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Haematopoietic stem cell transplantation in CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
  1. Fanny Mochel1,2,
  2. Cécile Delorme2,3,
  3. Virginie Czernecki3,
  4. Jerome Froger4,
  5. Florence Cormier2,3,
  6. Emmanuel Ellie5,
  7. Nathalie Fegueux6,
  8. Stéphane Lehéricy2,7,
  9. Serge Lumbroso8,
  10. Raphael Schiffmann9,
  11. Patrick Aubourg10,11,
  12. Emmanuel Roze2,3,
  13. Pierre Labauge12,
  14. Stephanie Nguyen13
  1. 1 Department of Genetics, University Hospital Pitié Salpêtrière, Paris, France
  2. 2 Sorbonne Université, Inserm U 1127, CNRS UMR 7225, ICM, Paris, France
  3. 3 Department of Neurology, University Hospital Pitié Salpêtrière, Paris, France
  4. 4 Department of Physical and Rehabilitation Medicine, Centre Hospitalier Universitaire de Nimes, Nimes, France
  5. 5 Department of Neurology, Centre Hospitalier de la Cote Basque, Bayonne, France
  6. 6 Department of Hematology, Montpellier University Hospital, Montpellier, France
  7. 7 Department of Neuroradiology, University Hospital Pitié Salpêtrière, Paris, France
  8. 8 Department of Biochemistry and Molecular Biology, Nimes University Hospital, Nimes, France
  9. 9 Institute of Metabolic Disease, Baylor Scott and White Research Institute, Dallas, Texas, USA
  10. 10 Department of Paediatric Neurology, Centre Hospitalier Universitaire de Bicêtre, Le Kremlin-Bicetre, France
  11. 11 Inserm U 1169, Universite Paris-Sud, Orsay, France
  12. 12 Department of Neurology, Montpellier University Hospital, Montpellier, France
  13. 13 Hematology Department, Montpellier University Hospital, Montpellier, France
  1. Correspondence to Dr Fanny Mochel, Department of Genetics, University Hospital Pitié Salpêtrière, Paris 75013, France; fanny.mochel{at}

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Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a severe neurodegenerative disease leading to death usually within a few years after symptoms onset.1 Patients present with cognitive decline, behavioural changes and pyramidal signs in the context of patchy white matter lesions. ALSP is a primary microgliopathy caused by haploinsufficiency of the colony-stimulating factor 1 receptor (CSF1R). CSF1R is critical for the development, maintenance and activation of microglia. We hypothesised that haematopoietic stem cell transplantation (HSCT) can be relevant in ALSP by correcting CSF1R loss-of-function in microglia. We provide the first prospective report of a patient with ALSP with a 30-month follow-up after a successful HSCT. We present in parallel the clinical outcome of a consecutive patient with similar age, sex and disease course who did not undergo HSCT.

Patients and methods

Patient 1 was in her early 30s when she developed leg stiffness after a mild head trauma. Her mother died of a rapidly progressive neurological disorder before age 40. Brain MRI revealed patchy and asymmetrical T2/FLAIR white matter hyperintensities (online supplementary file 1A) and T1 hypointensities. She was first misdiagnosed with multiple sclerosis. ALSP was then suspected because of the family history and hyperintense white matter lesions on diffusion weighted imaging (DWI). CSF1R-targeted analysis revealed a c.2498C>A, p.Thr833Lys mutation.

Supplementary data

A repeat brain MRI showed progression of T2/FLAIR (online supplementary file 1A) and DWI white matter lesions. Neuropsychological testing revealed mild alterations in executive and working memory (online supplementary file 2), irritability and emotional lability. At the time of HSCT, 18 months after symptoms onset, patient 1 displayed spastic quadriparesis and was only able to stand with aid for a few seconds. As there was no available 10/10 matched donor, a haplotype-mismatched 5/10 transplant was considered with the patient’s paternal half-sister. The HSCT protocol consisted in a myeloablative conditioning regimen associating busulfan and fludarabin followed by the infusion of a repleted G-CSF mobilised peripheral blood stem cell transplant. Prophylaxis of graft versus host disease consisted in antithymocyte globulin, high-dose cyclophosphamide, and subsequently cyclosporine and mycophenolate mofetil. The study was approved by INSERM (IRB00003888), and patient’s written informed consent was obtained.

Supplementary data

Patient 2 carried a distinct CSF1R mutation (c.2342C>T, p.Ala781Val); her initial presentation was previously reported.2 She gradually developed spasticity in her left hemibody in her early 30s, and her condition deteriorated following a mild head trauma. Five years after disease onset, she presented with quadriparesis, cognitive impairment, dysarthria and dysphagia. She was able to stand with aid for a few seconds.


