First Report of a Filipino with Mohr-Tranebjaerg Syndrome
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Video 1. Generalized dystonia in the index patient (mutation in TIMM8A, Mohr-Tranebjaerg syndrome), observed at rest and worsening during voluntary tasks. Choreiform movements of the left arm are also observed.
Authors: Johanna Melissa Penamora-Destriza, Aloysius Domingo, Thomas G.P.M. Schmidt, Ana Westenberger, Christine Klein and Raymond Rosales
Article first published online: 26 AUG 2015 | DOI: 10.1002/mdc3.12210
A number of inherited dystonia syndromes combine dystonia with parkinsonism or other neurological deficits. Of special interest and relevance to Filipinos is X-linked dystonia-parkinsonism (XDP, DYT3, “Lubag”; OMIM#314250), exclusively described thus far in males originating from Panay Island, Philippines. Dystonia in combination with parkinsonism, X-linked mode of inheritance, ancestry from the island, and the observation of an “XDP haplotype” upon genetic testing support this diagnosis.
Mohr-Tranebjaerg syndrome (MTS), or deafness-dystonia-optic neuropathy syndrome (OMIM#304700), also X-linked, is a rare progressive neurodegenerative disorder resulting from mutations in the TIMM8A gene. The prominent clinical manifestation resembles XDP in that the dystonia is focal, segmental, or multifocal at onset, with a predilection for the upper body regions. Furthermore, the dystonia also later generalizes (as with XDP), regardless of disease onset. Additional features that distinguish MTS from XDP include cognitive decline and progressive sensorineural hearing impairment.
We investigated the clinical and genetic features of a Filipino man with childhood-onset hearing impairment, adolescent-onset dystonia, and cognitive decline. After obtaining informed consent, general physical and neurological examinations, assessment of depression (Hamilton Depression Rating Scale; HAM-D) and cognitive impairment (Mini–Mental Status Exam [MMSE] and Montreal Cognitive Assessment [MoCA]), hemograms, blood chemistries, liver function, and ceruloplasmin testing, electromyography and nerve conduction velocity studies (EMG-NCV) on all extremities, EEG, cranial MRI, and visual and auditory evoked response studies were performed. DNA from blood from the index patient and his brother were analyzed for the presence of the XDP haplotype (methods described elsewhere[3, 5]) and were used for direct sequencing of the coding regions of the TIMM8A gene.
The index patient is a 21-year-old male who sought consultation for dystonia. Decreased hearing and delayed speech were recognized at 3 years of age. At age 9, he was prescribed hearing aids after otological evaluation. At 14, dystonia started and he had writing difficulties using the right hand, followed shortly by involuntary neck movements. Despite these, he finished school and was able to participate in sports. At 18 years of age, he developed oromandibular dystonia (OMD). The suspected clinical diagnosis then was XDP, resulting from focal dystonia that generalized and ancestry from Panay Island. Neurological examination revealed good mental function, normal fundoscopic findings, and bilateral sensorineural hearing loss. OMD, neck stiffness with anterocollis, and shoulder dystonia with choreiform arm movements were observed (see Video 1).
The patient was given clonazepam and biperiden; oromandibular and cervical botulinum toxin A injections were administered at 3- to 4-month intervals, with the goal of improved feeding and reducing severe neck hypertonia.
The patient's older brother was likewise deaf since childhood and started to have dystonia at age 16 years. At 18, he was mute-deaf, with severe cervical and bilateral hand dystonia. Their maternal grandmother hails from Panay Island. There is no dystonia or deafness from maternal relatives (Fig. 1).
Figure 1. Pedigree of brothers with deafness and dystonia. No information is available about the brothers of their maternal great grandmother.
Additionally, the index patient has mild depression on HAM-D (score of 9), MMSE was 22/30, and MoCA score was 11/30. All ancillary tests were noncontributory apart from auditory evoked potentials that showed absent responses bilaterally.
On genetic testing, both brothers were negative for the disease-specific XDP haplotype. Sequencing of TIMM8A revealed an A>G transition occurring at the first nucleotide of exon 1 in both (c.1A>G; p.Met1?; Fig. S1). This mutation is not present among >87,500 alleles screened within the Exome Aggregation Consortium (ExAC).
TIMM8A codes for translocase of inner mitochondrial membrane 8 (Yeast) homolog A. This protein is a mitochondrial intermembrane chaperone that is involved in the import and insertion of multipass hydrophobic transmembrane proteins from the cytoplasm into the mitochondrial inner membrane.
Loss-of-function mutations of the TIMM8A protein manifest as MTS, characterized as sensorineural hearing impairment in early childhood, slowly progressive ataxia or dystonia in adolescence, visual impairment secondary to optic atrophy beginning at approximately 20 years of age, and dementia beginning usually at age 40.[4, 7] To date, a total of only 91 affected individuals from 37 different families of different ethnicities have been identified. Of these, only six come from the Asian population (i.e., Japanese). We found a novel c.1A>G transition in TIMM8A in our patients, replacing the start methionine, leading either to a complete lack of TIMM8A (p.0) or to a new translation initiation site up- or downstream of the original one, possibly with an alternative reading frame.
In the Philippines, the XDP Registry (updated January 2010) has identified 505 cases. Meanwhile, this is the first report of a genetically confirmed case of MTS in a Filipino. The patient and his brother, with ancestors from Panay Island, clinically resemble XDP, but the presence of early deafness and cognitive impairment are red flags against the diagnosis. Accordingly, genetic testing for the XDP haplotype was negative in both brothers.
Accompanying neurological features suggest alternate diagnoses when detected promptly, and confirmatory genetic testing is helpful in these cases. In a population where certain dystonia syndromes are prevalent owing to a founder haplotype, the recognition of additional features is vital in the detection of another condition.