Deafness-Dystonia-Optic Neuronopathy (DDON)
1. Disease Entity 1.1 OMIM Numbers 1.2 Applicable ICD10 Diagnosis Codes 1.3 Disease Description 1.4 Nomenclature 1.5 Epidemiology 1.6 Etiology 2. Diagnosis 2.1 Clinical Presentation 2.2 Audiologic Features 2.3 Neurologic Features 2.4 Ophthalmic Features 2.5 Establishing a Genetic Diagnosis of DDON 2.6 Differential Diagnosis
3. Management, Therapeutic Considerations, and Prognosis 3.1 Management of Visual Features 3.2 Prognosis
Deafness-Dystonia-Optic Neuronopathy (DDON)
OMIM Numbers: 304700
Applicable ICD10 Diagnosis Codes:
Deafness-Dystonia-Optic Neuronopathy (DDON) is a rare neurodegenerative syndrome hallmarked by early childhood sensorineural hearing loss and the sequential onset of a movement disorder during adolescence, a decline in visual function as a young adult, and dementia occurring by middle age.
Deafness-Dystonia-Optic Neuronopathy (DDON), formerly known as Mohr-Tranebjaerg Syndrome, encompasses conditions previously thought to be separate entities: Opticoacoustic nerve atrophy (Jensen syndrome) and deafness-dystonia syndrome.  Note the deliberate use of the term neuronopathy to reflect the pathological loss of neuronal bodies within the CNS rather than neuropathy, which denotes a functional disruption of the peripheral nervous system.
As a rare genetic condition, DDON’s exact prevalence is currently unknown. First described within multiple generations of a single Norwegian family in 1960,  scientific literature continues to identify case reports and novel variants regularly. The last comprehensive tally of with DDON occurred in 2012 and cited 91 patients from 37 families. This disorder is not limited to individuals of Northern European descent and has been identified in populations across the world, including those of Chinese, Japanese, Filipino, Spanish, and African American ethnicity. Males are predominately affected by DDON due to its X-Linked recessive inheritance pattern. Females may be affected as obligate carriers and typically present with fewer, less prominent clinical symptoms. 
TIMM8A, located on Xq22.1, is the gene implicated in the development of DDON.TIMM8A encodes for a mitochondrial protein of the same name. The TIMM8A protein localizes to the mitochondria’s intermembrane space to function as a Translocase of the Inner Mitochondrial Membrane (TIMM). When complexed with other small TIMM proteins, they act as chaperones guiding nuclear encoded proteins across the intermembrane space to then pass through the internal mitochondrial membrane. Increased expression of the TIMM8A gene product occurs in large neurons within the CNS and in specific components of the brain stem, cerebellum, and basal ganglia. 
Mechanistically, loss of function of the TIMM8A gene occurs due to the x-linked recessive (XL-R) inheritance of a pathogenic variant, a de novo mutation, or a contiguous deletion involving the TIMM8A gene.  Of note, the location of the TIMM8A gene at Xq22 abuts the gene for encoding Bruton’s Tyrosine Kinase. Multiple case reports have documented a contiguous deletion including both the TIMM8A gene and BTK gene, causing DDON to occur with the immunodeficiency syndrome X-linked agammaglobulinemia (XLA).
The exact pathophysiological mechanism of DDON is not fully elucidated. Several papers identified abnormal mitochondrial morphology as thin and elongated in DDON cell lines. Neighbors et al. suggests that this mitochondrial morphology reflects TIMM8A’s absence and impacts the regulation of mitochondrial fusion and fission, with overall dysfunction leading to oxidative damage and subsequent degeneration of neurons. Several publications correlate the similarities in symptom presentation between DDON and Autosomal Dominant Optic Atrophy (ADOA) Syndromes caused by mutations in the OPA1 gene and protein.  Both feature sensorineural hearing loss and optic atrophy, with atrophy plus syndrome (ADOA+) additionally presenting with hyperreflexia.  The OPA1 protein also regulates mitochondrial fusion and fission. Dysfunction of the OPA1 protein produces a shortened, more globular mitochondria morphology, which directly opposes the those found in DDON.  Kang et al. demonstrated that knockout of the TIMM8A protein impaired Complex IV along the electron transport chain causing reactive oxygen species formation and facilitated the formation of proapoptotic factors such as the release of cytochrome C. 
Early childhood sensorineural hearing loss (HL) is the invariable primary manifestation of DDON. Compared to later features of the syndrome where the age of onset, severity, and progression may vary significantly between individuals, HL reliably presents within the first few years of life. Typically, there is a sequential development of dystonia or ataxia during the teenage years, a decrease in visual acuity beginning as a young adult, and the onset of dementia around forty years old. All three components are slowly progressive in nature that worsen with age. Additional features of DDON occur in childhood and include the variable presence of intellectual disability and psychiatric symptoms.
