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Deafness-Dystonia-Optic Neuronopathy Syndrome

Synonyms: DFN-1, Deafness-Dystonia Syndrome, Mohr-Tranebjaerg Syndrome
, MD, PhD
Professor of Medical Genetics and Genetic Audiology
Department of Audiology
H:S Bispebjerg Hospital
Wilhelm Johannsen Center for Functional Genomics
Institute of Cellular and Molecular Medicine
The Panum Institute
University of Copenhagen
Copenhagen, Denmark
; kd.uk.dnus@greajbenart

Initial Posting: ; Last Update: January 31, 2013.

Summary

Disease 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 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. DDON syndrome occurs as either a single-gene disorder resulting from mutation in TIMM8A or a contiguous gene deletion syndrome at Xq22, which also includes X-linked agammaglobulinemia caused by disruption of BTK, located telomeric to TIMM8A. The diagnosis of DDON syndrome is established by clinical findings.

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. Dystonia and associated symptoms may improve with GABA β-agonists.

Prevention of secondary complications: Intravenous immunoglobulin (IVIG) to prevent bacterial infections when agammaglobulinemia is present.

Surveillance: Regular neurologic evaluation and assessment for dementia and/or psychiatric manifestations; annual developmental and speech/language assessments in childhood.

Agents/circumstances to avoid: Live viral vaccines if agammaglobulinemia is present.

Genetic counseling. DDON syndrome is inherited in an X-linked manner. Women who are carriers have a 50% chance of transmitting the TIMM8A mutation in each pregnancy. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and may have mild hearing loss or focal dystonia at an older age. Thus, with each pregnancy, a woman who is a carrier has a 25% chance of having an affected son. Males who are capable of reproducing pass the disease-causing mutation to all of their daughters and none of their sons. Prenatal testing for pregnancies at increased risk is possible for families in which the disease-causing mutation has been identified.

Diagnosis

Clinical Diagnosis

The deafness-dystonia-optic neuronopathy (DDON) syndrome occurs as either a single-gene disorder resulting from mutation in TIMM8A or a contiguous gene deletion syndrome at Xq22.

DDON syndrome is suspected in males with the following:

  • Progressive sensorineural hearing impairment with prelingual or postlingual onset:
  • 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 recessive inheritance

Agammaglobulinemia can occur when DDON syndrome is caused by a contiguous gene deletion syndrome that also includes X-linked agammaglobulinemia (XLA), caused by deletion of BTK located telomeric to TIMM8A.

Testing

Because DDON syndrome may occur as part of a contiguous gene deletion syndrome that includes BTK, testing for the laboratory findings of XLA can be performed. Such testing includes:

  • Concentration of serum immunoglobulins. The serum IgG concentration is typically less than 200 mg/dL; the concentrations of IgM and IgA are less than 20 mg/dL [Ochs & Smith 1996, Minegishi et al 1999, Conley et al 2000]. Particular attention should be given to serum IgM concentration. Although decreased serum IgG and IgA concentrations can be seen in children with a constitutional delay in immunoglobulin production, low serum IgM concentration is almost always associated with immunodeficiency. Most (not all) males with XLA have some measurable serum IgG (usually 100-200 mg/dL) and approximately 10% of affected males have concentrations of IgG greater than 200 mg/dL.
  • Antibody titers to vaccine antigens. Males with XLA fail to make antibodies to vaccine antigens such as tetanus, H. influenzae, or S. pneumoniae.
  • Lymphocyte cell surface markers. The most consistent feature in XLA is the markedly reduced number of B lymphocytes (CD 19+ cells) in the peripheral circulation (<1%).

Molecular Genetic Testing

Gene. TIMM8A is the only gene in which mutations are known to cause DDON syndrome.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in DDON Syndrome

Test MethodMutations DetectedMutation Detection Frequency by Test Method 1
Sequence analysisTIMM8A sequence variants 2Unknown 3, 4
Deletion / duplication analysis 5Partial-, whole-, and contiguous gene deletionsUnknown 6, 7

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. The mutation detection rate has not been reported. To date, 13 individuals with mutations diagnosed by sequencing TIMM8A have been reported [Jin et al 1996, Tranebjaerg et al 2000a, Swerdlow & Wooten 2001, Tranebjaerg et al 2001, Ujike et al 2001, Varga et al 2002, Binder et al 2003, Ezquerra et al 2005, Aguirre et al 2006, Aguirre et al 2007, Blesa et al 2007, Kim et al 2007]. Five additional cases have not been reported [Tranebjaerg, unpublished]. A recent comprehensive summary of all published and otherwise identified DDON cases revealed the existence of 91 patients from 37 families [Tranebjaerg 2012]. Among them 19 cases are familial, and 18 are apparently sporadic. The de novo origin was confirmed in six instances [Tranebjaerg 2012]

4. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. Fourteen males from 11 families with a contiguous gene deletion syndrome, encompassing partial deletion of neighboring BTK, have been reported [Jin et al 1996, Richter et al 2001, Pizzuti et al 2004, Brookes et al 2007, Jyonouchi et al 2007, Sedivá et al 2007]. In one the males, the deletion extended in the centromeric direction [Jyonouchi et al 2007]. Three additional unrelated cases with deletions of TIMM8A have been observed [Tranebjaerg, unpublished]. In 16 families, DDON occurred as part of a contiguous gene deletion syndrome including BTK. As expected, in 11 of the 16 families occurrence was sporadic, and in five familial [Tranebjaerg 2012].

7. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic, multiexonic, or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish of the diagnosis in a proband. In clinically suspected cases sequence analysis of TIMM8A is the logical strategy, as TIMM8A contains only two exons.

Carrier testing for at-risk female relatives requires prior identification of the disease-causing mutation in an affected family member.

Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by deletion/duplication analysis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

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 symptom. Typically, the disease 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 symptoms such as personality change and paranoia may appear in childhood and progress. The deafness and blindness severely compromise communication in late adulthood.

The hearing impairment appears to be more consistent in age of onset and progression than the neurologic, visual, and neuropsychiatric signs, 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 age 18 months; however, some affected individuals have apparent congenital prelingual hearing impairment [Swerdlow & Wooten 2001, Ujike et al 2001]. The hearing loss progresses rapidly, with profound hearing loss typically presenting before age ten years. Vestibular function is normal.

The hearing loss results from an auditory neuropathy as shown by intact otoacoustic emissions (OAEs) 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]. However, it should be noted that some individuals with DDON syndrome have intact otoacoustic emissions [Richter et al 2001, Brookes et al 2007].

Of note, isolated hearing impairment without other manifestations of DDON syndrome has not been reported with TIMM8A mutations.

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 (SEPs) and disturbed central motor conduction to lower extremities in motor evoked potentials (MEPs) [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 (VEP) testing [Tranebjaerg et al 2001].

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.

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 (ERG) [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]. Skewed X-chromosome inactivation may contribute to this phenomenon [Orstavik et al 1996, Plenge et al 1999]; however, X-chromosome inactivation studies were not reported in the families with the most severely involved female carriers [Swerdlow & Wooten 2001, Swerdlow et al 2004].

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 findngs 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 (EM) 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.Gln38* stop mutation, but no abnormalities could be demonstrated in cultivated fibroblasts [Blesa et al 2007]. No mutations 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].

In three individuals with complete deletion of TIMM8A, respiratory chain complexes I+III in platelets were decreased to 60% but were within the normal range in liver and muscle, which also showed normal levels of mitochondrial proteins despite confirmed absence of the TIMM8a-TIMM13 complex [Sedivá et al 2007].

Genotype-Phenotype Correlations

The limited number of affected individuals, the extremely variable clinical course, and the family-specific nature of each mutation identified limits detection of genotype-phenotype correlations. It is noteworthy that the clinical features in individuals with a contiguous gene deletion and in individuals with smaller mutations are indistinguishable, apart from presence or absence of agammaglobulinemia [Tranebjaerg 2012]. Female probands have been reported [Swerdlow & Wooten 2001, Klempir et al 2010, Ha et al 2012].

The extent of the deletion in males with a contiguous deletion syndrome has been characterized in a number of individuals [Arai et al 2011, Tranebjaerg 2012]. Recent studies of deletion breakpoints have shown preferential involvement of Alu elements in smaller deletions (<10 kb) both in individuals with isolated X-linked agammaglobulinemia with deletions and in people with DDON with BTK deletion [Arai et al 2011, Tranebjaerg 2012].

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 loss [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) [OMIM 311150], reported by Jensen [1981], Jensen et al [1987], and Reske-Nielsen et al [1988], and deafness-dystonia syndrome [OMIM 304700], reported clinically in two families by Scribanu & Kennedy [1976] and Hayes et al [1998], are the same as DDON syndrome. TIMM8A mutations 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 total of at least 67 affected individuals in at least 31 different families from Norway (1 family), Denmark (1), USA (7), the Netherlands (3), Australia (3), Croatia (2), Lebanon (1), Spain (5), Japan (1), UK (1), Germany (1), Czech Republic (2), Estonia (1), Russia (1), Guadeloupe (1), and Italy (1) have been identified [Jin et al 1996; Tranebjaerg et al 2000a; Richter et al 2001; Swerdlow & Wooten 2001; Tranebjaerg et al 2001; Ujike et al 2001; Varga et al 2002; Binder et al 2003; Pizzuti et al 2004; Ezquerra et al 2005; Aguirre et al 2006; Aguirre et al 2007; Blesa et al 2007; Brookes et al 2007; Jyonouchi et al 2007; Kim et al 2007; Sedivá et al 2007; Tranebjaerg, unpublished data (2007)]. 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 recessive inheritance.

