At Least Two Genetic Causes For Early Onset Dementia of Leukoencephalopathy Interview with:

Dr David Lynch MB, MRCPI Leonard Wolfson Clinical Fellow UCL Institute of Neurology Queen Square, London

Dr David Lynch

Dr David Lynch MB, MRCPI
Leonard Wolfson Clinical Fellow
UCL Institute of Neurology
Queen Square, London What is the background for this study? What are the main findings?

Response: In 2011 it was discovered that mutations in a gene called CSF1R cause a rare syndrome of early onset dementia often accompanied by movement disorders, spasticity and seizures, which is named adult onset leukoencephalopathy with axonal spheroids (ALSP). The hallmarks of ALSP are a characteristic appearance on MRI imaging and findings in brain pathological specimens – axonal swellings or ‘spheroids’. We manage a multidisciplinary group with expertise in leukoencephalopathies and have previously identified patients with mutations in CSF1R. However, we also found patients with a syndrome typical of ALSP who did not carry mutations in CSF1R.
In this study, we showed that some of these patients carry recessive mutations in a different gene, AARS2. This included a patient with characteristic axonal spheroids in brain tissue and typical ALSP clinical and imaging features. What should readers take away from your report?

Response: The message of our study is that there can be multiple genetic causes for seemingly identical syndromes. We showed that autosomal recessive mutations in the mitochondrial gene AARS2 can cause the same clinical, radiological and pathological syndrome as autosomal dominant mutations in the cell surface receptor CSF1R. This has important implications for genetic counselling in patients affected with ALSP and will increase the diagnostic rate in patients affected with leukoencephalopathies. What recommendations do you have for future research as a result of this study?

Response: We now know that there are at least two genetic causes of ALSP. However, what is unknown is how two genes with totally separate and diverse functions lead to the same clinical, radiological and pathological syndrome. Whether there is a shared mechanism or if the gene mutations overlap in a final common pathway of neurodegeneration will need further study. In addition, we know that there remain some patients with features of ALSP who are negative for mutations in both CSF1R and AARS2 so determining the genetic cause of their disorder is the next focus of our research. Is there anything else you would like to add?

Response: Leukoencephalopathies in adults are rare and it is known that most patients affected by them will never receive an accurate and definitive genetic diagnosis – something that is important for genetic counselling and prognostication. We advocate for patients affected by leukoencephalopathies to be referred early to a specialist centre with the capability to perform focused or whole exome sequencing. Thank you for your contribution to the community.


Analysis of Mutations in AARS2in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia
David S. Lynch, MRCPI; Wei Jia Zhang, MRCP; Rahul Lakshmanan, FRANZCR;et al
JAMA Neurol. Published online October 17, 2016. doi:10.1001/jamaneurol.2016.2229

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Last Updated on October 20, 2016 by Marie Benz MD FAAD