Clinical Description
Deafness-dystonia-optic neuronopathy (DDON) syndrome is a progressive disorder with prelingual or postlingual sensorineural hearing impairment in early childhood. The hearing impairment is always the presenting manifestation. Typically, DDON is associated with slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from approximately age 20 years, and dementia from approximately age 40 years. Psychiatric manifestations such as personality change and paranoia may appear in childhood and progress. The deafness and pronounced visual impairment severely compromise communication in late adulthood.
Note: The term "neuronopathy" refers to the destruction of the cell bodies of neurons and is different from "neuropathy," which is defined as a functional disturbance in the peripheral nervous system.
The hearing impairment appears to be more consistent in age of onset and progression than the neurologic, visual, and neuropsychiatric features, which vary in degree of severity and rate of progression. Life span may show extreme variation, even within a family. For example, in one large family, one member had rapidly progressive dystonia ("dystonia musculorum deformans") and died at age 16 years; other affected family members died in their sixties [Tranebjaerg et al 1995].
Audiologic features. The average age of onset of sensorineural hearing impairment is approximately 18 months, although some affected individuals have apparent congenital prelingual hearing impairment [Swerdlow & Wooten 2001, Ujike et al 2001]. The hearing impairment progresses rapidly and is typically profound before age ten years. Vestibular function is normal.
The hearing impairment results from an auditory neuropathy as shown by intact otoacoustic emissions associated with absent auditory brain stem responses in some individuals and convincing histopathologic evidence in five males with molecularly proven DDON syndrome with near-total loss of cochlear neurons and severe loss of vestibular neurons [Bahmad et al 2007, Wang et al 2019]. As expected from auditory neuropathy many individuals with DDON syndrome, at least in early stages of the disease, have intact otoacoustic emissions [Richter et al 2001, Brookes et al 2008, Wang et al 2019].
Of note, isolated hearing impairment without other manifestations of DDON syndrome has not been reported with TIMM8A pathogenic variants.
Neurologic features. The finding of gegenhalten (defined as diffuse resistance to movement of a limb) may be the first neurologic manifestation. The movement disorder may appear either as dystonia or ataxia. The onset may be as early as childhood, or much later. The movement disorder is progressive and the gait gradually becomes unstable. Affected individuals have brisk tendon reflexes, ankle clonus, and extensor plantar responses. Eventually they need a cane for walking and finally become wheelchair bound. Dystonic contractures may develop [Scribanu & Kennedy 1976, Jensen 1981, Jensen et al 1987, Tranebjaerg et al 1995, Hayes et al 1998].
Although many affected individuals develop dystonia by their thirties, some, ascertained through severely affected male relatives with a typical phenotype, have no detectable neurologic dysfunction in their thirties [Ujike et al 2001, Ha et al 2012].
Dysphagia develops late in the course and often causes aspiration pneumonia and its complications.
A mild peripheral sensory neuropathy may be present.
Spinal cord dysfunction was present in an individual with DDON syndrome with prolonged somatosensory evoked potentials and disturbed central motor conduction to lower extremities in motor evoked potentials [Binder et al 2003].
Seizures are not characteristic.
Neuropsychologic features. Behavioral abnormalities may be present from childhood, with mild intellectual disability, personality changes, restlessness, anxiety, reduced impulse control, aggressive outbursts, and compromised ability to concentrate. Later, paranoid psychiatric features may be present with fear of poisoned food, imaginary sensory impulses from skin, and imaginary foreign bodies in the eyes leading to self-mutilating behavior. Gradually, dementia develops.
Ophthalmologic features. Optic neuronopathy may be subclinical for many years [Ujike et al 2001] and may be apparent only when prolongation of the P100 wave latency is detected on visual evoked potential testing [Ponjavic et al 1996,Tranebjaerg et al 2001].
In childhood, color vision and visual fields are normal [Tranebjaerg et al 1995, Ponjavic et al 1996]. Visual impairment may first be evident in the late teens as photophobia, reduced visual acuity, acquired color vision defect, and central scotomas. Ophthalmologic examination in children reveals normal-appearing optic nerves; in adults, the optic nerves become pale. The appearance of the retina is usually normal, as are night vision and the electroretinogram [Ponjavic et al 1996].
Slowly progressive decline in visual acuity leads to legal blindness around age 30 to 40 years [Tranebjaerg et al 1995, Ponjavic et al 1996, Tranebjaerg et al 2000a, Tranebjaerg et al 2000b, Tranebjaerg et al 2001].
Other characteristics
Males with DDON syndrome have normal fertility.
Frequent occurrence of hip fractures in affected males appears to be associated with poor neuromuscular coordination and increased risk for stumbling rather than an abnormality in calcium metabolism or intrinsic bone abnormalities [
Tranebjaerg et al 1995].
Cardiomyopathy does not occur.
Decrease in respiratory capacity does not occur, except for that related to aspiration pneumonia.
Other Studies in Affected Males
Neuroimaging (CT, MRI, or PET scan) shows general brain atrophy in the majority of males from age 40 years or, in some cases, earlier [Tranebjaerg et al 2001].
More sophisticated neuroimaging studies such as PET/MRI reveal hypometabolic areas, predominantly over the right striatum and parietal cortex, and marked atrophy of the occipital lobes [Hayes et al 1998, Swerdlow & Wooten 2001, Ujike et al 2001, Binder et al 2003].
Neurophysiologic investigations show cochlear dysfunction.
Neuropathologic abnormalities include general brain atrophy and gliosis, microcalcifications, and neuronal cell death in spiral ganglion cells of the cochlea, Scarpa's ganglion, the retinal ganglion cell layer, the optic nerves, and the calcarine fissures (visual cortex) [Scribanu & Kennedy 1976, Reske-Nielsen et al 1988, Hayes et al 1998, Merchant et al 2001, Tranebjaerg et al 2001].
Otopathologic findings clearly support that DDON syndrome is an auditory neuropathy. Temporal bones from five individuals with molecularly verified DDON syndrome showed near-total loss of cochlear neurons and severe loss of vestibular neurons [Merchant et al 2001, Bahmad et al 2007].
The spinal cord is atrophic with loss of fibers in the dorsal roots and posterior columns, as seen in Friedreich ataxia [Tranebjaerg et al 2001].
Muscle biopsy shows normal enzyme activity of energy-generating systems, no structural abnormalities, and no aggregations of mitochondria. Electron microscopy reveals mild neurogenic atrophy [Tranebjaerg et al 1995, Tranebjaerg et al 2001, Binder et al 2003]. Activities of complexes I through IV of the mitochondrial respiratory chain in muscle biopsy revealed a mild deficiency for complex IV in a male with a de novo p.Gln38Ter stop variant, but no abnormalities could be demonstrated in cultivated fibroblasts [Blesa et al 2007]. No pathogenic variants were identified in the mtDNA genes encoding the complex IV subunits COI, COII, and COIII or in five tRNA mtDNA genes [Blesa et al 2007].