INTRODUCTION

Variants in the colony-stimulating factor 1 receptor (CSF1R) gene are associated with adult-onset central nervous system microgliopathies, including hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD), both of which lie within the broader classification of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) [1]. While cognitive impairment and spasticity are the predominant clinical symptoms, CSF1R-related ALSP may mimic frontotemporal dementia, multiple sclerosis, stroke, or vasculitis and may rarely produce atypical parkinsonism. This condition is inexorably progressive, although hematopoietic stem cell transplantation and microglial replacement may be beneficial. Given these considerations, identifying this disorder is crucial. Reports from diverse populations are rare but important for informing regional predilections. We report a series of four Asian Indian patients and delineate the literature on CSF1R-related ALSP.

CASE SERIES

Patient 1

A 40-year-old female from northern India developed behavioral issues for 2 years, urinary incontinence for 18 months, and right lower limb weakness and right upper limb posturing for 8 months. She had also experienced two seizures. On examination, the Montreal Cognitive Assessment (MoCA) score was 20/30. A detailed lobar assessment revealed impairments in complex attention, social cognition, language, memory, and executive function. Saccades were slow. The patient exhibited hypophonia, bradyphrenia, asymmetrical spasticity (right>left), and hyperreflexia. Right upper limb dystonia and right extensor plantar response were observed. Routine blood and cerebrospinal fluid (CSF) parameters were normal, and autoimmune and paraneoplastic panel results were negative. Magnetic resonance imaging (MRI) revealed confluent T2/fluid attenuated inversion recovery (FLAIR) hyperintensities in the periventricular, deep, and subcortical frontoparietal white matter; hyperintensity along the left corticospinal tract; and scattered diffusion restriction foci (Figure 1). A follow-up MRI after 11 months revealed new diffusion restriction foci in the pons (Supplementary Figure 1 in the online-only Data Supplement). Whole-exome sequencing (WES) revealed a heterozygous variant, c.2350G>A (p.Val784Met), in exon 17 of the CSF1R gene that is classified as likely pathogenic (PM1, PM2, PP3, and PP5). The patient was managed with levodopa, sertraline, levetiracetam, and lacosamide. Pulse methylprednisolone was administered due to an initial consideration of autoimmune encephalitis. The patient reported subjective improvement in behavioral issues with this treatment. She was subsequently administered intravenous immunoglobulin and mycophenolate mofetil. However, her condition continued to worsen.

Patient 2

A 38-year-old male from western India presented with slow activity accompanied by dysarthria, decreased movement and posturing of the right upper and lower limbs for 2 years. In the past 6 months, he had developed recent episodic memory impairment and difficulty reading and calculating. He had no significant past or family history. The examination revealed a MoCA score of 22/30, with impairments observed in recall, calculation, and reading. The patient exhibited hypometric saccades, generalized rigidity (right>left), and right upper limb dystonia (Supplementary Video 1 in the online-only Data Supplement). The deep tendon reflexes were normal. Cortical sensory loss (right>left upper limb) and apraxia were observed. A diagnosis of corticobasal syndrome (CBS) was considered. The results of routine blood and CSF tests were normal. A brain MRI revealed patchy and confluent T2/FLAIR hyperintensities in periventricular areas and deep white matter. Multifocal areas of diffusion restriction were observed in the bilateral internal watershed territories (left>right) and corpus callosum (Figure 1). WES revealed a heterozygous variant, c.2480T>A (p.Ile827Asn), in exon 18 of the CSF1R gene that is classified as likely pathogenic (PM1, PM2, PP3, and PP4). The patient showed no improvement with levodopa-carbidopa treatment or physiotherapy.

Patient 3

A 34-year-old female from northern India developed gait problems for 12 months, right-sided stiffness for 6 months, and dysarthria for 2 months. She exhibited spasticity and weakness involving the right side. Brisk deep tendon reflexes and a right extensor plantar response were observed. The results of the cognitive evaluation were normal. A brain MRI revealed T2/FLAIR periventricular white matter hyperintensities and punctate areas of diffusion restriction in the bilateral corona radiata (Figure 1). WES revealed a heterozygous variant, c.1765G>A (p.Gly589Arg), in exon 12 of the CSF1R gene that is classified as pathogenic (PS4, PM1, PM2, and PM5). The patient was started on baclofen and physiotherapy for spasticity and experienced moderate relief.

