimulation in 17-year-old patients [54, 66]. The Mitochondrial Medicine Society consensus for primary mitochondrial disease recommends that the sudden appearance of a new movement or tone disorder should lead to investigation of disease worsening and secondary causes, with neuroimaging, electrophysiological studies and baseline laboratory tests [67]; applying this consensus to Mohr-Tranebjærg syndrome is an extrapolation, because the disease does not have a consistent oxidative phosphorylation defect.

4.4. Newborn screening

There is no specific newborn screening. OAE-based newborn hearing screening may fail to detect auditory neuropathy, and the 2022 American College of Medical Genetics and Genomics (ACMG) document points to this limitation, together with late-onset deafness, as an argument for integrating genetic and congenital cytomegalovirus screening into newborn hearing screening in the future [14]. In programmes that include quantification of kappa-deleting recombination excision circles (KREC) for detection of agammaglobulinaemias, a child with XLA-MTS may be identified through the immunological route.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal diagnostic criteria [1]. The diagnosis is established in a proband with a suggestive picture and, in a male, a pathogenic or likely pathogenic TIMM8A variant in the hemizygous state, in a female, the same variant in the heterozygous state, or, in either sex, a contiguous Xq22.1 deletion that includes TIMM8A [1]. The findings that GeneReviews considers suggestive in a male are: prelingual or postlingual progressive sensorineural deafness with absent stapedial reflex, abnormal ABR and normal OAE; normal inner ear CT; movement disorder (dystonia or ataxia); personality changes, paranoia and dementia of gradual onset; gradual decrease in visual acuity with optic atrophy; dysphagia of gradual onset; and a family history compatible with X-linked transmission [1].

5.2. Non-genetic investigations

No non-genetic test is confirmatory [7]. Audiological assessment is central: pure-tone and speech audiometry, tympanometry with stapedial reflex testing, OAE, cochlear microphonics and ABR; the combination of present OAE, absent ABR and absent stapedial reflex with normal inner ear CT strongly suggests the disease in a boy [1, 7, 52]. MRI may show small cochlear nerves and should include the vestibular and facial nerves in the cochlear implant work-up [1, 52]. Ophthalmological assessment includes visual acuity, colour vision, visual fields for central scotomas and VEP; a normal electroretinogram distinguishes the disease from the retinal dystrophies of Usher syndrome [1, 7]. The Mitochondrial Medicine Society consensus recommends, for patients with mitochondrial disease, neuro-ophthalmological examination at diagnosis with optical coherence tomography (OCT) and electroretinogram [67]. Neurological examination, neuropsychological and neuropsychiatric assessment and neuroimaging complete the work-up [1]. First-line metabolic tests for mitochondrial diseases (lactate, organic acids, plasma amino acids) and MR spectroscopy are part of the Saudubray algorithm for movement disorders with mitochondrial import defects, but muscle biopsy and respiratory chain enzymology are normal or nearly normal in this disease [1, 68]. In a boy with DDON, measurement of IgG, IgA and IgM and CD19+ B lymphocyte flow cytometry are mandatory to identify XLA-MTS [7].

5.3. Genetic tests and their limitations

GeneReviews proposes two pathways. In a child with deafness and a family history suggestive of XLA, the first test should be chromosomal microarray (CMA), which detects the large deletions that include TIMM8A and BTK and that sequencing does not detect; in a young child with deafness and no other findings, especially with auditory neuropathy, a multigene deafness or auditory neuropathy panel that includes TIMM8A and deletion and duplication analysis should be used [1]. The 2022 ACMG guidance for hearing loss recommends, when there are syndromic signs, pre-test counselling and targeted testing (single gene, panel, exome, genome, karyotype, microarray or sequencing-based copy number analysis), and, without syndromic signs, a comprehensive panel with the genes curated by the Clinical Genome Resource (ClinGen) expert panel, followed by exome or genome if negative; the clinician should know the coverage, analytical sensitivity and types of variants detected by each test [14]. Panels and exome have identified TIMM8A variants in children with isolated auditory neuropathy, before any neurological or visual sign [51, 52], and exome resolved the diagnosis in the Portuguese index case after negative metabolic, endocrine, autoimmune, MRI and mitochondrial DNA studies [50]. The 2026 systematic review advocates extending first-line testing in any syndromic deafness with neurological or developmental signs to include the BTK locus by deletion and duplication analysis [5].