Differential Diagnosis

Specific disorders that share features with deafness-dystonia-optic neuronopathy (DDON) syndrome

Note: De novo mutations 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.

  • MELAS. The combination of optic atrophy, hearing loss, and neurologic signs suggests mitochondrial disorders such as MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes). See also Mitochondrial Disorders Overview. Dystonia is uncommon in MELAS. Short stature, generalized tonic-clonic seizures, recurrent headaches, anorexia, and recurrent vomiting are common in MELAS. Mutations in the mitochondrial DNA (mtDNA) gene MT-TL1 encoding tRNALeu(UUR) are causative.
  • MEGDEL syndrome [OMIM 614739], an autosomal recessive disorder of dystonia and deafness with Leigh-like features, impaired oxidative phosphorylation and 3-methylglutaconic aciduria, caused by mutations in the phospholipid remodeling gene SERAC1 [Wortmann et al 2012]. Fifteen affected individuals in 13 families have been identified and with a total of 14 different mutations.
  • Mitochondrial encephalomyopathy associated with SUCLA2 mutations, a progressive disorder characterized by hypotonia, dystonia, severe hearing impairment, abnormal muscle histopathology, and increased methylmalonic acid concentration. Ophthalmologic findings are normal. SUCLA2 encodes the ATP-forming β subunit of the Krebs cycle enzyme succinyl-CoA ligase [Elpeleg et al 2005, Ostergaard et al 2007]. Inheritance is autosomal recessive. 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 mutation [Ostergaard et al 2007].
  • Heredodegenerative X-linked disorders characterized by intellectual impairment, movement disorder, and hearing impairment that overlap clinically with DDON syndrome. These include: Arts syndrome, caused by mutations in PRPS1; Farlow syndrome [OMIM 301840]; Schimke syndrome [OMIM 312840]; Wells syndrome [OMIM 312910]; and Schmidley syndrome [OMIM 301790; Tranebjaerg et al 1997; Schwartz, personal communication (2002)]. TIMM8A mutations have not been identified in individuals with these disorders.
  • McLeod neuroacanthocytosis syndrome (MLS), a multisystem disorder with CNS, neuromuscular, and hematologic manifestations in males. CNS manifestations are a neurodegenerative basal ganglia disease including movement disorder, cognitive impairment, and psychiatric symptoms. Neuromuscular manifestations include a mostly subclinical sensorimotor axonopathy and clinically relevant muscle weakness or atrophy. The hematologic manifestations are red blood cell acanthocytosis, compensated hemolysis, and the McLeod blood group phenotype resulting from absent expression of the Kx erythrocyte antigen and reduced expression of the Kell blood group antigens. Heterozygous females have mosaicism for the Kell system blood group antigens and RBC acanthocytosis but lack CNS and neuromuscular manifestations. Mutations in XK are causative. Inheritance is X-linked.
  • Usher syndrome type I and Usher syndrome type II. Individuals with DDON syndrome may initially be suspected of having Usher syndrome [Kimberling, personal communication (2005)] because the hearing impairment in DDON syndrome may be congenital and the hearing impairment in Usher syndrome type II may be progressive [Sadeghi et al 2004]. In Usher syndrome type I and type II impaired vision results from retinal dystrophy, which manifests initially as impaired dark adaptation. Ophthalmoscopy and electroretinography (ERG) can be used to determine the cause of visual impairment.
  • Wolfram syndrome (WS) [OMIM 222300], an autosomal recessive neurodegenerative disorder characterized by juvenile onset of diabetes mellitus and optic atrophy that involves most organs. Hearing impairment is present in approximately 60% of affected individuals by age 20 years. A movement disorder, dementia, diabetes insipidus, and psychiatric abnormalities may occur. Mutations in WFS1, encoding wolframin 1, are identified in more than 80% of individuals with the typical phenotype [Khanim et al 2001]. Wolfram syndrome needs to be considered in simplex males (i.e., a single occurrence in a family) who appear to have DDON syndrome.

