Ataxia Series: Deconstructing late-onset idiopathic ataxia

Dr. José Luiz Pedroso: Thank you Orlando. My great pleasure to be here and try to explain this intriguing condition that we call ILOCA, idiopathic late onset cerebellar ataxia.

Prof. Orlando Barsottini: Thank you [00:01:00] and this is my first question. What is the real definition of idiopathic late onset cerebellar ataxia? And is there a consensus for age at onset of this condition?

Dr. José Luiz Pedroso: Yes. This is a very interesting question, but to answer this question, I'd like to mention how important is to be here with you because you were my mentor here in Brazil and was the first to elaborate and construct the division of ataxia unit in our university 20 years ago.

So we have long experience together working with patients with ataxia. And this is an honor to me to present this podcast for you. And [00:02:00] going direct to your question. ILOCA is intriguing condition because for a long time, for years or maybe decades or maybe a century, we didn't know the main challenges of ILOCA.

The term ILOCA is an idiopathic late onset cerebellar ataxia, and we know that idiopathic means that we do not know the cause. Similar to essential or primary tremor. What is the cause of essential tremor? It means that we do not know the cause, but considering all the development in genetic technologies to perform genetic testing and to identify new genes and new conditions.

Particularly with the next generation sequencing, we are [00:03:00] able to identify some cause of ILOCA. And there is a problem here because many authors, usually they consider ILOCA when the patients are late onset, more than 40 years old. It means that the disease usually start after 40-year-old.

But I have some consideration here because many genetic disease, such as Friedreich's ataxia and ARSACS and fragile-X may present w ith late onset after 40-year-old. So I believe the concept of ILOCA should be a patient with a poor and late onset ataxia that usually starts after 50-year-old and with a poor cerebellar ataxia.

So this is my opinion considering [00:04:00] all the difficult to characterize and to classify ILOCA.

Prof. Orlando Barsottini: José Luiz, probably ILOCA may have different cause. What are the most common etiologies of idiopathic late onset cerebellar ataxia?.

Dr. José Luiz Pedroso: Considering the last six or seven years we have now two main forms of idiopathic late onset cerebellar ataxia that were studied better through genetic etiologies. And we now have two main genes that may cause late onset cerebellar ataxia, which are RFC1 and also FGF 14.

Prof. Orlando Barsottini: Okay. How may neuroimaging help in diagnostic investigation of patients with late onset [00:05:00] cerebellar ataxia?

Dr. José Luiz Pedroso: Yes. Usually neuroimaging is mandatory to investigate patients with cerebellar ataxia because we have to rule out structural problems of the cerebellum such as tumors, malformation and others. The first point is to rule out another conditions such structural problems. And secondly, we have to understand that usually patients present with cerebellar atrophy.

For example, a patient with ILOCA, without cerebellar atrophy, we have to investigate, for example, Friedreich's ataxia. And of course there are some specific chains. For example, patients with ARSACS may present with signal chains in the pons and other abnormalities. For example, [00:06:00] patients with a fragile X permutation.

And tremor and ataxia may present with a specific abnormality with hyperintense signal, the dentate nucleus of the cerebellum. So usually we use the brain imaging more to rule out other cause than instead of to confirm that this patient may present some form of idiopathic late onset cerebellar ataxia.

Prof. Orlando Barsottini: Okay, I understand. If you suspected genetic cause. What genetic tests should we order for these patients? For example, a specific test for RFC1 or FGF 14 or whole exome or genome. What do you recommend for this case?

Dr. José Luiz Pedroso: Yes. I think this is the most important [00:07:00] question of this interview because we know that the most common genes related to ILOCA are RFC1 and FGF 14, and we must remember, that these genes are related to expansion and the particularly RFC1, it's in intronic expansion and they are a recessive disease.

So in RFC1, we usually request the PCR the long range PCR. It's enough to perform diagnostic testing in the RFC1 and also in FGF 14. This is a dominant condition. It's also called SCA 27 B. There are some difference here between these two conditions. For example, RFC1 usually present with sensor neuropathy associated [00:08:00] with vestibular ocular reflex chains with vestibular hypofunction or hyporeflexia, and FGF 14 usually has a less severe phenotype and a more late onset. Usually our RFC1 starts at a 50-year-old while FGF 14, around 69, 60-year-old. FGF 14 needs a more late onset cerebellar ataxia, and a more poor cerebellar ataxia. It's not common, but it's possible to have neuropathy and vestibular reflexion in patients with FGF 14.

And the clue for the diagnosing FGF 14 is the fluctuation of the symptoms and sometimes we can observe down beat nystagmus and two considering RfC1, we have to remember that cough [00:09:00] is extremely common in patients with RFC1 mutations. And it's important to remember that exome sequencing do not evaluate intronic expansions.

It's relevant to mention that usually whole exome sequencing is negative when we see patients with RFC1 and FGF14, we have to perform specifically the PCR and the investigation for these expansions specific tests. And remember that we have two types of genome sequencing. We have the short read genome sequencing and also the long read genome sequencing.

To identify these expansions that are usually high expansions. We have to perform long read genome sequencing. With this technique, we can identify these [00:10:00] expansions.

Prof. Orlando Barsottini: This is a important question in my view because many patients with late onset ataxia may have multiple system atrophy, especially the cerebral form. Could you discuss how differentiate multiple system atrophy and idiopathic late onset cerebellar ataxia?

Dr. José Luiz Pedroso: Yes. Good question because multiple system atrophy, particularly cerebellar form is an important differential diagnose for ILOCA. What are the main difference? Firstly, the progression usually patients with MSA present with a more rapid progression. And while patients with ILOCA, particularly related to these two genes, RFC1 and FGF [00:11:00] 14, they usually present with a slow progression.