Sensorineural hearing impairment presents around 18 months on average, but can appear as a congenital impairment. Typical findings include a period of no HL or mild HL during infancy that sharply declines to a profound hearing impairment within the first decade of life.  Postmortem histopathological evaluations of temporal bones in DDON patients documented a near complete loss of the cochlear neurons with preservation of the hair cells and the Organ of Corti, confirming the HL as a “true auditory neuropathy.” Vestibular ganglion loss, though not as severe, was additionally found on postmortem analysis. Vestibular function generally remains intact, though documentation exists of patients experiencing vestibular symptoms in later life. 
Manifestations of a movement disorder occur during childhood, or anytime thereafter and characterized clinically as dystonia or ataxia.  Dystonia refers to repetitive movements or abnormal postures caused by involuntary muscle contraction. Ataxia is the absence of coordination or control over voluntary muscle. Dystonia relates to neurodegeneration of the basal ganglia while ataxia corresponds to loss of the Purkinje cells of the cerebellum. One study found that symptomatology manifests more often in the upper body and extremities rather than the lower half. Examples of focal dystonias in DDON include torticollis, writer’s cramp, and blepharospasm.   Progression of the movement disorder impairs the patient’s gross motor skills, limits mobility due to postural instability, and causes gait disturbances.
Neurological examination of DDON patients may feature increased tendon reflexes, extensor plantar responses, and ankle clonus.    Hypometabolism in the occipital lobes, rostral parietal lobes, and basal ganglia on PET scan are radiology findings believed to be consistent with dystonia.  MRI documents sizable cortical atrophy of the occipital lobes and rostral parietal lobes that progresses to generalized cortical atrophy around age 40.  Postmortem neuropathological studies noted brain atrophy and gliosis, macrocalcifications, and atrophy of the spinal cord with degenerative changes of the posterior columns and reduction in the number of motor neurons. 
Visual impairment in DDON classically presents in males during early adulthood and slowly progresses to cause blindness by mid-to-late adulthood, often meeting the legal definition around age 40. Visual decline consistently manifests after the onset of sensorineural hearing loss.   Examination of available case reports details a phenotypic spectrum in DDON with significant variability of ophthalmic features and temporal onset.
Visual loss in DDON results from neuronopathy, the pathological destruction of neuronal cell bodies, of the central visual pathways.   Postmortem histopathological examination of DDON patients documented spongiosis, neuronal loss, and astrogliosis of the striate cortex that was most pronounced along the calcarine fissure in three males with DDON. Examination of the retina revealed significant atrophy of the ganglion cell layer of the retina with few nuclei remaining. Similarly, they found a reduced number of nuclei in the inner nuclear layer. The optic nerve fibers were described as vacuolized, decreased nerve fibers, and with increased amounts of fibrous tissue along their tracts. A separate, earlier examination of the optic nerves and chiasm from one individual demonstrated diffuse demyelination, gliosis, and calcifications.  Neurodegeneration of the central visual structures causes subsequent optic nerve atrophy and occipital cortex atrophy, to collectively produce a form of cortical blindness.   Binder et al. 2003 highlights the substantial hypometabolism of the occipital lobe on early PET scans later extends beyond the central visual components as diffuse cortical atrophy on MRI. This pattern is unique to DDON when compared to other disorders harboring congenital retinal and optic nerve degeneration, making vision loss due to peripheral neuronal damage alone an unlikely etiology in this syndrome. 
Ophthalmic examination and testing are normal during childhood. Full visual fields, normal visual acuity (VA), color vision, night vision, and an unremarkable fundus exam is expected, including a healthy appearance of the optic nerve head.  Dr. Tranebjaerg described the typical pattern of visual loss in a cohort of affected males from a single Norwegian family in the original 1995 publication. Initial symptoms presented as photophobia occurring around age 15, with preserved night and color vision, a progressive decline of visual acuity throughout adulthood, and corrective lenses failing to improve VA by their mid-thirties when acuity was 20/100 or less. 
Additional presenting symptoms includes a subjective complaint of blurred vision, objectively as a gradual decline in visual acuity,  or as an acquired color vision defect  during teenage to early adult years. However, several reports document that decreased VA may manifest later during their thirties,  or even be absent as found in one notable Japanese family with no visual disturbances in male patients ages 33 and 35.
Visual function continues to deteriorate causing significant impairment in the following decades. Several reports highlight visual field (VF) defects described as VF constriction to 30 degrees concentrically OU in a 32-year-old and VF restricted to 5 degrees in a 49-year-old. Color vision usually declines alongside visual acuity and becomes evident on Ishihara Plates during the late twenties or thirties. Notably, one male was found to have complete achromatopsia by age 32. 
Optic neuronopathy requires years of progression until the two cardinal findings in DDON, optic atrophy and progressive decline in visual function, become clinically evident. Therefore, optic nerve pallor on dilated fundoscopic exam to suggest optic atrophy is a later exam finding. A normal appearance of the retina is expected throughout the disease. . Several cases initially report temporal pallor of the optic discs which progresses, with others simply citing optic nerve pallor occurring anywhere between twenty to fifty years old. 