Patient 1 engrafted at day 15 but did not recover platelets. Complete donor chimerism was obtained at 7 months post-transplant after which immunosuppressive drugs were withdrawn. She presented a haemorrhagic cystitis, related to cyclophosphamide, and two bouts of pyelonephritis but no further complication from 6 months post-transplant. Initially, the patient’s pyramidal syndrome continued to worsen and she became wheelchair-bound 3 months after HSCT. Remarkably, from 6 to 30 months post-transplant, the patient’s condition stopped deteriorating and her Expanded Disability Status Scale score remained stable (online supplementary file 3). At last follow-up, she required help for transfers but was able to stand up with help. She retained functional mobility of her left upper limb and was able to feed herself, write and use her telephone. Cognitive testing remained stable except for more pronounced attention deficit (online supplementary file 2). Her mood improved over time. Brain MRI performed 4 months post-transplant showed progression of white matter lesions on T2/FLAIR (online supplementary file 1A) and DWI (figure 1) sequences, consistent with the patient’s clinical deterioration. However, from 12 to 30 months post-transplant, we observed decreased DWI lesions (figure 1) suggesting reduced disease activity, stable atrophy and slightly reduced white matter FLAIR hyperintensities at 24 and 30 months post-transplant (online supplementary file 1A). We also observed a transient contrast enhancement around periventricular white matter lesions, possibly reflecting an immune reaction between donor and recipient cells (online supplementary file 1B).

Supplementary data

Figure 1

Evolution of DWI brain lesions in patient 1. (A–B) MRI from June 2016, 3 months before HSST. Arrows indicate DWI hyperintense lesions. (C–D) MRI from February 2017, 4 months after HSCT with increased lesion load at M+4. (E–F) MRI form October 2017, 12 months after HSCT. (G–H) MRI form October 2018, 24 months after HSCT. (I–J) MRI from April 2019, 30 months after HSCT. Arrows indicate DWI hyperintense lesions, with decreased lesion load at M+12, M+24 and M+30. DWI, diffusion weighted imaging; HSCT, haematopoietic stem cell transplantation.

Patient 2 refused to undergo HSCT in view of the risk of the procedure and continued to rapidly decline due to severe spasticity and loss of her communication skills. She was bedridden within 5 years following symptoms onset, with severe cognitive impairment and dysphagia necessitating enteral alimentation. She was in a vegetative state at last follow-up (online supplementary file 3).


We present the positive long-term outcome of HSCT in a patient with CSF1R-related ALSP. This patient presented with a rapidly progressive disease evolution before HSCT, as usually observed in ALSP.1 Her dreadful neurological decline stopped from 6 months post-transplant and DWI lesions kept regressing 30 months post-transplant. A consecutive patient with similar age, sex and disease course who did not undergo HSCT suffered a dramatic worsening of her disease. A patient with ALSP, misdiagnosed as metachromatic leukodystrophy and transplanted for that reason, seems to have remained stable but no further detail is available.3 Instead, we provide the first detailed prospective report of HSCT in CSF1R-related ALSP. Further observations are encouraged to confirm the ability of HSCT to halt disease progression in ALSP.

These observations emphasise how critical it is to diagnose ALSP, particularly in patients with rapidly progressive pyramidal signs and/or cognitive alterations associated with white matter lesions. Important diagnostic clues for ALSP are hyperintense white matter dots on DWI and/or punctate calcifications in the absence of gadolinium enhancement, T2* microbleeds or spine lesions.1 The favourable clinical outcome of patient 1 post-transplant, the rapid disease progression in ALSP and the possibility of acute exacerbations (eg, following head trauma) suggest that HSCT should be considered in the early phase of the disease. Patient 1 continued to deteriorate and MRI lesions progressively extended in the first months post-transplant as the colonisation of the donor cells into the brain takes several months to occur while the disease continues to progress.4

A major challenge for HSCT in ALSP is the identification of biomarkers reflecting disease progression. Neurofilament light chain is elevated in the plasma and CSF of patients with ALSP.5 Its potential as a biomarker of disease activity is yet to be shown. Novel imaging methods that can monitor demyelination may also help to properly time HSCT in patients with ALSP.


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  • Contributors Conception and design of the study: FM, RS, PA, ER, PL, SN. Acquisition and analysis of data: FM, CD, VC, JF, FCD, EE, NF, SL, SL, RS, PA, ER, PL, SN. Drafting a significant portion of the manuscript or figures: FM, CD, VC, SN.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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