David S Lynch1, Wei Jia Zhang2, Rahul Lakshmanan3, Justin A Kinsella4, Günes Altiokka Uzun5, Merih Karbay5, Zeynep Tüfekçioglu5, Hasmet Hanagasi5, Georgina Burke6, Nicola Foulds7, Simon R Hammans8, Anupam Bhattacharjee9, Heather Wilson9, Matthew Adams3, Mark Walker10, James A R Nicoll10, Jeremy Chataway11, Nick Fox12, Indran Davagnanam3, Rahul Phadke13, Henry Houlden14. 1. Department of Molecular Neuroscience, University College London Institute of Neurology, London, England2The Leonard Wolfson Experimental Neurology Centre, University College London Institute of Neurology, London, England. 2. Department of Molecular Neuroscience, University College London Institute of Neurology, London, England3Department of Neurology, Royal Free Hospital, London, England. 3. Lysholm Department of Neuroradiology, The National Hospital for Neurology and Neurosurgery, London, England. 4. Dementia Research Centre, Department of Neurodegeneration, The National Hospital for Neurology and Neurosurgery, University College London Institute of Neurology, London, England6University College Dublin, Department of Neurology, St Vincent's University Hospital, Dublin, Ireland. 5. Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. 6. Department of Neurology, Queen Alexandra Hospital, Portsmouth, England9Wessex Neurological Centre, University Hospital Southampton, Southampton, England. 7. Wessex Clinical Genetics Services, Princess Anne Hospital, Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, England. 8. Department of Neurology, Queen Alexandra Hospital, Portsmouth, England. 9. Department of Neurology, Royal Free Hospital, London, England. 10. Clinical Neurosciences, Clinical & Experimental Sciences, University of Southampton, Department of Cellular Pathology, Southampton General Hospital, Southampton, England. 11. Department of Neuroinflammation, University College London Institute of Neurology, London, England. 12. Dementia Research Centre, Department of Neurodegeneration, The National Hospital for Neurology and Neurosurgery, University College London Institute of Neurology, London, England. 13. Division of Neuropathology and Department of Neurodegenerative Disease, The National Hospital for Neurology and Neurosurgery, University College London Institute of Neurology, London, England. 14. Department of Molecular Neuroscience, University College London Institute of Neurology, London, England14Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery, London, England.
Abstract
IMPORTANCE: 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 CSF1R (colony-stimulating factor 1) gene. The discovery that CSF1R 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 CSF1R gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic CSF1R 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. OBJECTIVE: To genetically characterize a group of patients with typical features of ALSP who do not carry CSF1R mutations. DESIGN, SETTINGS, AND PARTICIPANTS: In this case series study, 5 patients from 4 families were identified with clinical, radiologic, or pathologic features of ALSP in whom CSF1R mutations had been excluded previously by sequencing. Data were collected between May 2014 and September 2015 and analyzed between September 2015 and February 2016. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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 (AARS2) 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. CONCLUSIONS AND RELEVANCE: This work indicates that mutations in the tRNA synthetase AARS2 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.
IMPORTANCE: 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 CSF1R (colony-stimulating factor 1) gene. The discovery that CSF1R 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 CSF1R gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic CSF1R 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. OBJECTIVE: To genetically characterize a group of patients with typical features of ALSP who do not carry CSF1R mutations. DESIGN, SETTINGS, AND PARTICIPANTS: In this case series study, 5 patients from 4 families were identified with clinical, radiologic, or pathologic features of ALSP in whom CSF1R mutations had been excluded previously by sequencing. Data were collected between May 2014 and September 2015 and analyzed between September 2015 and February 2016. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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 (AARS2) 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. CONCLUSIONS AND RELEVANCE: This work indicates that mutations in the tRNA synthetase AARS2 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.
Authors: Jason H Peragallo; Stephanie Keller; Marjo S van der Knaap; Bruno P Soares; Suma P Shankar Journal: Ophthalmic Genet Date: 2017-08-18 Impact factor: 1.803
Authors: T Konno; K Yoshida; I Mizuta; T Mizuno; T Kawarai; M Tada; H Nozaki; S-I Ikeda; O Onodera; Z K Wszolek; T Ikeuchi Journal: Eur J Neurol Date: 2017-10-19 Impact factor: 6.089