Table 5.1. Yield of testing methods in probands with DDON (GeneReviews)

The proportions in Table 5.1 indicate the fraction of variants detectable by each method in a published series and not the clinical sensitivity of a specific test [1]. Normal sequencing does not exclude the diagnosis, because about half of patients have deletions; dosage analysis or microarray covering Xq22.1 is required [7]. Deletions may be underestimated by array: in a Scottish boy, the array indicated 17–19 kb and mate-pair sequencing revealed 39.9 kb with an inverted 59 bp insertion [6]. Genome sequencing and long-read technologies make it possible to resolve breakpoints in repetitive regions [6]. Intronic and splicing variants may require transcript studies [32]. Parental germline mosaicism is not detected by tests on leucocyte DNA [1, 6]. When testing is negative, the possibility of a genetic cause remains, and the ACMG suggests follow-up with a geneticist every 3 years because syndromic signs may appear with age [14].

5.4. Report content and interpretation

The report should state the gene, the transcript with version (NM_004085.4), the variant in HGVS nomenclature at the complementary DNA and protein levels, the zygosity (hemizygous or heterozygous) and the class according to the criteria of the ACMG and the Association for Molecular Pathology (ACMG/AMP); for deletions, the genomic coordinates, the reference assembly and the genes included, with explicit mention of BTK [1, 8]. In clinical practice, pathogenic and likely pathogenic variants have the same value for decision-making [1]. Loss-of-function variants usually meet the PVS1 criterion and missense variants often remain of uncertain significance [5]. Maternal segregation studies, transcript analysis and the auditory phenotype (auditory neuropathy) help to reclassify variants of uncertain significance [32, 53].

5.5. Algorithm

Table 5.2. Diagnostic sequence proposed from the sources

5.6. Prenatal and preimplantation diagnosis

Once the familial alteration has been identified, prenatal diagnosis in an at-risk pregnancy and preimplantation genetic testing are possible [1]. The discussion should take place before pregnancy, and differences in perspective among professionals and within families regarding the use of prenatal diagnosis should be acknowledged [1].

6. Differential Diagnosis

6.1. Principles

The differential is organised around three axes: early-onset sensorineural deafness with an auditory neuropathy pattern, the association of deafness and dystonia, and the combination of optic atrophy, deafness and neurological signs suggesting mitochondrial disease [1, 62]. Deafness does not appear to be frequently associated with other hereditary dystonias, which gives diagnostic weight to the combination [1]. De novo TIMM8A variants may, in a family, mimic autosomal recessive transmission and make it difficult to distinguish X-linked from autosomal dystonias [1]. In a series of 20 patients with deafness-dystonia syndrome seen between 1994 and 2011, the cause was identified in 7: methylmalonic aciduria, meningoencephalitis, perinatal hypoxic-ischaemic injury, 7q21 deletion, a TIMM8A variant and Woodhouse-Sakati syndrome; in the remaining 13 no cause was found, despite a family history in most [62]. A patient with a typical clinical picture of deafness-dystonia treated with deep brain stimulation had a normal TIMM8A [66]. Other genetic causes of deafness-dystonia cited recently are myoclonus-dystonia (SGCE), Baraitser-Winter syndrome (ACTB) and Siddiqi syndrome (FITM2) [54].

Table 6.1. Differential diagnosis

6.2. Main differentials

Faced with prelingual deafness in a boy without a family history, frequent causes should be excluded before considering DDON, and the audiological pattern is the main discriminator: auditory neuropathy narrows the differential to OTOF, PJVK, DIAPH3 and neurodegenerative and mitochondrial diseases [1, 51]. In the Chinese series of nine probands with auditory neuropathy, three had OTOF variants and six had variants in other genes, one of them in TIMM8A [51]. X-linked deafness without other manifestations may correspond to other DFN loci, including PRPS1 [1].

