What is it? Exercise-induced episodic gait disorder in a young boy

Dr. Shekeeb Mohammad: Thank you, Hugo.

Dr. Hugo Morales Briceno: So I would like to start by reading the patient's clinical history and neurological examination findings to our audience, and then I will ask you to describe what you see in terms of the video examination. Now this is a 7-year-old boy, born to non-consanguineous parents by cesarean section, with no significant perinatal events.

He had normal motor and developmental milestones. He presented with a history of abnormal posturing of the leg induced on exertion [00:02:00] from three years of age. Initially, it involved the right side and subsequently involved the left leg. It was precipitated by vigorous play and running and lasted for about 30 minutes.

There was no history of seizures. Interestingly, his younger sibling is a five-year-old boy, born by cesarean section and with normal milestones. He also had similar symptoms involved with both lower limbs in the last year. His episodes were short lasting and recover in five minutes. Both patient were treated with levodopa without any response, and his parents were neurologically normal and there was no family history of epilepsy. Now Shekeeb, tell me what do you see in the video, and if you can describe that to our audience.

Dr. Shekeeb Mohammad: Thanks for the clinical background. So I've got two videos that have been provided to me. One is at baseline and one is after this child [00:03:00] has done some exercise in the form of prolonged walking. So looking at the baseline video first, what I see is a young boy who is walking in a clinic examination room his gait appears quite normal.

There may be slight asymmetry in the arm swing, but this video snippet is too small to over draw any conclusions from the same. I cannot see any extra adventitious movements. I cannot see any posturing, and he's walking with his feet heel strike in a proper manner. He's not toe walking. So that is his baseline video.

And I can see good facial expression, symmetric arm movements apart from that slightly asymmetric arm swing, which I said we shouldn't draw too much emphasis on without seeing him a bit more.

Dr. Hugo Morales Briceno: Thank you. And you see the the second part examination. Do you see anything different from the baseline?

Dr. Shekeeb Mohammad: Okay, so now we've got another video, which is after he has been made to walk and jump. Apparently for some time, [00:04:00] we don't know the exact duration, but what we can see here is that his gait has dramatically changed. He is walking a bit more slowly still with a relatively narrow base and good balance.

But the main striking feature is posturing of both hands as well as his feet, slightly asymmetric in the feet, more on the right left, but the compared to the left, but it appears bilateral and it appears to involve the upper limb as well. So this is a change and this phenomenology, at least on the video.

Appears to be representative of what we would call as dystonic posturing as clinicians obviously need to confirm that with examining his tone. I'll just have a quick look again at his facial expression in this second video and see if he can see anything else. He was smiling in the first video.

He still is, so again we won't overdraw conclusions. Sometimes when you given movement disorder videos, you try to bracket everything, whether it is a [00:05:00] dystonic smile or grimacing, but I don't think we can say that. But what I could say is after exercise, this boy who previously had a normal gait has now got a asymmetric but generalized dystonic gait.

And dystonic posturing of the upper limbs as well.

Dr. Hugo Morales Briceno: Thank you, Shekeeb. Now I'll give you more information about his examination. He had normal cognition as per reported in the study chronical nerves. No motor and center examination were unremarkable. Reflexes were present preserved and there were no pathological reflexes or spasticity.

Importantly, there were no Kayser-Fleischer rings. Now with this information on hand, can you just build a syndrome in terms of what you saw and you know about the examination?

Dr. Shekeeb Mohammad: Okay, we have some background history. We have seen the videos and now we have got this additional information. Just to recap, his early histories thought to be normal, and he has an onset of exercise related [00:06:00] dystonia, which we've seen in the video from three years of age. As far as we know, this hasn't been associated with epilepsy or a cognitive decline, and these are important things to note that as far as we know, he doesn't have neurodevelopmental problems among developmental delay, and he has not got epilepsy. So what we are left with is a predominant history of episodic dystonia. And then when you're confronted with that history of something that is episodic or paroxysmal, then we try and see what are associations with triggers and with relieving factors.

So we know that with exercise, these episodes come on and that's been the history and that's what we have seen in the video. So with the amount of information we have what I would say is that this is suggestive of paroxysmal exercise induced dystonia in a child who's otherwise intellectually normal, doesn't have a history of [00:07:00] epilepsy, and has got a history of similar episodes in a younger brother.

Dr. Hugo Morales Briceno: Yeah. So now we have the syndrome, so paroxysmal exercise in dystonia with other normal and neurological examination, but with a family history. I'll give you some results on specifications. He had a normal full blood count including glucose, renal liver tests, including cerebral plasmin and ammonia.

And he had also lactate that was elevated to 34 milligrams of deciliter with the maximum being 19 to 20. Also it was tested with organic amino acid profile that was reported to be normal. Had a CSF where the glucose levels were also normal. Now, with this in mind, now that you have these results where this syndrome is, you think would be heading to, or what are the clues here that can help you with their diagnosis?

Dr. Shekeeb Mohammad: Again, we have [00:08:00] some additive information. I would just mention something I forgot is some negative history. So I think the time of the day when these episodes happen, any relation to fasting or not, would also be important in this case. Particularly things that happen early in the morning.