Hearing impairment. Hearing impairment shows genetic heterogeneity (see Deafness and Hereditary Hearing Loss 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 symptoms 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 syndrome at Xq22 involving TIMM8A and BTK.

Dystonia. Dystonias are a heterogeneous group of disorders (see Dystonia Overview). Hearing impairment does not seem to be commonly associated with other dystonias. The typical first symptom in DDON syndrome is impaired hearing in childhood, which helps distinguish it from other types of dystonia, either primary or secondary [Nemeth 2002].

Ataxia. Friedreich ataxia, characterized by slowly progressive ataxia with onset usually before age 25 years, may be associated with sensorineural hearing impairment (10% of individuals) and often subclinical optic atrophy (25% of individuals), but individuals with Friedreich ataxia rarely present with hearing impairment or optic atrophy. In contrast, hearing loss is always a presenting finding in DDON syndrome. Dystonia and other movement disorders are uncommon in Friedreich ataxia. Tendon reflexes are usually (not always) depressed in Friedreich ataxia and brisk in DDON syndrome. Cardiomyopathy is common in Friedreich ataxia and is not observed in DDON syndrome. Inheritance of Friedreich ataxia is autosomal recessive. Molecular genetic testing of FRDA detects disease-causing GAA trinucleotide repeat expansions in more than 95% of affected individuals and other sequence variants in the remainder.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with deafness-dystonia-optic neuronopathy (DDON) syndrome, the following evaluations are recommended:

Affected males

  • Neurologic evaluation for dystonia and ataxia
  • Screening developmental assessment in children for early intervention and special educational planning
  • Formal audiologic assessment
  • Speech and language evaluation for assessment of speech therapy requirements
  • Ophthalmologic evaluation, including ERG
  • In adults, evaluation for dementia and/or psychiatric disturbance
  • Medical genetics consultation

Carrier females

  • Audiologic assessment
  • Neurologic evaluation for focal dystonia
  • Medical genetics consultation

Treatment of Manifestations

Educational. Educational programs appropriate to the developmental and sensory deficits, including training in tactile sign language, should be provided.

Audiologic. Hearing aids have been used in affected males with only variable success [Tranebjaerg et al 1995], probably because of the central location of the auditory damage. The use of cochlear implantation (CI), reported in one instance, had a dubious outcome in a four year-old boy with immunodeficiency and DDON syndrome caused by a de novo deletion of exon 1 of TIMM8A and deletion of exons 17-19 of BTK [Brookes et al 2007].

Dystonia. Dystonia and associated neck pain and spasticity improved over a two-year period in two individuals treated with GABA β-agonists [Kreisel et al 2004]. In contrast, symptoms did not seem to improve with treatment with levodopa, carbamazepine, or trihexyphenidyl hydrochloride [Ujike et al 2001].

Favorable short-term outcome as assessed by the Burke-Fahn-Marsden dystonia rating scale from pallidal deep brain stimulation has been reported in two cases of DDON. However, longer-term benefit in additional patients has not yet been reported [Romito et al 2011, Cif et al 2012].

Ophthalmologic. Spectacle correction is appropriate where indicated.

Prevention of Secondary Complications

Agammaglobulinemia (see X-Linked Agammaglobulinemia). Management focuses on prevention of bacterial infections with the use of intravenous immunoglobulin (IVIG).

Surveillance

The following are appropriate:

  • Long-term follow-up to monitor the highly variable rate of progression and degree of involvement of different organ systems
  • Regular neurologic evaluations to follow the progression of dystonia and consider pharmacologic treatment
  • Annual developmental and speech/language assessment in childhood, with appropriate adaptation of educational programming
  • Annual audiologic assessment
  • Regular assessment for dementia and/or psychiatric manifestations, with initiation of appropriate care or treatment

Agents/Circumstances to Avoid

Live viral vaccines should be avoided if agammaglobulinemia is present.

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 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

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

  • If the mother is a carrier, the chance of transmitting the TIMM8A mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and may present with mild hearing loss or focal dystonia at an older age. Thus, with each pregnancy, a woman who is a carrier has a 25% risk of having an affected child.
  • If the disease-causing mutation cannot be detected in DNA from the leukocytes of the mother of the only affected male in a family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Males who reproduce pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members of the proband. The proband's maternal aunts and their offspring may be at risk of being carriers or of being affected (depending on their gender, family relationship, and the carrier status of the proband's mother).

Carrier Detection

Carrier testing of at-risk female relatives is possible if the disease-causing mutation in the family has been identified.

Specific risk issues. The absence of symptoms in most female carriers may present families with additional challenges in clarifying risk status. It is unknown whether X-chromosome inactivation studies could be used to detect skewed X-chromosome inactivation in carriers.