Wolfram syndrome is the differential to consider in a male with an isolated case who appears to have DDON, because it shares optic atrophy, deafness, movement disorder, dementia and psychiatric changes, but has juvenile diabetes and no dystonia [1]. Usher syndrome is distinguished by retinal dystrophy and an abnormal electroretinogram, whereas in DDON the retina, night vision and electroretinogram are normal [1]. Friedreich ataxia shares atrophy of the posterior columns, but deafness is rarely the initial sign and there is cardiomyopathy [1]. Classic mitochondrial diseases, such as MELAS, usually have raised lactate, epilepsy and stroke-like episodes [1]. MEGDEL syndrome and SUCLA2 deficiency are identified by 3-methylglutaconic aciduria and methylmalonic aciduria, respectively [1]. Saudubray's table of deafness in inborn errors of metabolism places Mohr-Tranebjærg syndrome alongside the mitochondrial DNA syndromes (neuropathy, ataxia and retinitis pigmentosa or NARP, Pearson syndrome, MELAS, myoclonic epilepsy with ragged red fibres or MERRF, Kearns-Sayre syndrome, maternally inherited diabetes and deafness), Wolfram syndrome, OPA1, KARS1, cellular trafficking disorders, PIK3C2A, Perrault and PHARC syndromes, riboflavin transporter deficiencies, thiamine-responsive megaloblastic anaemia with diabetes and deafness, and PRPP synthetase superactivity [68].

Dystonia with iron deposits in the globus pallidus described in an adolescent without deafness carrying a TIMM8A variant extends the differential to neurodegeneration with brain iron accumulation; in that patient, PANK2, C19orf12 and ATP13A2 were normal and ferritin, transferrin, caeruloplasmin and serum copper were within reference values [34].

6.3. Class of mitochondrial protein import defects

TIMM8A belongs to the group of mitochondrial protein import defects, which Saudubray includes in the classification of nuclear defects of oxidative phosphorylation [46]. The phenotypes of these genes are heterogeneous and do not form a uniform syndromic class; Table 6.2 brings them together as context for the differential of mitochondrial diseases with deafness or neurological signs.

Table 6.2. Mitochondrial protein import defects cited in Saudubray, with the OMIM phenotype

In the same Saudubray chapter, the eight X-linked oxidative phosphorylation genes are grouped into three patterns: only heterozygous females affected, presumably with male embryonic lethality (NDUFB11, COX7B, HCCS); both sexes affected (HSD17B10); and disease only in males or very mild in females (NDUFA1, TAZ, TIMM8A, AIFM1) [46]. For AIFM1, the third pattern describes the tendency and not a limit: a girl with mitochondrial encephalomyopathy and cardiomyopathy due to a heterozygous de novo variant with skewed X inactivation has been described [84].

7. Treatments and Risk Management Strategies

7.1. Principles and evidence base

There is no treatment that modifies the course of the disease; management is supportive, multidisciplinary and anticipatory [1, 7]. The available recommendations come from the GeneReviews chapter, which is expert guidance and not trial evidence, and from case reports; no disease-specific clinical guideline was identified, and ClinGen has not assessed TIMM8A for actionability [7]. For general aspects, the ACMG guidance for hearing loss applies and, by extrapolation, the Mitochondrial Medicine Society consensus on care in primary mitochondrial disease, whose applicability to an import defect without a consistent oxidative phosphorylation defect has not been studied [14, 67]. Table 7.1 brings together the measures proposed by GeneReviews; the recommended initial evaluation is in section 11.

Table 7.1. Treatment of manifestations (GeneReviews)

7.2. Hearing and communication

Because the lesion is a neuronopathy of the spiral ganglion, conventional hearing aids have variable success [1]. Sign language teaching should begin early, and training in tactile sign language is recommended because vision is also lost [1, 7]. The Mitochondrial Medicine Society consensus recommends, for deafness in mitochondrial disease, digital hearing aids if moderate to severe, cochlear implant if profound, noise protection and caution with aminoglycosides [67]. The ACMG guidance recommends temporal bone imaging by CT or MRI when cochlear implantation is being considered or there is auditory neuropathy, and follow-up by a multidisciplinary team with otorhinolaryngology, genetics, audiology and speech and language therapy [14].

The first published cochlear implant in a patient with DDON was placed at 4 years in a boy with XLA and profound deafness; after 2 years of use, performance was marginal, with low scores in speech, language and audiometry tests, and the most comfortable stimulation level required higher currents than usual [65]. In a systematic review of cochlear implants in postsynaptic auditory neuropathies (14 studies, 25 patients, at least 28 implants, all at Oxford Centre for Evidence-Based Medicine evidence level IV), only one study concerned DDON; 22 of the 25 patients had modest to significant benefit [85]. Of the two boys with XLA-MTS in the 2022 series, one had a cochlear implant and profound deafness and the other received a left implant at 6 years, after hearing aids, but preferred sign language as a means of communication [6]. A 28-year-old man with bilateral cochlear implants was able to receive deep brain stimulation [16], and there is another report of cochlear implantation and deep brain stimulation in the same patient [86]. Published outcomes in DDON are variable [65, 85], and the decision weighs the foreseeable timing of visual loss and the value of sound perception for communication and safety.