Patient 4

A 35-year-old female from northern India developed a gradual decrease in the use of the left upper and lower limbs and left hemineglect for 11 months. She exhibited decreased interaction with family members, slowness, and tremulousness of her upper limbs for 3 months. For the past 2 months, she experienced episodic memory impairment. Cognitive examination revealed a MoCA score of 21/30; impaired attention and fluency; and abnormal frontal, parietal, and temporal lobe functions. The patient exhibited rigidity, bradykinesia (left>right), and postural tremors involving the upper limbs (left>right). Coordination and deep tendon reflexes were normal. A brain MRI revealed periventricular white matter changes with punctate areas of diffusion restriction in the bilateral centrum semiovale (Figure 1). WES revealed a heterozygous variant, c.2546_2548delTCT (p.Phe849del), in exon 19 of the CSF1R gene that is classified as likely pathogenic (PM1, PM2, PM4, and PM6). Familial segregation revealed that the patient’s asymptomatic parent and brother did not carry the variant. No improvement was noted with levodopa-carbidopa or clonazepam treatment.

DISCUSSION

ALSP is a broad term that was used previously to denote two apparently distinct entities, HDLS and POLD. However, with the discovery of CSF1R as a causative gene in 2011, the two syndromes were found to overlap significantly, suggesting that they may be a single entity.1 CSF1R-related leukoencephalopathy (CSF1R-L), an overarching term for these disorders, was reported to be the most frequent cause of adult-onset leukodystrophies in one case series of 48 European patients, accounting for 10% of cases [2]. In a large Chinese cohort of adult patients with genetic leukoencephalopathies, CSF1R-L contributed to 7% of the cases [3]. Interestingly, autosomal recessive variants in the CSF1R gene can lead to brain abnormalities, neurodegeneration and dysosteosclerosis syndrome, which is characterized by onset in the perinatal/infancy period, delayed development, dysmorphism, osteopetrosis and a grave prognosis [4].

In 2018, Konno et al. [5] proposed diagnostic criteria for CSF1R-related ALSP, combining clinical, radiological, and genetic features. The sensitivity and specificity of these criteria in an external European cohort were 82% and 66%, respectively [6]. In our series, all four patients fulfilled the criteria for “definite” ALSP. ALSP due to AARS2 variants was identified in 2016. Patients who do not harbor variants in either CSF1R or AARS1/2 have also been reported, suggesting that additional causative genes remain unidentified.

Compared with the mean age at onset of 43 years reported in the current literature on CSF1R-L, the mean age at onset was 35.3 years in this series [7]. The mean reported disease duration is 6.8 years, but disease duration was considerably shorter in our series, ranging from 11 months to 2 years. Determining whether these findings are replicated in other Indian cohorts would be interesting. In a recently published Chinese cohort, the median duration of symptoms was 2 years [8]. The prominent features in our series included cognitive impairment, dysarthria, parkinsonism, pyramidal involvement, and seizures, which is consistent with the published literature. Atypical parkinsonism, including early and prominent parkinsonism, dementia with Lewy body-like disease, and asymmetrical parkinsonism resembling CBS, has been observed in CSF1R-L patients [9]. The response to levodopa therapy is poor. In addition, the phenotypic heterogeneity of CSF1R-L has led to diagnostic difficulties, with patients being treated for stroke, demyelinating disorders, vasculitis, and autoimmune encephalitis. In our series, one patient was treated for possible autoimmune encephalitis.

Radiological features may provide strong clues for diagnosis. Diffusion MRI is particularly helpful, as dot-like periventricular diffusion restrictions may be observed [10]. Another useful imaging feature may be the “stepping-stone” pattern of calcifications in frontal pericallosal areas, which is more visible on computed tomography (CT) scans. The calcifications are often tiny and may be missed unless thin-slice 1 mm CT images are used. The cerebellar peduncles and dentate nuclei are characteristically spared in this condition, enabling discrimination from demyelinating disorders. An important radiological sign is hyperintensity of the pyramidal tracts on diffusion weighted imaging, which was observed in all four of our patients.