So this is an important clue. And other point are the brain imaging. Usually in brain imaging, we can see the hot cross bun sign in the MSA and other movement disorder such as tremor and Parkinsonism and other features, but mainly autonomic dysfunction. When we have autonomic dysfunction, we have to think on MSA.

Another clue is the sleep, because REM sleep behavior disorder is very common in alpha synucleinopathy, such as MSA, but it's not common in ILOCA.

Prof. Orlando Barsottini: You have already mentioned RFC1 and FGF 14 genes. But in my opinion, other important question, do we have any form of treatment [00:12:00] for these patients or for a specific form of idiopathic late onset cerebellar ataxia?

Dr. José Luiz Pedroso: Yeah, an important point related to treatment because, we have to consider that we have limitation in specific treatment in patients with a hereditary cerebellar ataxias. But specifically for FGF 14, we can use 4-Aminopy ridine and the patients may present an improvement in gait and in the fluctuation of symptoms.

So pay attention for this possible diagnose because 4-aminopyridine could help patients to improve gait. So this is an important clue.

Prof. Orlando Barsottini: And I know you have a particular opinion about this [00:13:00] topic. In your opinion, you are an ataxia specialist. Why do we need to deconstruct the term idiopathic late onset ataxia.

Dr. José Luiz Pedroso: Yes, a wonderful question. I like to answer this question because I have some criticism about this definition, ILOCA. I think we should stop using ILOCA because many cases are not idiopathic anymore. They need investigation, genetic investigation. So many of these patients that we see today with RFC1 and FGF 14 were in the past, patients diagnosed with ILOCA.

So after genetic development with new genes describe it, I think we should change [00:14:00] our view on patients with late onset cerebellar ataxia. Considering that we have many genes related to these patients, I think it's not idiopathic anymore. So this is why I usually prefer the term deconstruct for ILOCA because now we have specific disease, and not only RFC1 and FGF 14, we may have patients with Friedreich's ataxia with late onset fragile-x premutation with tremor and ataxia.

Some forms of SCAs, some point mutations, SCAs may present with a very late onset, for example, SCA 45. So there are other genetic forms. There are some forms of ARSACS gene presenting with late onset with patients starting symptoms after forties. So this is why I usually [00:15:00] say that we should deconstruct the term ILOCA.

Prof. Orlando Barsottini: Now regarding patients with ILOCA and negative genetic investigation. Could you tell us about your clinical approach and how to investigate a patient with idiopathic late onset cerebellar ataxia?

Dr. José Luiz Pedroso: Perfect. This is a practical question, and when I see a patient with late onset cerebellar ataxia, particularly after forties. That I avoided the term ILOCA late onset cerebellar ataxia. We firstly should perform in the deep phenotyping. So if you have sensorial neuropathy, vestibular areflexia, you are allowed to perform a specific test for [00:16:00] RFC1.

So it depends on the phenomenology and clinical features. If you have a patient with a more late onset, for example starts at 60. We have to observe if this patient has some symptoms fluctuation that may worse with caffeine or may be will with tobacco, and they may worse symptoms and worse gait.

Also these patients may present with a phenomenology that we call downbeat nystagmus. So these are some phenomenology observation that could help the investigation of these two conditions, RFC1 and FGF 14 respectively. But of course we have other cause, if we have a negative investigation, today it's possible to perform the long read genome sequencing.

If [00:17:00] you do not have genome sequencing available, you can perform exome sequencing because there are some point mutations that may cause late onset cerebellar ataxia. So we have to investigate firstly, the main two genes related to expansions such as RFC1 and FGF 14. If you find nothing on this investigation, you are allowed to perform exosome sequencing or maybe better at long read genome sequencing if available. So these are my consideration as for investigation. And remember that we still have the late onset Friedreich's at axia. The VLOCA very late onset ata xia usually starts after forties, so it's caused by an expansion, you may have to [00:18:00] perform genetic testing to Friedreich's ataxia to rule out also this condition, the VLOCA.

So there are many cause, but we usually start with the phenomenology and with these two genes, RFC1 described seven years ago and also FGF 14 described four years ago.

Prof. Orlando Barsottini: We are nearing the end of our interview. What are the take home message to our listeners?

Dr. José Luiz Pedroso: Yes. I think the main take home message here are first that you frequently will face patients with late onset cerebellar ataxia without family history after 40-year-old. And remember that we should rule out acquired forms of ataxia firstly. So this is the [00:19:00] first step. Do not forget some syndromic forms of late onset cerebellar ataxias, such as fragile-x ataxia.

As related to premutation in FMR1 gene. Also, we should rule out Friedreich's ataxia also ARSACS gene, and we should remember another condition that may present with late onset which is SPG7, spastic paraplegia type seven. And the classic ILOCA are related to patients with a poor cerebellar ataxia that usually present with progressive and slow progression of ataxia that starts after 40-year-old or 50-year-old.

And remember mainly the two genes recently described RFC1 and FGF 14. Do not forget to investigate these patients with these [00:20:00] specific tests. And of course, exome sequence could help, but it's difficult to find point mutations in this phenotype. But long read genome may help to discover new genes and also to better investigate all genetic features of a patient with a idiopathic late onset cerebellar ataxia.

Prof. Orlando Barsottini: Thank you Jose Luiz for sharing these insights and thank you to our listeners for joining us. We hope this episode helps you approach late onset cerebellar patients with greater confidence. Thank you. [00:21:00]