7.3. Dystonia and the motor system

Physiotherapy aims to maximise mobility and reduce late orthopaedic complications (contractures, scoliosis, hip dislocation), with positioning and mobility equipment (wheelchairs, walkers, orthoses) [1]. For hypertonia and dystonia, GeneReviews recommends involving specialists to manage baclofen, tizanidine, botulinum toxin, antiparkinsonian drugs or orthopaedic procedures, without indicating specific doses for this disease [1]. The pharmacological response described is scant: one patient improved with alcohol and GABAergic substances [87]; baclofen and tiapride were ineffective in a 17-year-old boy with severe dystonia [54]; botulinum toxin had no effect on the tongue dystonia and hand tremor of a 28-year-old man [16]; and levodopa/carbidopa 25/100 mg three times a day brought no benefit in a Spanish adolescent [34]. None of these drugs has an approved indication for Mohr-Tranebjærg syndrome; choice and dosing follow the general rules for the treatment of dystonia and spasticity and the respective summaries of product characteristics. The Mitochondrial Medicine Society consensus calls for caution with drugs that alter tone, as they may worsen cognition, muscle strength and, secondarily, respiratory effort, gastrointestinal motility and urinary function, and with botulinum toxin because of systemic effects and worsening of weakness [67].

Deep brain stimulation (DBS) has discordant results (Table 7.2). Bilateral DBS of the globus pallidus internus (GPi), in a 28-year-old man with dystonia since puberty, produced marked immediate improvement and an 82% improvement in dystonic symptoms more than 2 years later, despite the presence of bilateral cochlear implants [16]. In a 21-year-old patient with a deafness-dystonia phenotype and a normal TIMM8A, GPi DBS at 17 years reduced the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) score from 75 to 10 at 3 months and kept it at 15 points at 4 years [66]. In contrast, in a Chinese boy with the c.133-2del variant, GPi DBS at 17 years (BFMDRS motor 97) gave partial benefit; at 21 years the dystonia was generalised and severe; the addition of subthalamic nucleus (STN) DBS brought improvement for only a few months (BFMDRS motor 106 and disability 30 at 3.5 years), and superior cerebellar peduncle DBS, with transient improvement of the trunk and neck, ended at 12 months with BFMDRS motor 102 and disability 28 [54]. The authors conclude that not all forms of deafness-dystonia respond to DBS [54]. The Mitochondrial Medicine Society consensus proposes considering DBS in mitochondrial movement disorders taking prognosis and morbidity into account [67], and the European network ERN-RND has a multidisciplinary committee for DBS in dystonia that can be consulted for complex cases [18].

Table 7.2. Deep brain stimulation in patients with deafness-dystonia (case reports)

These data are isolated reports, without comparison or standardised follow-up; they do not allow the response rate to be estimated, and the distinction between patients with and without a TIMM8A variant is relevant, because the best long-term outcome described occurred in a patient without an identified variant [66].

7.4. Swallowing, nutrition and respiration

Oromotor function should be assessed at each visit, with clinical feeding assessment or a radiological swallowing study if there is choking, poor weight gain, frequent respiratory infections or unexplained food refusal; swallowing therapy may include thickening or cooling of food and, if dysfunction is severe, a nasogastric tube or gastrostomy [1]. In the Portuguese index case, severe dysphagia after the encephalopathy required gastrostomy, removed within a year [50]. Aspiration pneumonia is the main respiratory complication [1].

7.5. Behaviour, cognition and psychiatry

Behavioural changes and psychiatric disorders are treated by the usual methods, with neuropsychiatric assessment in patients with dementia or psychiatric disorder [1]. Interventions used in autism spectrum disorder, including applied behaviour analysis, may be useful, and severe aggression warrants child psychiatry input [1]. The Mitochondrial Medicine Society consensus recommends formal neurodevelopmental screening and baseline neuropsychological assessment, repeated when there are cognitive, behavioural or personality changes [67]. Augmentative and alternative communication, from low to high technology, should be assessed by a speech and language therapist, and does not hinder speech development [1].