Initial evidence of pathological dysfunction along the visual pathway occurs when measuring visual evoked potentials (VEP). Prolongation of the P100 wave latency on VEP reflects degeneration and subsequent loss of conduction along the central visual pathways. The P100 value remains stable and varies little as an individual with normal visual functioning ages. Abnormal waveforms and amplitudes reflect a central loss of the axons. Increased P100 latency values provide early evidence of impairment when subjective visual complaints and objective exam findings are absent. This is exemplified by the data presented in Tranebjaerg et al. 2001 from a male with evidence of cortical atrophy on neuroimaging at 9-years-old, but no visual complaints, and a normal fundoscopic at age 21. VEPs measured at 10 years old documented prolongation of the P100 wave latency, which further increased at age 20, demonstrating the presence of neuronopathy despite a normal ophthalmic exam. Literature consistently reports abnormal VEPs with prolonged latency of P100 wave, with progression to no measurable response. Early VEPs measured in other children between the ages of 7 to 10 without evidence of cortical atrophy on MRI’s were reported as normal in multiple studies.
Full-field electro-retinography (ffERG) testing examines the response of rods and cones to color and patterned stimuli to assess the inherent function of the photoreceptors. Response is based on the amplitude and implicit times of b-waves generated. Multiple investigations have utilized ERG to evaluate if retinal pathology is present and contributing visual decline. The majority of cases report normal functioning on ERG to suggest a central etiology of visual impairment. However, two individuals are reported in literature with abnormal ERG findings and results consistent with retinal degeneration. Ponjavic et al. 1996 described one male with central scotomas on Goldmann VF, retinal degeneration, and large caliber choroidal vessels, which was thought to be consistent with central areolar choroidal dystrophy. This may represent an incidental finding that is unrelated to this genetic disorder as no research correlates a genetic association between the two currently. Both Pizzuti et al. 2004 and Mendonca et al. 2011 describe the same individual with a normal retina, pale optic nerves, absent VEP responses, and amplitude reduction of the fotopic, scotopic and flicker responses on ERG. They purpose that retinal dysfunction may be associated with the well documented central neurodegeneration occurring in DDON. Additional research is needed to determine the extent of retinal dysfunction in this syndrome.
Female obligate carriers do not typically present with visual deficits, but only mild hearing impairment and forms of focal dystonia. Specific patterns in X-chromosome inactivation potentially contribute to the incomplete penetrance of visual impairment. Reports of female probands experiencing cortical blindness and the absence of visual impairment among members of a Japanese family with a shared pathogenic variant contribute to the varied phenotypic spectrum of DDON. Of note, blepharospasm appears frequently in literature as form of focal dystonia and occurs in both males and females. 
Establishing a Genetic Diagnosis of DDON
A formal diagnosis of DDON is established in the proband based on the presence of a TIMM8A pathogenic variant in a male, a female proband who is heterozygous for a pathogenic TIMM8A variant, or a continuous gene deletion encompassing the TIMM8A gene at X22.1q. Pathogenic variants are inherited in an X-LR manner. Approximately 20 pathogenic variants of the TIMM8A gene have been described. No correlation between genotype and phenotypic presentation exists to predict a moderate versus more severe clinical course.
In patient with hearing loss and a positive family history suggesting of X-LA, chromosomal microarray testing should be used to detect the presence and extent of the deletion. A multigene panel that includes the TIMM8A gene, among others, should be employed in a young patient presenting with hearing loss fitting a pattern of auditory neuropathy. Genetic testing of additional family members, specifically the proband’s biological mother and maternal grandmother, may be performed to determine if the TIMM8A variant was inherited or a de novo mutation. Further information regarding genetic counseling may be found on DDON’s GeneReviews authored by Dr. Tranebjærg.
Management, Therapeutic Considerations, and Prognosis
No specific treatment exists for DDON. Given the syndrome results from aberrance in a single gene, advances in medical research provides hope for a targeted therapy. Neighbors et al. 2020 proposed the use of a pharmaceutical similar to those used currently in CF patients to “read through” the variant’s specific premature stop codon to produce a full TIMM8A protein.
Management of Visual Features:
Regular ophthalmic examination is recommended to monitor visual loss and rate of progression. Exams should include assessment of visual acuity, color vision, visual field testing, VEPs, and thorough fundoscopic examination. Refraction to best visual acuity is the recommended management and providers should suggest early intervention through community or school services and the use of visual aids.
The degree of visual impairment varies significantly in published literature and cannot be predicted. As an older adult, deafness and poor visual function impair communication significantly. Life expectancy of those with DDON varies considerably among individuals, even within a shared familial variant. Cases range from a significantly shortened lifespan to others living well into their elderly years. Comorbid psychiatric manifestations causes a significant hindrance in social development and the patient’s ability to develop independence. Early interventions paired with strong social support and services for the patient and family aim to maximize positive adaptions from a young age. 
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