We'd be worried, wondering about problems with glucose transport, but at the same time, now that we've got the information the CSF glucose is normal which would make glucose transporter deficiency unlikely. We also are given a blood lactate level that is high. And a minor acid profile that is normal.

Wilson's disease can mimic many things, and we know that the absence of  Kayser-Fleischer rings, normal ceruloplasmin would make this very unlikely to be a neurological manifestation of Wilson's disease. So there are some things that we think would be unlikely. At the same time, I think we have to now come back and see with his history what our major differentials.

And has this helped us or [00:09:00] not? So with this boy's history so far, and looking at the video with paroxysmal exercise induced disc kinesia thinking about what are the main causes that are associated these include glucose transport deficiency.

And some individuals who manifest with GTP cyclohydrolase deficiency. For those disorders glucose transporter can be ruled out with the information we are given. If we do not have CSF monoamines, then we cannot rule out GTP cyclohydrolase deficiency based on that.

But the absence of levodopa response would argue against that being the case. Then we are left with other groups of disorders that can have exercise induced dystonia, and practically most of them would be associated with some neuroimaging changes. And they would help if we were to explore that.

Before we go into that, obviously, the marker, the blood lactate being high. Maybe suggestive of some disorders that involve energy [00:10:00] metabolism. It would be more reliable if we saw an elevated CSF lactate and possibly CSF pyruvate. But that's what we are left with at the moment, that we don't think this is glucose transport deficiency.

Unlikely that this is GTP cyclohydrolase deficiency with the lack of levodopa response. But it could be some of the other differentials that involve energy pathway metabolism or a minor acid metabolism that we may get a clue from looking at neuroimaging.

Dr. Hugo Morales Briceno: So I can see that you have formulated some hypotheses about the syndrome base or what the evidence that you have, including the lactate, but also the negative findings from the test. Now I'm gonna give you the results of the brain MRI, but I'm gonna ask you to describe the findings. So you had the brain MRI or the prevent and the younger sibling.

So can you tell us what you see here? So our audience can picture mentally what's happening on the brain?

Dr. Shekeeb Mohammad: Yes, so I've been given two [00:11:00] images. These are axial T2-weighted images for the sibling and an axial T2-FLAIR which appears to be for the proband. So looking at the proband images, remembering that this child is now in the late first decade of life, we can see a hyper intense signal in both the globi pallidi.

And this is the area that is pointed out with the arrows. At this age in the late first decade, normally the progression of MRI signal is that we all start accumulating iron, and compared to the neighboring putamen, the globus pallidus should appear darker. It should not appear brighter like you see in this case.

So that is clearly abnormal. It is nearly symmetric appearing. And then when we look at the younger sibling, this is and also in axial image. This is a T2-weighted image. And you see a similar finding, possibly some cystic change at the very anterior part of the globi pallidi. But you do see very symmetric [00:12:00] hyperintensities in the globus pallidus.

So again, the sibling is now five years of age and at this age this would be abnormal. The globus pallidus should be similar intensity, if not a little bit darker, depending on the magnetic strength of the MRI compared to the neighboring putamen.

Dr. Hugo Morales Briceno: Now we have a childhood on paroxysmal exercise in this dystonia with a normal brain MRI, with a specific lesion in the pallidum. With this combination, what are your three top differential diagnosis?

Dr. Shekeeb Mohammad: Yes. So this narrows down our differential list significantly, and if we combine the clinical presentation of this patient with the MRI, the three major differentials that we are left are monogenic disorders that lead to pyruvate dehydrogenase complex deficiency. Disorders that can lead to problems in lene, which is in a minor acid metabolism and disorders that can lead to GABA [00:13:00] pathway disorders, particularly one called succinic semialdehyde dehydrogenase deficiency.

So if you intersect the clinical presentation and the MRI, you're left with those three main differentials.

Dr. Hugo Morales Briceno: Thank you, Shekeeb. Now I'm gonna reveal the final diagnosis of these patients. So based on whole exome sequencing, the patients had two pathogenic variants on the gene of ECHS1. Which is mitochondrial short chain enoyl coenzyme A hydratase 1 deficiency, which is a recessive disorder that can lead to this presentation. The parents of this patient had a genetic analysis. The first variant was observed in the mother, which is an exon five, and the second on the father, which is the exon one. Which confirms are recessive inheritance. Now I'd like to take the opportunity to give a take home message based on what you [00:14:00] have described to us Shekeeb, and this is a bit very important in clinical phenotype, but also in the clinical setting when you see the patients coming to your clinic.

So categorizing the pattern of paroxysmal dyskinesia based on triggers can help to generate a list of potential differential diagnosis and etiologies. Also the presence of abnormal neuroimaging findings can point to certain neurometabolic disorders, as you pointed out, one could be mitochondrial but also let's not forget organic aciduria, as metabolic aciduria can also have similar presentation.

If you are interested in more details of this case this case was published in annuals of Indian Academy of Neurology Journal. The title is Paroxysmal Exercise-Induced Dyskinesia in Siblings Due to ECHS1 Gene Mutation First Indian Case reports. Thanks again for listening and still there for the next, What Is It? episode. Thank you very much, Shekeeb.

Dr. Shekeeb Mohammad: [00:15:00] Thank you. Thanks for having me.