7.6. Immunodeficiency in XLA-MTS

Patients with a deletion that includes BTK need lifelong immunoglobulin replacement, intravenous or subcutaneous, and the rest of XLA treatment [5, 57]. A Scottish boy with XLA-MTS had chronic lung disease with bronchiectasis at 21 years [6].

7.7. Agents to use with caution, intercurrent illness and perioperative care

GeneReviews does not list agents to avoid [1]. The Mitochondrial Medicine Society consensus, valid for primary mitochondrial disease and applied here by extrapolation, recommends caution with valproic acid, statins, metformin, high-dose or prolonged paracetamol, aminoglycosides (auditory risk), linezolid, tetracyclines, azithromycin, erythromycin, topiramate, vigabatrin and botulinum toxin; with the exception of valproate in POLG disorders, these drugs are not contraindicated [67]. The same consensus recommends that patients have an emergency care plan and, when appropriate, medical alert identification, that prolonged fasting be avoided and that dextrose-containing fluids be used before, during and after procedures, except in the exceptions indicated (pyruvate defects, ketogenic diet, previous adverse reaction to glucose) [67]. In anaesthesia, the risk of complications is increased in mitochondrial patients; it is recommended to minimise fasting, add glucose to fluids, use volatile anaesthetics and muscle relaxants with caution (the latter in patients with myopathy or depression of the respiratory centre), avoid propofol or limit it to short procedures because of the risk of propofol infusion syndrome, titrate anaesthetics slowly and prefer local anaesthetics, which are well tolerated; there is no established relationship with malignant hyperthermia [67]. DBS under general anaesthesia and cochlear implantation were performed in the published patients without complications reported in the abstracts [16, 65].

7.8. Pregnancy, lactation and transition

The sources consulted do not describe pregnancies in symptomatic heterozygous women or in patients with XLA-MTS, and there are no specific recommendations for pregnancy or lactation. Transition to adult care coincides with the period of greatest risk of dystonia progression and onset of visual loss, and GeneReviews recommends planning the transition in the education plan during adolescence [1, 13].

7.9. Regulatory table and clinical trials

There is no disease-modifying treatment, and the sources consulted did not identify medicines with an approved indication for Mohr-Tranebjærg syndrome [7]; the orphan designation databases of the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were not consulted. A search of ClinicalTrials.gov on 31 October 2026 found no studies for «Mohr-Tranebjaerg», «TIMM8A» or «DDON», and the 10 studies returned for «deafness dystonia» concern other diseases [15]. The European trials register was not consulted. Table 7.3 summarises the situation.

Table 7.3. Regulatory and clinical research status

7.10. Developments in the last 6–12 months and preclinical research

Between November 2025 and October 2026 the following works were published, with no clinical trial: a systematic review of 75 patients proposing that XLA-MTS be treated as a distinct clinico-genetic entity (published in June 2026; case-report evidence) [5]; the first transcript analysis of a TIMM8A splicing variant (c.132+5G>A, March 2026; human study of one patient) [32]; and the report of DBS failure at three targets in a patient with c.133-2del (December 2025; case report) [54]. In July 2025 the first patient with dystonia and iron deposition in the globus pallidus without deafness was described (case report), treated experimentally with pantothenic acid and pantethine, with no published outcome [34]. At the preclinical level, overexpression of CHCHD2 reversed mitochondrial dysfunction in stem cell-derived neurons from a patient (2025) [39], vitamin E reversed the apoptotic vulnerability of neuronal cells lacking hTim8a (2019) [35], and there is a Timm8a1 mouse model with hearing and cognitive impairment (2021–2022) [40, 41]. None of these data currently supports the clinical use of antioxidants or any other targeted therapy.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

Transmission is X-linked recessive, and the rules apply both to intragenic TIMM8A variants and to contiguous Xq22.1 deletions [1]. The father of an affected male is not a carrier and does not need to be tested [1]. If the proband has a brother with the same alteration, the mother is an obligate heterozygote; if a woman has more than one affected son, with no other affected relatives, and the alteration is not detected in her leucocyte DNA, germline mosaicism is most likely [1]. In 2019 GeneReviews recorded that maternal germline mosaicism had been suspected but not molecularly demonstrated; in a Dutch family with a 2.1 kb deletion of exon 2, the grandmother, who had an affected son and a carrier daughter and would be an obligate carrier, did not have the deletion in blood, which suggests germline mosaicism [1, 6]. In a male with no other affected relatives, the mother may be heterozygous or the alteration may have arisen de novo; de novo variants and deletions are well documented, including the C66W variant, p.Gln38Ter, the c.45_61dup duplication in a Chinese patient and a 63.5 kb deletion [1, 6, 45, 51, 55].

