CSF1R-related disorder in China

And today I have the pleasure of speaking to Dr. Xiaojun Huang , who is an associate. Senior physician and Dr. Jingying Wu, who's a physician both from the Department of Neurology at Shanghai Six People's Hospital affiliated to Shanghai Zhaotong University School of Medicine. Today, we're going to be talking about an article that they've published in the Movement Disorders Journal, May 2024 issue.

The Phenotypic and Genotypic Spectrum of CSF1R-Related Disorder in China. Thanks for joining us today, both of you.

[00:00:53] Dr. Jingying Wu: Thank you, Dr. Schaefer.

[00:00:55] Dr. Sara Schaefer: So in order to get a little bit of background, I'm [00:01:00] hopefully not the only person who's less familiar with this disease, CSF1R related disorder. Can you give us some background on the terminology, first of all, as this seems to have shifted a lot over time, and tell us about what's already known about this disease in the literature and what you hoped to add to the literature with your study?

[00:01:22] Dr. Jingying Wu: Of course so to clarify CSF1R related disorder, firstly, we need to know LSP, which is short for adult onset leukoencephalopathy with neural axonal spherules and pigmented glia. It's actually a group of hereditary white matter diseases characterized by rapidly progressive cognitive, motor, or psychiatric impairment in forties mostly.

And the CSR gene mutations is the main genetic cause for LSP. And we call this group of LSP as CSFR [00:02:00] related disorder. So current clinical studies actually mostly focused on Japanese, European, and American populations, but lack of systematic understanding of the phenotypic and genetic characteristic of CRD in China.

Therefore we did this research to illustrate the characteristic of Chinese patients.

[00:02:22] Dr. Sara Schaefer: So as you just mentioned, your paper outlines a summary of the genetic and phenotypic Features of CSF1R related disorders in 103 patients in China. What were the methods for including patients in your study and was information collected specifically for the study or solely based on retrospective chart reviews?

[00:02:45] Dr. Jingying Wu: Yes for patients if they are with adult onset in local encephalopathy, and shown with rapidly progressive cognitive motor or psychiatric disorders. We'll ask them to undergo [00:03:00] whole axon sequency, if they are willing to, and if they are, they will further ask for the enrollment if they carry heterozygous CS1 variants.

So our study is a retrospective study, and yes, we collected information. But the information, some is actually reported before, and some is solely for our research.

[00:03:21] Dr. Sara Schaefer: And what were the main clinical findings in the analysis?

[00:03:26] Dr. Jingying Wu: Clinically, we found that the core features of Chinese CRD patients are progressive parkinsonism and cognitive decline, especially for parkinsonism. It's actually Chinese patients shows higher proportion of parkinsonism than other population reported.

[00:03:44] Dr. Sara Schaefer: Yeah, that was interesting to me that you mentioned that parkinsonism was the first presenting feature, most commonly, and that this was different than other populations that have been studied. But ultimately, I believe cognitive [00:04:00] impairment was the predominant feature later in the disease. Is that correct?

[00:04:04] Dr. Jingying Wu: Yes, correct.

[00:04:05] Dr. Sara Schaefer: And what did you find when you analyze the MRIs of these patients?

[00:04:10] Dr. Jingying Wu: We found that patients usually manifested with bilateral asymmetric wide meta change, especially in T two and DWI sequence and also cortical atrophy and enlargement of ventricles besides in ct, we can also found point like calcifications at about, 11 percent of our cohort which is actually much lower than as a proportion before.

[00:04:38] Dr. Sara Schaefer: Yeah, that was also interesting to me. So calcifications, it seems is a little bit more of a pathognomonic feature for this. Maybe not totally pathognomonic, but something that's a little bit more unusual than just white matter changes or atrophy or enlarged ventricles that we might see in a lot of different diseases.

But you noted a smaller [00:05:00] proportion in your population. And you speculated that that may actually have to do with the way the imaging was performed. Right? 

[00:05:08] Dr. Jingying Wu: Right. We use less. In the Japanese cohort reported before they are perform the thin layer CT to better demonstrate the calcification, but in most patients in our cohort, actually, they only did the very normal CT, not the thin layer CT. That might be related to the lower proportion of calcification in our cohort.

[00:05:33] Dr. Sara Schaefer: And how did these findings relate to patient genotype? Or in other words, what were the genotype phenotype correlations that you found?

[00:05:42] Dr. Jingying Wu: First of all, we found a hotspot mutation in China. Actually, we also noticed that these mutations are also reported elsewhere in the world. In which the 2,381 base were changed from T to C, responsible for over 60 [00:06:00] percent of the prevalence in our cohort. We also found that compared to patients with missense mutations, patients with non mutation had a higher proportion of cognitive impairment as the initial manifestation.

Besides Tyrosine kinase domain is the most important structure for CSF1R gene especially for downstream signaling. So we also compare patients carrying mutations in TKD domain and other domains like immunoglobulin like domains. And we found that those with immunoglobulin like domain mutations were more likely to develop epilepsy and cerebellar atrophy.

