What is it? A young boy with deafness and twisting limb movements

It's on making expert reasoning visible. How hypotheses are formed, revised, and sometimes discarded as new information emerges. I'm your host, Hugo Morales, and in this episode I'm discussing a case with Associated Professor, Ai Huey Tan movement disorder specialist at the University in Malaya, in Kuala Lumpur.

Ai Huey, thank you for coming today.

Dr. Ai Huey Tan: Thank you very much for inviting me, Hugo.

Dr. Hugo Morales Briceno: It is a pleasure having you here. Now I'll start by reading the patient's [00:01:00] clinical history and neurological examination findings to our listeners, and then I will ask you to describe the phenomenology of the patient's video. Now let's go to the case. This is a 21-year-old right-handed Filipino male. Who presented with a progressive writing difficulty due to hand twisting, starting at the age of 14, followed by involuntary neck movements shortly after the hand. Despite these, he finished school and was able to participate in sports. At the age of 18, he developed involuntary jaw movements. His prenatal and early developmental history was normal. His older brother also had some problems with hearing as this patient had and developed abnormal limb posturing at age 16.

So overall, this is a patient that presented progressive writing difficulties then neck and then jaw in the context of hearing loss. There's no history [00:02:00] of tremor, Parkinsonism, dystonia, or dementia in the family for at least the last three generations. Their maternal grandmother was from Panay the Philippines, but she had no relatives with dystonia or Parkinsonism. And the examination of this patient showed a normal mental function. He had a MOCA test score of 12 out of 30, and a mental of 22 outta 30. The eye movements were normal. Motor strain power is normal as well as reflexes and sensory examination. It had normal fundoscopic examination, however, there was a profound bilateral sensory neuronal hearing loss. Now let's go to the video Ai Huey, what do you think what we seen in the video? And can you describe the phenomenlogy for us please?

Dr. Ai Huey Tan: Yeah. Thank you very much for sharing this interesting case, Hugo. So when we see in this video when seated at rest [00:03:00] this young man had a sustained abnormal posture and movement involving predominantly his upper body. These movements are pattern and repetitive. Some with the twisting nature and some, especially the neck and the upper limb movements worsen with voluntary action.

Based on this, the main phenomenology we see in this video here is dystonia. Now on a closer look we see this young man also has a jaw opening oral mandibular dystonia. He has a cervical dystonia characterized by an anterocollis and in some segments of the video, a right torticollis as well. His right upper limb seem to be hyper extended at the elbow with dystonic posturings of his fingers while his left upper limb is flexed at the elbow and hyper extended at the wrist with his left hand, mainly in a fisted [00:04:00] position in most segments. His left upper limb movement, I must say, is somewhat less predictable at times and also irregular compared to the other movements we see in other parts of the body. And this is especially so at the proximal joint or the shoulder joint.

And one, we also start thinking of a possible chorea ballistic movement here. And I think that further examination of the left upper limb will be warranted as well. But taken together, the main phenomenology that we see in this young man is dystonia predominantly involving the lower face, the neck, and both the upper limbs.

Dr. Hugo Morales Briceno: Thank you Ai Huey. Now thinking about the distribution of dystonia and when you're mentioning about the oromandibular dystonia. So what are you thinking in a 21-year-old with oromandibular dystonia was evocative diagnostic pathways, what do you [00:05:00] think in this cases.

Dr. Ai Huey Tan: Yeah. Certainly the body distribution of dystonia is an important note. Here we see a predominant upper body involvement with very prominent oromandibular dystonia. Now there are several conditions that can present with very prominent oral mandibular dystonia acquired causes like tardive dystonia can also present with oromandibular dystonia, and let's not forget that, but there are quite a long list of genetic disorders that can present with prominent oromandibular dystonia. And I want to first mention the treatable Wilson's disease. Let's not forget this in this context. Secondly is also the neuro degenerative brain, ion accumulation disorders such as PKAN and then also inborn error of metabolism such as GM1 gangliosidosis, and also glutaric acidemia. [00:06:00] Now we also need to consider other genetic dystonias that can commonly present with predominant oromandibular dystonia involvement including KMT2B BRKRA Type 1, ATP1a3, and VPS 16. Now, not to forget X-linked dystonia Parkinsonism here I'm particularly mentioning this because in the history we were told that the maternal grandmother is from Panay, Philippines. And we know that X-linked dystonia Parkinsonism or XDP is an X-linked dystonia where it has been exclusively described among male individuals from Panay. However in XDP usually they present at an older age of onset, p robably early to mid adulthood. And they do not present with deafness such as in this case where the patient also have early childhood onset deafness.

