Deafness-Dystonia-Optic Neuronopathy Syndrome
Summary
Clinical characteristics.
Males with deafness-dystonia-optic neuronopathy (DDON) syndrome have prelingual or postlingual sensorineural hearing impairment in early childhood, slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from optic atrophy beginning at approximately age 20 years, and dementia beginning at approximately age 40 years. Psychiatric symptoms such as personality change and paranoia may appear in childhood and progress. The hearing impairment appears to be consistent in age of onset and progression, whereas the neurologic, visual, and neuropsychiatric signs vary in degree of severity and rate of progression. Females may have mild hearing impairment and focal dystonia.
Diagnosis/testing.
The diagnosis of DDON syndrome is established in either a male proband who has a hemizygous TIMM8A pathogenic variant (~50% of affected males) or a female proband who has a heterozygous TIMM8A pathogenic variant (~50% of affected females) or a contiguous gene deletion of Xp22.1 involving TIMM8A (~50% of affected males and females).
Management.
Treatment of manifestations: Educational programs for developmental and sensory deficits, including training in tactile sign language. Because auditory neuronopathy is the cause of the hearing loss, hearing aids have only variable success. Physical medicine and rehabilitation, physical and occupational therapy to improve fine and gross motor skills and mobility, to prevent contractures, and to provide adaptive devices to improve activities of daily living. Standard treatment of behavioral issues / psychiatric disorders. Ensure appropriate social work involvement to connect families with local resources, respite, and support, especially care coordination with multiple subspecialty appointments, equipment, medications, and supplies.
Surveillance: Regular neurologic evaluation and assessment for dementia and/or psychiatric manifestations; annual developmental, speech/language, vision assessments in childhood; regular physical therapy / occupational therapy for review of activities of daily living, gross motor and fine motor needs; routine follow up of the social support and social services needs of the family/caregivers.
Genetic counseling.
DDON syndrome is inherited in an X-linked manner. If the mother of a proband with DDON syndrome has the causative genetic alteration (i.e., a TIMM8A pathogenic variant or a contiguous gene deletion of Xp22.1 involving TIMM8A), the chance of transmitting the genetic alteration in each pregnancy is 50%. Males who inherit the genetic alteration will be affected; females who inherit the genetic alteration will be heterozygotes and may have mild hearing impairment and focal dystonia. Males who reproduce pass the genetic alteration to all of their daughters and none of their sons.
Prenatal diagnosis for pregnancies at increased risk and preimplantation genetic diagnosis are possible if the DDON-causing genetic alteration in the family is known.
Diagnosis
Formal diagnostic criteria for deafness-dystonia-optic neuronopathy (DDON) syndrome have not been established.
Scope of this chapter. Deafness-dystonia-optic neuronopathy (DDON) syndrome occurs as either a single-gene disorder resulting from a pathogenic variant in TIMM8A or a contiguous gene deletion at Xq22.1 that includes BTK and additionally causes X-linked agammaglobulinemia (XLA). XLA will not be discussed further in this chapter.
Suggestive Findings
Deafness-dystonia-optic neuronopathy (DDON) syndrome is suspected in males with the following:
- Progressive sensorineural hearing impairment with prelingual or postlingual onset:
- Absent stapedius reflex
- Abnormal findings on auditory brain stem response testing
- Normal evoked otoacoustic emissions, indicating normal outer hair cells [Richter et al 2001]
- Normal findings on CT scan of the inner ear [Mohr & Mageroy 1960, Tranebjaerg et al 1995]
- Movement disorder (dystonia/ataxia)
- Gradual onset and slow progression of personality changes, paranoia, dementia
- Gradual decrease in visual acuity associated with optic atrophy
- Gradual onset and slow progression of dysphagia
- A family history consistent with X-linked inheritance
Establishing the Diagnosis
The diagnosis of deafness-dystonia-optic neuronopathy (DDON) syndrome is established in a proband who has one of the following on molecular genetic testing (see Table 1) [Tranebjaerg 2012]:
- A hemizygous TIMM8A pathogenic variant in a male proband (~50% of affected males) or a heterozygous TIMM8A pathogenic variant in a female proband (~50% of affected females)
- A contiguous gene deletion of Xp22.1 involving TIMM8A (~50% of affected males and females)
Options for molecular genetic testing can include a chromosomal microarray analysis (CMA) or use of a multigene panel depending on the phenotype and family history.
Note: The clinical features of DDON in individuals with a contiguous gene deletion and in individuals with smaller pathogenic variants are indistinguishable, apart from the additional presence of X-linked agammaglobulinemia in the former.