[00:06:42] Dr. Sara Schaefer: Now, you mentioned that there are some core clinical features. Parkinsonism, cognitive impairment are the really big ones in this disorder, and also bulbar symptoms and other things. And there are a variety of imaging features, which you also describe in the paper as heterogeneous. You can have [00:07:00] atrophy in lots of different parts of the brain.

You can have a little bit of white matter change, a lot of white matter change. It really seemed like patients could have almost any feature, pyramidal signs, cranial nerve deficits, weakness, autonomic dysfunction, abnormal peripheral nerves, finding seizures, as you mentioned, and even elevated intracranial pressure, which was a particular surprise to me on lumbar puncture and various levels and locations of leukoencephalopathy and atrophy on MRI.

What would you advise a clinician in terms of keeping this disorder in mind? What about a patient's presentation would make you particularly think about this disorder?

[00:07:40] Dr. Jingying Wu: We think that to diagnose a CRD patient, we need to check the following three points. First of all, do he or she manifest with rapidly progressive parkinsonism, cognitive decline, or psychiatric problems? Especially, it should be a rapid [00:08:00] one. Secondly, in MRI, can we found a symmetrical bilateral wide meta change, especially near lateral ventricles in T2 or DWI sequence.

And this change should be a constant change, which is different from multiple sclerosis, it will not disappear as a time going on. And the third point is that do he or she has a dominant family history. Or if possible to perform a gene sequence to figure out whether he or she carrying the CSFR mutations.

[00:08:37] Dr. Sara Schaefer: Okay, that's helpful. Yeah, it did seem like the rapidity of onset was of particular value here, as well as, like I said, the calcifications, which is a little bit less typical of some of the other chronic changes that we see in patients. Interestingly, you do mention that female patients experienced higher severity of [00:09:00] cognitive symptoms and higher white matter burden than male patients.

And this was despite lower rates of CSF changes, like increased protein in the CSF and things like that. Why do you think the phenotype in females is different?

[00:09:14] Dr. Jingying Wu: I think the CSF difference in CRD may be related to many factors. For one thing, CRD is a primary microglialpathy So previously study has confirmed that significant sex difference in microglia during development, the maintenance of neurological homos status and immune response. So it may lead to the difference in the risk of pathogenesis and the pathogenic mechanism of CRD in different sex. And besides like other neurological diseases such as Parkinson's disease, Alzheimer's disease, autism, so sex difference may be related to the sex hormone levels and [00:10:00] metabolic levels, but we are not sure about that, the study need to figure out.

[00:10:04] Dr. Sara Schaefer: Yeah, it's all speculation at this point, right? But an interesting observation. How do your findings compare to previous findings in other patient populations? You did mention a couple things, that parkinsonism was more likely to be the presenting feature, that calcifications were found less in this population, though that may be related to the thinness of the cuts on the imaging techniques. Were there any other big differences that you noted and what are the indications of that?

[00:10:33] Dr. Jingying Wu: So besides what we mentioned before, we want to emphasize the importance of DWI sequence, especially for the differential diagnosis and early detection of white matter change. So this disease are very easily to confused with the multiple sclerosis. And we think DWI can be very helpful to the early diagnosis of the disease.

We also noticed the [00:11:00] autonomic involvement and peripheral neuropathy in CRD, which is rarely reported before. It's also emphasized the importance of the change of the name from CSF1R related leukoencephalopathy to right now the CSFR related disorder. So it indicated that it's not only a white matter disease, but also related to the many symptoms besides the central nervous system.

[00:11:28] Dr. Sara Schaefer: Yeah, that makes sense. As I said before, it seems like it can present with almost anything and it's a very systemic neurological condition that affects both peripheral and central and autonomic nerves. So that's very interesting. What do you think are the next steps in terms of understanding this disease better?

[00:11:47] Dr. Jingying Wu: We want to continue to carry out a natural history study for CRD patients and for those asymptomatic carriers. And we think that it will [00:12:00] provide a deeper and more accurate understanding of this disease and maybe provide a better reference for diagnosis and the treatment.

[00:12:10] Dr. Sara Schaefer: Do you want to speak at all to the interesting thing that you noted about the fact that Parkinsonism was more common as a presenting feature in this population and the fact that stem cell transplants have been shown to potentially be more efficacious for Parkinsonism and motor symptoms as opposed to cognitive and therefore might be of more use in the Chinese population.

[00:12:35] Dr. Jingying Wu: Yes. We found that the, actually in our study, we found that the motor predominant patients showed less severe MRI performance with lower proportion of family history and compared to the cognitive predominant ones although no difference in other parts. But very similarly, it has been reported before that the stem cell [00:13:00] transportation, which is actually the only therapy for this disease right now might be more effective motor predominant patients. So, in our cohort, we found that the Chinese patients are more likely to perform as a motor predominant ones. So maybe, Chinese patients will respond to the stem cell transportation, but we need clinical trials to confirm that.

[00:13:25] Dr. Sara Schaefer: Great. Thank you. Thank you for being here and for speaking with us today about this paper.

[00:13:30] Dr. Jingying Wu: Thank you, Dr. Schaefer.

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