Dr. Hugo Morales Briceno: [00:07:00] I like your approach with the differential diagnosis based on phenomenology and before moving to the results of the first line investigations. The presence of this symptoms, the distribution, the family history, this is something that straightforward makes you think of this is most likely genetic as opposed to acquire.

And perhaps this is relevant in the context of any patient with dystonia deafness, one of the most common things of this combination is, but this patient that didn't have any history of that. Now we heading into this genetic diagnostic category, I'm gonna give you the results of the investigations that can help you to delineate what your differential diagnosis.

The liver, renal, and hematological tests were normal. Cerulo plasmin and copper were normal. Alpha-fetoprotein was normal. He had a brain MRI that was reported to be [00:08:00] normal. And this is the case in the report. Additional investigations include nerve conduction studies with electromyography, which were also normal and EEG and auditory evoke potentials, showed absent responses bilaterally. So this is something that supports your diagnosis of the deafness. Now you have this construct of your syndrome with negative or normal investigations. What then is the next step to support your diagnostic hypothesis? What test would you like to request in this case?

Dr. Ai Huey Tan: Yeah. Thanks very much Hugo. Maybe we can probably discuss a little bit more about the approach to this case. Besides looking at the body distribution of the dystonia. I think as you have mentioned, age of onset and family history is quite important, and here we have an [00:09:00] adolescent onset case with a positive family history with an older brother having the same deafness dystonia syndrome, making a genetic cause more likely. Now regards to the family pedigree, it looks like the syndrome only affected one single generation in this family, and this might indicate an autosomal recessive pattern of inheritance, or autosomal dominant with reduce penetrance, or as both affected individuals are male then X-linked disorders need to be also considered. Now, an important note to look out for in a family pedigree for X-linked disorders is that there should not be any male to male transmission or ie. the father passing the genetic traits to the son in the family.

And if we think about x-linked related disorder that cause deafness, dystonia syndrome, we are thinking about Mohr-Tranebjaerg syndrome, or [00:10:00] another hypo myelinating disorder, such as BCAP31 disorder, which can present with very severe intellectual disability. Now, besides the age of onset and family history and body distribution in dystonia, it's always very important to look for other associated features such as, other movement disorders such as Parkinsonism or myoclonus.

The presence of developmental delay, learning difficulty, cognitive decline or epilepsy as well as vision and hearing loss in the dystonia cases we see in clinic. And in this case, patient did have a combined dystonia, and here we are looking at a deafness dystonia syndrome. As you have mentioned, is important to make sure this is not an acquired cause, like a perinatal insult, such as hypoxic ischemic injury or neonatal infection in the past, and then we can also [00:11:00] look for any presence of facial dysmorphism that may suggest other deafness dystonia syndrome such as ACTB disorder. The other group of diagnosis related to deafness dystonia syndrome will be our mitochondrial disorders or inborn error metabolism such as methylmalonic acidemia, as well as LAR two.

And these patients sometimes can have fluctuations in their model conditions recurrent encephalopathy, for example. And I think this is an important point to look out for. And also not to forget the Woodhouse Sakati syndrome that present with alopecia, diabetes, as well. So I think that in terms of the investigation the first step will definitely be to have a MRI brain of the patient.

And you mentioned that the MRI brain is normal. And this is really quite helpful as I [00:12:00] think that, as we have mentioned in our differential diagnosis, it's very important to rule out mineral deposition disorders, copper or iron. As well as to make sure that we didn't miss a hypo myelination signs in the brain and also basal ganglia lesions that are associated with mitochondrial or inborn error of metabolism.

I think it's also very important to always make sure that we have done a Wilson screen and your ceruloplasmin results is negative. So taken together with these investigation a good next step will probably be considering genetic testing in this man.

Dr. Hugo Morales Briceno: Now, I'll give you some results in genetic testing. Both brothers were negative for the disease specific x-linked dystonia, Parkinsonism haplotype, so that was good. And sequencing or a gene, which is a TIMM8 A reveal adenine to [00:13:00] one in transition occurring in the first nucleotide of Exon 1.

This mutation was not present in the exome aggregation consortium, so it's considered to be pathogenic. So therefore, they confirmed the diagnosis of the  Mohr-Tranebjaerg syndrome. And here the take home messages that within the syndrome of deafness dystonia this can be acquired genetic, and the genetic etiologies can have a further syndromic associations including the dementia, cognitive decline, imaging abnormalities, serum biomarkers, and systemic signs.

This case was taken from Movement Disorder Clinical Practice. The title is The First Report of a Filipino with  Mohr-Tranebjaerg syndrome in 2015. Thank you very much Ai Huey for helping us to discuss this case and highlighting the approach of this syndrome and to our listeners.

Hope to see you the next time in the next case.

Dr. Ai Huey Tan: Thank you [00:14:00] very much.