Three of our four patients had missense variants in the CSF1R gene, and one had an in-frame deletion. All the variants have been previously reported and are located within the intracellular tyrosine kinase domain of CSF1R. Missense variants in the tyrosine kinase domain, mostly in exons 18 and 19, constitute the majority of disease-causing variants. CSF1R is a tyrosine kinase receptor that plays a key role in maintaining microglial brain function. Nonsense variants producing premature stop codons and frameshift variants located outside of the tyrosine kinase domain have also been detected. None of our patients had a family history of the disease. Therefore, this condition may be due to de novo variants, incomplete penetrance or mosaicism. Parental genetic studies were performed in only 1 patient in our series, and the results were negative.

While cohorts of Asian CSF1R-L patients have been reported from Japan [7], China [3,8], Taiwan [11], and Korea [12], reports from the Indian subcontinent are limited [13-19]. We have summarized these reports from India in the Supplementary Table 1 in the online-only Data Supplement. All previously reported Indian patients (n=8) presented with rapidly worsening cognitive impairment, often combined with behavioral issues, extrapyramidal involvement, and seizures. Eight patients demonstrated typical white matter and callosal involvement with sparing of subcortical U-fibers and involvement of projection fibers and the brainstem, and most patients demonstrated diffusion restriction in the involved white matter.

We expand the literature from India by reporting four patients with CSF1R-L. Our patients had prominent symptoms of dementia, atypical parkinsonism, and spasticity. The age at onset and disease duration were lower than those in Western cohorts. Future research should focus on establishing larger cohorts to better delineate phenotypic, genotypic, and imaging features.

Supplementary Materials

Supplementary Video Legends

Video 1. Video of case 2 showing hypometric horizontal and vertical saccades, and rigidity and bradykinesia involving all four limbs (right more than left) with dystonia of the right upper limb.

Notes

Ethics Statement

The study was approved by the institutional review board and informed consent was obtained from all patients (IRB number: IEC-273/16.05.2023, RP-10/23, OP-20/12.01.2024).

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

The study was partially supported by an institutional intramural grant awarded to Divyani Garg (Project code A-977).

Acknowledgments

None

Author Contributions

Conceptualization: Divyani Garg. Data curation: Divyani Garg, Abhishek Vaingankar, Anu Gupta, Farsana Mustafa. Formal analysis: Divyani Garg, Abhishek Vaingankar. Funding acquisition: Divyani Garg. Investigation: Ajay Garg. Methodology: Divyani Garg, Anu Gupta, Roopa Rajan. Project administration: Divyani Garg. Resources: Ayush Agarwal, Divya M Radhakrishnan, Awadh Kishor Pandit, Rohit Bhatia, Mamta Bhushan Singh, Venugopalan Y Vishnu, Ajay Garg, Achal Kumar Srivastava. Supervision: Divyani Garg. Validation: Divyani Garg. Visualization: Divyani Garg, Anu Gupta. Writing— original draft: Divyani Garg. Writing—review & editing: Abhishek Vaingankar, Anu Gupta, Roopa Rajan, Farsana Mustafa, Ayush Agarwal, Divya M Radhakrishnan, Awadh Kishor Pandit, Rohit Bhatia, Mamta Bhushan Singh, Ajay Garg, Achal Kumar Srivastava.

Figure 1.

