Analysis of Mutations in <i>AARS2</i> in a Series of <i>CSF1R</i>-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia
Authors: David S. Lynch, Wei Jia Zhang, Rahul Lakshmanan, Justin A. Kinsella, Günes Altiokka Uzun, Merih Karbay, Zeynep Tüfekçioglu, Hasmet Hanagasi, Georgina Burke, Nicola Foulds, Simon R. Hammans, Anupam Bhattacharjee, Heather Wilson, Matthew Adams, Mark Walker, James A. R. Nicoll, Jeremy Chataway, Nick Fox, Indran Davagnanam, Rahul Phadke, Henry Houlden
Journal: JAMA Neurology (2016)

<h3>Importance</h3> Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a frequent cause of adult-onset leukodystrophy known to be caused by autosomal dominant mutations in the<i>CSF1R</i>(colony-stimulating factor 1) gene. The discovery that<i>CSF1R</i>mutations cause ALSP led to more accurate prognosis and genetic counseling for these patients in addition to increased interest in microglia as a target in neurodegeneration. However, it has been known since the discovery of the<i>CSF1R</i>gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic<i>CSF1R</i>mutations. These patients include those in whom the pathognomonic features of axonal spheroids and pigmented microglia have been found. Achieving a genetic diagnosis in these patients is important to our understanding of this disorder. <h3>Objective</h3> To genetically characterize a group of patients with typical features of ALSP who do not carry<i>CSF1R</i>mutations. <h3>Design, Settings, and Participants</h3> In this case series study, 5 patients from 4 families were identified with clinical, radiologic, or pathologic features of ALSP in whom<i>CSF1R</i>mutations had been excluded previously by sequencing. Data were collected between May 2014 and September 2015 and analyzed between September 2015 and February 2016. <h3>Main Outcomes and Measures</h3> Focused exome sequencing was used to identify candidate variants. Family studies, long-range polymerase chain reaction with cloning, and complementary DNA sequencing were used to confirm pathogenicity. <h3>Results</h3> Of these 5 patients, 4 were men (80%); mean age at onset of ALSP was 29 years (range, 15-44 years). Biallelic mutations in the alanyl-transfer (t)RNA synthetase 2 (<i>AARS2</i>) gene were found in all 5 patients. Frameshifting and splice site mutations were common, found in 4 of 5 patients, and sequencing of complementary DNA from affected patients confirmed that the variants were loss of function. All patients presented in adulthood with prominent cognitive, neuropsychiatric, and upper motor neuron signs. Magnetic resonance imaging in all patients demonstrated a symmetric leukoencephalopathy with punctate regions of restricted diffusion, typical of ALSP. In 1 patient, brain biopsy demonstrated axonal spheroids and pigmented microglia, which are the pathognomonic signs of ALSP. <h3>Conclusions and Relevance</h3> This work indicates that mutations in the tRNA synthetase<i>AARS2</i>gene cause a recessive form of ALSP. The CSF1R and AARS2 proteins have different cellular functions but overlap in a final common pathway of neurodegeneration. This work points to novel targets for research and will lead to improved diagnostic rates in patients with adult-onset leukoencephalopathy.