Option 1
In a child with hearing loss and evidence of a family history suggestive of XLA, CMA should be performed first. CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including TIMM8A) that cannot be detected by sequence analysis.
Option 2
In a young child with hearing impairment and no other phenotypic findings, there should be a strong suspicion of DDON if the auditory phenotype is auditory neuropathy. A deafness / hearing impairment or an auditory neuropathy multigene panel that includes TIMM8A and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., BTK as described by Sedivá et al [2007]) may not be detected by these methods and would require CMA for detection (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Table 1.
Molecular Genetic Testing Used in DDON Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| TIMM8A | Sequence analysis 3, 4 | 22/42 5 |
| Gene-targeted deletion/duplication analysis 6 | 20/42 7 | |
| CMA 8 | 18/42 9 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis
- 5.
Tranebjaerg [2012], Montaut et al [2018], Wang et al [2019]
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Sedivá et al [2007]) may not be detected by these methods.
- 7.
Most deletions not detectable by sequence analysis are large deletions that include BTK. A single intragenic exon 2 deletion has been reported [Ha et al 2012].
- 8.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including TIMM8A) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the Xq22.1 region. CMA designs in current clinical use target the Xq22.1 region.
- 9.
Tranebjaerg [2012], Szaflarska et al [2018], Wang et al [2019]
Clinical Characteristics
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.
Heterozygotes
Older females from the original family described by Tranebjaerg et al [1995] possibly had mild involvement. Recently, females ascertained through families with classically affected males have been shown to have mild hearing impairment and focal dystonia (e.g., "writer's cramp") [Swerdlow & Wooten 2001, Swerdlow et al 2004]. While skewed X-chromosome inactivation may contribute to this phenomenon [Orstavik et al 1996, Plenge et al 1999], X-chromosome inactivation studies were not reported in the families with the most severely involved heterozygous females [Swerdlow & Wooten 2001, Swerdlow et al 2004].
Female probands have been reported [Swerdlow & Wooten 2001, Klempir et al 2010, Ha et al 2012].
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].
Genotype-Phenotype Correlations
The limited number of affected individuals, the extremely variable clinical course, and the family-specific nature of each pathogenic variant identified limits detection of genotype-phenotype correlations.
It is noteworthy that the clinical features of DDON in individuals with a contiguous gene deletion and in individuals with smaller pathogenic variants are indistinguishable, apart from presence or absence of X-linked agammaglobulinemia in those with a contiguous gene deletion [Tranebjaerg 2012] (see Genetically Related Disorders).
Nomenclature
In 1960, Mohr and Mageroy described an X-linked recessive childhood-onset sensorineural hearing impairment, which was believed to be nonsyndromic and thus was designated DFN-1, indicating that it was the first described X-linked nonsyndromic form of hearing impairment [Mohr & Mageroy 1960]. Tranebjaerg et al [1995] reinvestigated the family, updated the pedigree, and identified associated neurologic, visual, and behavioral findings. The syndrome was renamed Mohr-Tranebjaerg syndrome and later deafness-dystonia-optic neuronopathy (DDON) syndrome.
Opticoacoustic nerve atrophy (Jensen syndrome), reported by Jensen [1981], Jensen et al [1987], and Reske-Nielsen et al [1988], and deafness-dystonia syndrome, reported clinically in two families by Scribanu & Kennedy [1976] and Hayes et al [1998], are the same as DDON syndrome. TIMM8A pathogenic variants have been identified in individuals with these two disorders [Tranebjaerg et al 1997, Tranebjaerg et al 2000b, Tranebjaerg et al 2001].
Prevalence
The prevalence of DDON syndrome is unknown. It has been identified in several populations worldwide.
A recent comprehensive review chapter identified 91 affected individuals from 37 families [Tranebjaerg 2012].
Dystonia of all types occurs with a prevalence between 70 and 329 per million [ESDE Collaborative Group 2000]. No large-scale molecular genetic testing of cohorts of males with dystonia has been published.
Hearing impairment has a prevalence of 1:800, approximately 1% of which is attributed to X-linked inheritance.
Differential Diagnosis
Specific disorders that share features with deafness-dystonia-optic neuronopathy (DDON) syndrome. See Table 2.
Note: De novo pathogenic variants in TIMM8A in some families may mimic autosomal recessive inheritance and thus complicate the ability to distinguish between X-linked and autosomal causes of dystonia.
Table 2.