Table 8.1. Risks for relatives

8.2. Testing of carriers and at-risk relatives

Molecular testing of at-risk female relatives is possible when the familial alteration is known [1]. Without an identified alteration, the absence of signs in most young heterozygous females makes clarification difficult, and it is not known whether X-inactivation studies would be useful [1]. The great variability within and between families prevents reliable prediction of severity [1]. Cascade screening may identify patients not yet diagnosed: in the Portuguese family, the diagnosis of the index case led to testing of the mother and four sisters, resulting in the identification of a carrier sister and her three affected sons, already followed for developmental delay [50]. Molecular diagnosis in a child with isolated auditory neuropathy makes it possible to anticipate surveillance of the other manifestations and to inform the family [6, 52].

8.3. Family planning, prenatal and preimplantation diagnosis

The appropriate time to determine genetic risk, clarify carrier status and discuss prenatal diagnosis and preimplantation genetic testing is before pregnancy, and counselling should be offered to affected or at-risk young adults [1]. With the familial alteration known, prenatal diagnosis in an at-risk pregnancy and preimplantation testing are possible [1]. The authors of the Portuguese family stress the high recurrence risk for carriers and the need to offer reproductive options [50].

8.4. Counselling of minors

Testing of at-risk male relatives has direct clinical benefit, because it allows early auditory, ophthalmological and neurological surveillance and, in deletions that include BTK, the diagnosis of XLA [7, 50]. Testing of asymptomatic girls solely to determine carrier status has no medical benefit in childhood and should, as a rule, be discussed when the young woman can take part in the decision; this guidance derives from the general principles of counselling and not from a specific recommendation in the disease sources.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

The prevalence of Mohr-Tranebjærg syndrome is unknown [1]. Orphanet gives a point prevalence of less than 1 per 1,000,000, worldwide [2]. The available figures are counts of published cases and not rates: 91 affected individuals from 37 families in a 2012 review, 69 patients in the 2019 review of the Chinese series and 75 molecularly confirmed patients with individual data in the 2026 systematic review (51 with classic MTS and 24 with XLA-MTS) [1, 5, 52]. By 2018, 17 patients from 14 families with a contiguous deletion including TIMM8A and BTK had been described, and about 20 patients or families with TIMM8A deletions by 2022 [6, 57]. The context figures cited by GeneReviews concern the disorders of which the syndrome is a rare cause: dystonia of all types has a prevalence of 70–329 per million in the 2000 study of eight European countries, and deafness has a prevalence of about 1 in 800, of which approximately 1% is attributed to X-linked transmission; there are no large-scale molecular screens of males with dystonia that would allow the fraction due to TIMM8A to be estimated [1, 88]. X-linked recessive deafness accounted for 1.7% of childhood deafness in 1995 [22].

9.2. Geographical distribution and populations

The disease has been identified in several populations worldwide [1]. Up to 2001, the four known families were described as Caucasian, starting with the original Norwegian family, and the Japanese family published that year was the first non-Caucasian one [22, 29]. Patients or families from Spain, Italy, the Netherlands, Poland, Scotland, Australia, China, Japan, the Philippines and Portugal were subsequently published [6, 13, 32, 45, 50, 52, 53, 55–57, 60, 89, 90]. The 2019 Chinese series was the first description in Chinese patients and indicates that the disease is not exceptional among children with auditory neuropathy [52]. No founder variants have been described; variants are, as a rule, private to each family [1].

In Portugal, the only published description in the sources consulted is that of a family from the North, followed at Centro Hospitalar Tâmega e Sousa and at Centro de Genética Médica Jacinto Magalhães of Centro Hospitalar Universitário de Santo António, with four affected males (an adult aged 31, a boy aged 11 and monozygotic twins aged 6) carrying NM_004085.4:c.45_61dup p.(His21ArgfsTer11) [8, 50]. The sources consulted do not include data from Brazil, which does not demonstrate the absence of patients.

