Hereditary leukoencephalopathy with axonal spheroids: a spectrum of phenotypes from CNS vasculitis to parkinsonism in an adult onset leukodystrophy series.
BACKGROUND
Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a hereditary, adult onset leukodystrophy which is characterised by the presence of axonal loss, axonal spheroids and variably present pigmented macrophages on pathological examination. It most frequently presents in adulthood with dementia and personality change. HDLS has recently been found to be caused by mutations in the colony stimulating factor-1 receptor (CSF1R) gene.


METHODS
In this study, we sequenced the CSF1R gene in a cohort of 48 patients from the UK, Greece and Ireland with adult onset leukodystrophy of unknown cause.


RESULTS
Five pathogenic mutations were found, including three novel mutations. The presentations ranged from suspected central nervous system (CNS) vasculitis to extrapyramidal to cognitive phenotypes. The case histories and imaging are presented here, in addition to neuropathological findings from two cases with novel mutations.


CONCLUSIONS
We estimate that CSF1R mutations account for 10% of idiopathic adult onset leukodystrophies and that genetic testing for CSF1R mutations is essential in adult patients presenting with undefined CNS vasculitis or a leukodystrophy with prominent neuropsychiatric signs or dementia.
Department of Molecular Neuroscience, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK The Leonard Wolfson Experimental Neurology Centre, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London UK.
David S
http://orcid.org/0000-0003-0615-7159
DS
Lynch
Division of Neuropathology and Department of Neurodegenerative Disease, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK.
Zane
Z
Jaunmuktane
Department of Molecular Neuroscience, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK.
Una-Marie
UM
Sheerin
Division of Neuropathology and Department of Neurodegenerative Disease, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK.
Rahul
R
Phadke
Division of Neuropathology and Department of Neurodegenerative Disease, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK.
Sebastian
S
Brandner
Aristotle University of Thessaloniki, Thessaloniki, Greece.
Ionnis
I
Milonas
Department of Neuropathology, Addenbrooke's Hospital, Cambridge, UK.
Andrew
A
Dean
Department of Neurology, Queens Medical Centre, Nottingham, UK.
Nin
N
Bajaj
Department of Neurology, Cork University Hospital, Wilton, Cork, Ireland.
Nuala
N
McNicholas
Department of Neurology, Cork University Hospital, Wilton, Cork, Ireland.
Daniel
D
Costello
Department of Neurology, Cork University Hospital, Wilton, Cork, Ireland.
Simon
S
Cronin
University College Dublin, St. Vincent's University Hospital, Dublin, Ireland.
Chris
C
McGuigan
Department of Neurodegeneration, Dementia Research Centre, London, UK.
Martin
M
Rossor
Department of Neurodegeneration, Dementia Research Centre, London, UK.
Nick
N
Fox
Department of Neuroinflammation, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK.
Elaine
E
Murphy
Department of Neuroinflammation, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK.
Jeremy
J
Chataway
Department of Molecular Neuroscience, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, UK.
Henry
H
Houlden
D000328:Adult; D001369:Axons / Q000473:pathology*; D005260:Female; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000150:complications / Q000235:genetics / Q000473:pathology*; D006801:Humans; D056784:Leukoencephalopathies / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020734:Parkinsonian Disorders / Q000150:complications / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics*; D020293:Vasculitis, Central Nervous System / Q000150:complications / Q000235:genetics / Q000473:pathology*
D016184:Receptors, Colony-Stimulating Factor