Other Genes of Interest in the Differential Diagnosis of DDON Syndrome
| Gene(s) 1 | Disorder | MOI | Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/DDON syndrome | Distinguishing from DDON syndrome | |||
| MT-TL1 2 | MELAS | Mat |
|
|
| SERAC1 | MEGDEL syndrome | AR | Dystonia & deafness | Leigh-like features, impaired oxidative phosphorylation, & 3-methylglutaconic aciduria |
| SUCLA2 | SUCLA2-related mtDNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria 3 | AR |
|
|
| PRPS1 | Arts syndrome 4 | XL | Intellectual impairment, ataxia, & hearing impairment | Arts syndrome findings range from isolated hearing impairment to hearing impairment assoc w/optic atrophy, hypotonia, ataxia, ID, & signs of peripheral neuropathy, but not dystonia. |
| XK | McLeod neuroacanthocytosis syndrome | XL | Movement disorder, cognitive impairment, & psychiatric symptoms in males |
|
| CDH23 CIB2 MYO7A PCDH15 USH1C USH1G USH1H 5 | Usher syndrome type I | AR |
|
|
| ADGRV1 USH2A WHRN 5 | Usher syndrome type II | AR | ||
| WFS1 | Wolfram syndrome | AR |
|
|
| FXN | Friedreich ataxia | AR |
|
|
AR = autosomal recessive; CNS = central nervous system; ERG = electroretinogram; ID = intellectual disability; Mat = maternal; MELAS = mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes; MOI = mode of inheritance; mt = mitochondrial; RBC = red blood cell; XL = X-linked
- 1.
Genes are in alphabetic order.
- 2.
The m.3243A>G pathogenic variant in the mitochondrial gene MT-TL1 is present in approximately 80% of individuals with MELAS. Pathogenic variants in MT-TL1nor other mtDNA genes, particularly MT-ND5, can also cause this disorder.
- 3.
The disorder was identified in a Muslim family and ten remotely related individuals from the Faroe Islands, where a high carrier frequency (1 in 33) is caused by a founder variant [Ostergaard et al 2007].
- 4.
See also other heredodegenerative X-linked disorders characterized by intellectual impairment, movement disorder, and hearing impairment, including Farlow syndrome (OMIM 301840), Schimke syndrome (OMIM 312840), Wells syndrome (OMIM 312910), and Schmidley syndrome (OMIM 301790).
- 5.
See Phenotypic Series: Usher syndrome for additional genes associated with this phenotype in OMIM.
- 6.
Ophthalmoscopy and electroretinography can be used to determine the cause of visual impairment.
Hearing impairment. Hearing impairment shows genetic heterogeneity (see Hereditary Hearing Loss and Deafness Overview). The diagnosis of DDON syndrome needs to be considered in males with prelingual hearing impairment in the absence of family history of hearing loss if more common genetic causes (e.g., DFNB1, Pendred syndrome) have been excluded. X-linked hearing impairment without additional manifestations may be linked to other DFN loci (see DFNX1 Nonsyndromic Hearing Loss and Deafness).
The presence of immunodeficiency and hearing impairment in a male should raise the possibility of a contiguous gene deletion at Xq22 involving TIMM8A and BTK.
Dystonia. Dystonias are a heterogeneous group of disorders (see Hereditary Dystonia Overview). Hearing impairment does not appear to be commonly associated with other dystonias.
Management
Evaluations Following Initial Diagnosis
Affected males. To establish the extent of disease and needs in a male diagnosed with deafness-dystonia-optic neuronopathy (DDON) syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Males with DDON Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Hearing impairment | Formal audiologic assessment w/focus on possibility of auditory neuropathy | To determine extent of hearing impairment |
| Speech & language assessment | To determine speech therapy needs | |
| Dystonia/Ataxia | Neurologic assessment | To provide baseline information |
| Orthopedics / physical medicine & rehabilitation / PT / OT evaluation | Incl assessment of:
| |
| Vision impairment | Ophthalmologic evaluation incl VEP | Incl visual acuity, color vision testing, visual field testing for evidence of central scotomas |
| Development | Developmental assessment; consider specialized testing for deaf &/or visually impaired persons. | Incl motor, adaptive, cognitive evaluation for early intervention / special education |
| Psychiatric/ Behavioral | Neuropsychiatric evaluation | For individuals w/dementia &/or psychiatric disturbance |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor | Incl genetic counseling |
| Family support/resources | Assess:
|
OT = occupational therapy; PT = physical therapy; VEP = visual evoked potential
Heterozygous females. The evaluation of a heterozygous female depends on whether she is a symptomatic proband (see Table 3) or primarily a healthy female relative of a male proband.
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with DDON Syndrome
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Poor visual acuity / blindness | Corrective lenses / standard treatment | Community vision services through early intervention or school district |
| Hearing impairment / deafness | Treatment of SNHL, w/focus on auditory neuropathy, depends on degree of hearing impairment. 1 |
|
| Cochlear implant |
| |
| Communication |