9.3. Special populations

Heterozygous females are a population with their own needs, owing to the possibility of focal dystonia and mild deafness and to reproductive risk [1, 12]. Patients with XLA-MTS combine the infectious risk of XLA with the needs of the neurological disease [5]. Adults with progressive deafblindness and dementia need deafblind services and carer support [1].

9.4. Reference networks and patient organisations

In the European Union, patients can be referred to ERN CRANIO, which has a working group dedicated to congenital deafness and representation of patients with genetic deafness, to ERN-RND, whose dystonia area includes a multidisciplinary committee for deep brain stimulation in dystonia, to ERN-EYE for rare eye diseases and to ERN RITA for the immunodeficiency of the contiguous forms [17–20]. GeneReviews lists as resources Dystonia UK, the Dystonia Medical Research Foundation, the American Society for Deaf Children, BabyHearing.org, the National Association of the Deaf and the MedlinePlus Genetics page on the syndrome [1].

10. Illustrative Clinical Case

Sousa and colleagues described in 2023 a Portuguese family with four affected males, followed in Penafiel and Porto [50]. The index case, the first child of non-consanguineous parents, had developmental delay in childhood, especially of language, without motor delay, and sensorineural deafness diagnosed early and treated with hearing aids [50]. At 10 years, generalised epilepsy was diagnosed, treated with valproic acid during adolescence and adulthood and, later, with levetiracetam and lacosamide [50]. In late adolescence, severe behavioural changes and progressive cognitive decline appeared, with several psychiatric admissions [50]. At 27 years, during an admission for aggression, he had generalised tonic-clonic seizures followed by severe and prolonged encephalopathy with hospital-acquired pneumonia; non-convulsive status epilepticus and central nervous system lesions were excluded by MRI [50]. After this episode he was left with limited speech and dysarthria, severe dysphagia requiring gastrostomy for less than a year, generalised increase in tone with moderate spasticity of the lower limbs, hyperreflexia, spastic gait possible only with assistance and mild dystonia of the right hand; over the following 5 years functional decline was rapid and each systemic illness aggravated the deficits [50]. Metabolic, endocrine and autoimmune panels, brain and spinal MRI and mitochondrial DNA sequencing were normal, electromyography showed a mild axonal sensory neuropathy and ophthalmological examination at 29 years was normal [50]. Exome sequencing identified, at 31 years, the hemizygous variant c.45_61dup p.(His21Argfs*11) in TIMM8A, then undescribed, classified as likely pathogenic; the same variant was found in the mother and in one of the four sisters [50]. On the MANE transcript, the variant corresponds to NM_004085.4:c.45_61dup p.(His21ArgfsTer11), and is identical, after normalisation, to the de novo variant described as c.61_62insGGACCCGCAGTTGCAGC in a Chinese patient with auditory neuropathy [8, 51].

Genetic counselling of the family allowed three nephews, sons of the carrier sister, to be diagnosed [50]. The oldest, aged 11, had normal neonatal OAE, was referred at 4 years for expressive language delay, with a diagnosis of global developmental delay, and at 8 years had a full-scale intelligence quotient of 55 (verbal 51, performance 65); the 70 dB bilateral deafness was only diagnosed at 9 years, and hearing aids brought slight improvement, without recovery of the language delay [50]. The monozygotic twins, aged 6, had passed OAE newborn hearing screening in both ears; both had unilateral strabismus, global developmental delay with quotients of 64 and 70 on the Griffiths scale (38 and 52 on the language subscale) and behavioural problems; one had macrocephaly, two simple febrile seizures and a left temporal arachnoid cyst with anterior temporal hypoplasia, and the other had an episode of cervical dystonia at 6 years; audiograms suggested deafness, with ABR under sedation scheduled [50]. The pedigree is in Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC10267341/figure/F1/) [50].

