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 Xq22.1 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, and vision assessments in childhood; regular physical therapy and 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 Xq22.1 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 a pregnancy at increased risk and preimplantation genetic testing are possible if the DDON-causing genetic alteration in the family is known.

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 (or likely pathogenic) variant in a male proband (~50% of affected males) or a heterozygous TIMM8A pathogenic (or likely pathogenic) variant in a female proband (~50% of affected females)
• A contiguous gene deletion of Xq22.1 involving TIMM8A (~50% of affected males and females)

Note: (1) 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. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (3) Identification of a hemizygous or heterozygous TIMM8A variant of uncertain significance does not establish or rule out the diagnosis.

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.

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.

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.

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.

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

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Deafness-dystonia-optic neuronopathy (DDON) syndrome is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the DDON syndrome-causing genetic alteration (i.e., a pathogenic variant in TIMM8A or a contiguous gene deletion at Xq22.1); therefore, he does not require further evaluation/testing.
• If a male proband has a sib with the same DDON syndrome-causing genetic alteration, the mother of the proband is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the DDON syndrome-causing genetic alteration cannot be detected in her leukocyte DNA, she most likely has germline mosaicism (maternal germline mosaicism has been suspected but not molecularly proven in any published cases).
• If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous for the DDON syndrome-causing genetic alteration or the affected male may have a de novo DDON syndrome-causing genetic alteration, in which case the mother is not a heterozygote. De novo deletions have been documented in multiple cases [Tranebjaerg et al 2000a, Blesa et al 2007, Brookes et al 2008, Tranebjaerg 2012].

Parents of a female proband

• A female proband may have inherited the DDON syndrome-causing genetic alteration from either her mother or her father, or the DDON syndrome-causing genetic alteration may be de novo.
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo DDON syndrome-causing genetic alteration from those with an inherited genetic alteration. Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can help to determine if the genetic alteration was inherited. (Note: Parental germline mosaicism would not be detected by molecular genetic testing of leukocyte DNA.)

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has a DDON syndrome-causing genetic alteration, the chance of transmitting it 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 present with mild hearing loss or focal dystonia at an older age (see Clinical Description, Heterozygotes).
• If the proband represents a simplex case and if the DDON syndrome-causing genetic alteration cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Sibs of a female proband. The risk to sibs depends on the genetic status of the parents:

• If the mother of the proband has the DDON syndrome-causing genetic alteration, the chance of transmitting it 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 present with mild hearing impairment or focal dystonia at an older age (see Clinical Description, Heterozygotes).
• If the father of the proband has a DDON syndrome-causing genetic alteration, he will transmit it to all of his daughters and none of his sons.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the DDON syndrome-causing genetic alteration cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.

Offspring of a male proband. Males who reproduce pass the DDON syndrome-causing genetic alteration to all of their daughters and none of their sons.

Offspring of a female proband. Women with a DDON syndrome-causing genetic alteration have a 50% chance of transmitting the genetic alteration to each child.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the genetic alteration, the parent's family members may be at risk.

Heterozygote Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is possible if the DDON syndrome-causing genetic alteration in the family has been identified.

Specific risk issues. The absence of manifestations in most young heterozygous females may present families with additional challenges in clarifying risk status if the DDON syndrome-causing genetic alteration in the family has not been identified. It is unknown whether X-chromosome inactivation studies could be used to detect skewed X-chromosome inactivation in heterozygotes.

Related Genetic Counseling Issues

The progression of individual symptoms shows considerable inter- and intrafamilial variability, making a reliable prediction of the degree of severity difficult. Some families have shown skewed X-chromosome inactivation in heterozygous females, which may explain the occurrence of mild manifestations in some heterozygous females [Orstavik et al 1996, Plenge et al 1999].

Family planning

• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the DDON syndrome-causing genetic alteration has been identified in the family, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TIMM8A encodes the 97-amino acid mitochondrial import inner membrane translocase subunit TIMM8A involved in the mitochondrial transport processes. The yeast ortholog, Tim8p, is similar to five small yeast mitochondrial intermembrane space proteins – Tim8p, Tim9p, Tim10p, Tim12p, and Tim13p – but is most similar to Tim8p, which exists as a soluble 70-kd complex with Tim13p and Tim9p [Koehler et al 1999a, Koehler et al 1999b].

TIMM8A contains putative Zn-binding domains with four conserved cysteine residues. The product is involved in mitochondrial protein import [Koehler et al 1999a, Koehler et al 1999b], and like the yeast Tim8p, it assembles in a 70-kd complex in the mitochondrial intermembrane space with mitochondrial import inner membrane translocase subunit TIMM13, the protein encoded by TIMM13. Evidence from yeast indicates that this complex is critical for the import of TIMM23, which therefore may be insufficiently present in the inner membrane, resulting in the human disorder [Roesch et al 2002].

Protein expression and immunocytochemical studies indicate that TIMM8A and TIMM13 are coexpressed at high levels in Purkinje cells in the cerebellum, but not in glial cells [Roesch et al 2004]. Expression and import studies show that the calcium-binding aspartate/glutamate carriers, citrin and aralar1, are new substrates for the TIMM8A/TIMM13 protein complex [Roesch et al 2004]. The morphology of muscle mitochondria and biochemical characterization are only borderline abnormal [Koehler et al 1999a, Koehler et al 1999b, Paschen et al 2000, Tranebjaerg et al 2000a, Rothbauer et al 2001, Tranebjaerg et al 2001].

Mechanism of disease causation. DDON occurs through a loss-of-function mechanism.

Deletion of TIMM8A as part of a contiguous gene deletion that includes BTK occurs frequently, resulting in the presence of both DDON and X-linked agammaglobulinemia (XLA) [Tranebjaerg 2012]. Of note, deletion breakpoints preferentially involve Alu elements in smaller deletions (<10 kb) in individuals with both DDON and XLA [Arai et al 2011, Tranebjaerg 2012].

Although some variants are inherited, de novo variants are often observed [Tranebjaerg 2012].

TIMM8A-specific laboratory technical considerations

• TIMM8A comprises only two exons.
• TIMM8A has a pseudogene, TIMM8AP1. Since TIMM8AP1 is a processed pseudogene, and since there are a sufficient number of sequence differences between the gene and pseudogene, it appears unlikely that TIMM8AP1 will interfere with the analysis of TIMM8A.

Revision History

• 21 November 2019 (bp) Comprehensive update posted live
• 31 January 2013 (me) Comprehensive update posted live
• 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically
• 3 April 2008 (me) Comprehensive update posted live
• 8 April 2005 (me) Comprehensive update posted live
• 5 February 2004 (cd) Revision: change in testing
• 6 February 2003 (me) Review posted live
• 23 August 2002 (lt) Original submission

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