Related Genetic Counseling Issues

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

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing is possible for pregnancies of women who are carriers if the TIMM8A mutation has been identified in the family. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Dystonia Society
    89 Albert Embankment
    3rd Floor
    London SE1 7TP
    United Kingdom
    Phone: 0845 458 6211; 0845 458 6322 (Helpline)
    Fax: 0845 458 6311
    Email: support@dystonia.org.uk
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    #2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • Dystonia Medical Research Foundation
    One East Wacker Drive
    Suite 2810
    Chicago IL 60601-1905
    Phone: 800-377-3978 (toll-free); 312-755-0198
    Fax: 312-803-0138
    Email: dystonia@dystonia-foundation.org
  • my baby's hearing
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Deafness-Dystonia-Optic Neuronopathy Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Deafness-Dystonia-Optic Neuronopathy Syndrome (View All in OMIM)

300356TRANSLOCASE OF INNER MITOCHONDRIAL MEMBRANE 8, YEAST, HOMOLOG OF, A; TIMM8A
304700MOHR-TRANEBJAERG SYNDROME; MTS
311150OPTICOACOUSTIC NERVE ATROPHY WITH DEMENTIA

Molecular Genetic Pathogenesis

The DDON syndrome was the first example of a disorder in which the underlying functional mechanism in yeast was correlated with a human disorder. The DDON syndrome is an example of mitochondrial dysfunction resulting from mutations in a nuclear gene; however, the specific mechanisms of mitochondrial dysfunction have not yet been resolved. Deficient assembly of the TIMM8a-TIMM13 complex in human fibroblasts has been observed in vitro in research studies [Hofmann et al 2002, Roesch et al 2002, Roesch et al 2004].

Normal allelic variants. The TIMM8A cDNA is 1,167 bp in length, excluding the poly(A)+ tail [Jin et al 1996]. The gene has two exons. The nucleotide change c.796_798dupTGA in TIMM8A is a normal allelic variant found in 27/29 Norwegian normal control males.

Pathologic allelic variants. To date, 32 unrelated individuals have been identified with TIMM8A mutations, including the following:

The missense mutations, one nonsense mutation [Blesa et al 2007], and one splice site mutation [Tranebjaerg, unpublished] arose de novo [Tranebjaerg et al 2000a, Binder et al 2003] (see Table 2).

Table 2. TIMM8A Allelic Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Normal c.796_798dupTGA
(831InsTGA)
--NM_004085​.2
NP_004076​.1
Pathologic c.112C>Tp.Gln38*
c.198C>Gp.Cys66Trp

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. The encoded peptide consists of 97 amino acids with a predicted molecular weight of 11 kd. The peptide is involved in mitochondrial transport processes; however, 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].

Mitochondrial import inner membrane translocase subunit Tim8 A is similar to five small proteins: Tim8p, Tim9p, Tim10p, Tim12p, Tim13p (encoded by TIM8, TIM9, MRS11, MRS5, and TIM13, respectively) of the yeast mitochondrial intermembrane space, 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]. The human orthologs of the yeast genes TIM9, MRS11, MRS5, and TIM13 map to autosomal chromosomal loci and are candidate genes for other hearing impairment/heredodegenerative disorders. Mitochondrial import inner membrane translocase subunit Tim8 A (named to distinguish it from the different members of this protein family) 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 the protein encoded by TIMM13, mitochondrial import inner membrane translocase subunit Tim13. Evidence from yeast indicates that this complex is critical for the import of Tim23, 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 (encoding mitochondrial import inner membrane translocase subunit Tim8 A) and TIMM13 (encoding mitochondrial import inner membrane translocase subunit Tim13) 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].

Abnormal gene product. Individuals with complete deletion of TIMM8A or with intragenic mutations causing a frameshift have absent, truncated, or malfunctioning protein. The p.Cys66Trp missense mutation disrupts the second CX(3)C domain and was identified in an individual with a phenotype as severe as that seen in individuals with nonsense mutations. In vitro studies have shown that the consequence of the missense mutation is deficient assembly of TIMM8A-TIMM13 into a 70-kd complex [Hofmann et al 2002, Roesch et al 2002], the likely consequence of which is an effect on the import and insertion of hydrophobic membrane proteins into the inner mitochondrial membrane.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Chapter Notes

Revision History

  • 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 to live Web site
  • 8 April 2005 (me) Comprehensive update posted to live Web site
  • 5 February 2004 (cd) Revision: change in testing
  • 6 February 2003 (me) Review posted to live Web site
  • 23 August 2002 (lt) Original submission
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