The case illustrates several practical points. Deafness due to auditory neuropathy may not be detected by OAE newborn screening and may be diagnosed late, after language delay is already established [14, 50]. The molecular diagnosis in the adult, obtained by exome after an extensive negative work-up, had direct consequences for three children in the family and for the reproductive planning of the carriers [50]. Epilepsy is not characteristic of the syndrome, and the authors discuss whether it is concomitant or part of the phenotype [1, 50]. The prolonged use of valproic acid described in the report should not be taken as recommended practice: the Mitochondrial Medicine Society consensus advises caution with this drug in patients with mitochondrial disease, especially in POLG disorders, although its application to this syndrome is an extrapolation [67].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Deafness is profound before 10 years, legal blindness appears at around 30–40 years and dementia from 40, but the severity and pace of the neurological, visual and psychiatric manifestations vary greatly, even within a family [1]. Dystonia progresses, at a median of 11 years, to moderate to severe disability [13]. Patients come to use a cane and then a wheelchair, and late dysphagia exposes them to aspiration pneumonia [1]. Life expectancy is highly variable: in the Norwegian family, one patient with rapidly progressive dystonia died at 16 years and others in the sixth decade, and the four patients with temporal bone studies died between 49 and 67 years [1, 48]. In forms with XLA, prognosis also depends on infection control, and bronchiectasis in early adulthood has been described [6]. The available data come from published families and cases, without prospective cohorts, and do not allow survival to be estimated.

11.2. Evaluation after diagnosis

After diagnosis in a male, GeneReviews recommends formal audiological assessment geared to auditory neuropathy, speech and language assessment, baseline neurological examination, assessment by physical and rehabilitation medicine, physiotherapy and occupational therapy (gross and fine motor skills, mobility, daily activities, need for devices), ophthalmological assessment with acuity, colour vision, visual fields for central scotomas and VEP, developmental assessment with tests adapted to deaf or visually impaired people, neuropsychiatric assessment if there is dementia or psychiatric disorder, genetics clinic consultation and assessment of family support needs [1]. To these are added immunoglobulin measurement and B lymphocyte count, when the nature of the alteration does not exclude involvement of BTK [7]. In heterozygous females, the evaluation depends on whether they are symptomatic probands or healthy relatives of a proband [1].

11.3. Surveillance

Table 11.1. Recommended surveillance

The two sources diverge on the audiology interval (annual in GeneReviews, every 1 to 2 years in the Mitochondrial Medicine Society consensus); for a deafness that progresses rapidly in the first decade, the annual interval of GeneReviews is the one that corresponds to the disease-specific source [1, 67]. In adults, the sources do not set intervals for visual and neurological assessment; follow-up is guided by clinical course, with attention to signs of dementia [1].

12. Summary and Final Considerations

Mohr-Tranebjærg syndrome is an X-linked recessive neurodegenerative disease caused by loss of function of TIMM8A, which encodes a small chaperone of the mitochondrial intermembrane space associated with TIMM13 [1, 30]. The cellular mechanism remains under discussion: the initial model of defective Tim23 import has been complemented by data from neuronal cells and mice pointing to complex IV assembly defects, oxidative stress, changes in mitochondrial morphology and apoptotic vulnerability [35, 39, 40]. The lesion is a neuronopathy affecting the spiral ganglion, Scarpa's ganglion, retinal ganglion cells, the visual cortex, the basal ganglia and the posterior columns [1, 48].

The typical picture begins with early-childhood deafness with an auditory neuropathy pattern, profound before 10 years, followed by dystonia of craniocervical or brachial onset with generalisation, visual loss from 20 years and dementia from 40, with behavioural and psychiatric changes from childhood [1, 13]. The spectrum is broader: there are children with isolated auditory neuropathy, an adolescent with dystonia and iron deposition without deafness, and women with focal dystonia or with disabling disease [13, 34, 52]. About half of patients have contiguous Xq22.1 deletions, and those that include BTK add XLA to the neurological picture; therefore sequencing without dosage analysis does not exclude the diagnosis, and all boys with DDON should have immunoglobulins and B lymphocytes assessed [1, 7]. OAE newborn hearing screening may fail to detect the deafness, and molecular diagnosis in children with auditory neuropathy makes it possible to anticipate surveillance and family counselling [14, 50].

There is no disease-modifying treatment and there are no clinical trials [15]. Management rests on early auditory habilitation with sign language and tactile sign language, cochlear implantation with moderate expectations, motor rehabilitation, symptomatic treatment of dystonia, DBS in selected cases, whose results range from 82% improvements to failures at three targets, psychiatric and social support and, in XLA-MTS, lifelong immunoglobulin replacement [1, 16, 54, 65]. Counselling follows the rules of X-linked transmission, with attention to de novo variants and germline mosaicism [1, 6]. The main limitations of current knowledge are the absence of prevalence data, the reliance on case reports with publication bias, the lack of prospective natural history studies and the absence of a specific guideline [1, 5, 7].

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