Progressive asymmetrical WM lesions with callosal and corticospinal tract involvement: a comparative MRI analysis of four cases. First row (case 1): axial T1 (A) and T2-WI (B) images reveal asymmetrical confluent lesions (arrows), hypointense on T1 and hyperintense on T2, involving the bilateral frontal and left parietal WM, along with the anterior corpus callosum. The posterior corpus callosum remains spared (dotted arrows). There is associated atrophy, as indicated by prominent cortical sulci and enlarged frontal horns. Sagittal FLAIR (C) shows thinning and atrophy of the anterior corpus callosum (arrows), with the splenium unaffected (dotted arrows). Coronal FLAIR (D) highlights asymmetrical hyperintensities in the frontal lobes (more prominent on the left) and along the left corticospinal tract (dotted arrow). Axial diffusion (E) and the ADC map (F) display scattered foci of diffusion restriction in the corona radiata. Second row (case 2): axial T1 (A), T2-WI (B) images show asymmetrical confluent T1-hypointense (arrows) and T2-hyperintense lesions in the bilateral parietal (arrows) and frontal WM with more involvement in the parietal region. Sagittal FLAIR (C) shows hyperintensity and atrophy of the corpus callosum, with the splenium more affected than the genu (arrows). Coronal FLAIR (D) highlights asymmetrical hyperintensities in the frontal lobes (more prominent on the left) and bilateral corticospinal tracts (left>right, dotted arrow). Atrophy is evident, indicated by prominent cortical sulci and enlarged frontal horns. Axial diffusion (E) and ADC map (F) reveal scattered foci of diffusion restriction in the corpus callosum (arrow) and corona radiata. Third row (case 3): axial T1-WI (A) shows mild atrophy along the sylvian fissures. Axial T2-WI (B) images reveal asymmetrical confluent lesions in the bilateral frontal and parietal WM (arrows). Sagittal FLAIR (C) shows hyperintensity and atrophy of the entire corpus callosum (arrows). Coronal FLAIR (D) demonstrates asymmetrical hyperintensities in the frontal lobes and bilateral corticospinal tracts ([left>right], arrows). Atrophy is indicated by prominent cortical sulci and enlarged frontal horns. Axial diffusion (E) and ADC map (F) show scattered foci of diffusion restriction in the corona radiata. Last row (case 4): axial T1-WI (A) shows atrophy, indicated by prominent cortical sulci (arrows). Axial T2-WI (B) demonstrates asymmetrical confluent lesions in the bilateral frontal and parietal WM (arrows). Sagittal T2-WI (C) reveals hyperintensity and atrophy of the corpus callosum (arrows). Coronal T2-WI (D) highlights hyperintensities in the frontal lobes and bilateral corticospinal tracts (left>right, arrow). Axial diffusion (E) shows scattered foci of diffusion restriction in the left centrum semiovale. ADC map (F) shows scattered foci of diffusion restriction in the left centrum semiovale. DWI, diffusion weighted imaging; ADC, apparent diffusion coefficient; WM, white matter; MRI, magnetic resonance imaging; T1-WI, T1-weighted imaging; T2-WI, T2-weighted imaging; FLAIR, fluid attenuated inversion recovery.

REFERENCES

• 1. Wade C, Lynch DS. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. Handb Clin Neurol 2024;204:263–271.ArticlePubMed
• 2. Lynch DS, Jaunmuktane Z, Sheerin UM, Phadke R, Brandner S, Milonas I, et al. Hereditary leukoencephalopathy with axonal spheroids: a spectrum of phenotypes from CNS vasculitis to parkinsonism in an adult onset leukodystrophy series. J Neurol Neurosurg Psychiatry 2016;87:512–519.ArticlePubMedPMC
• 3. Wu C, Wang M, Wang X, Li W, Li S, Chen B, et al. The genetic and phenotypic spectra of adult genetic leukoencephalopathies in a cohort of 309 patients. Brain 2023;146:2364–2376.ArticlePubMedPMCPDF
• 4. Dulski J, Souza J, Santos ML, Wszolek ZK. Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP. Orphanet J Rare Dis 2023;18:160.ArticlePubMedPMCPDF
• 5. Konno T, Yoshida K, Mizuta I, Mizuno T, Kawarai T, Tada M, et al. Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation. Eur J Neurol 2018;25:142–147.PubMed
• 6. Ayrignac X, Carra-Dallière C, Codjia P, Mouzat K, Castelnovo G, Ellie E, et al. Evaluation of CSF1R-related adult onset leukoencephalopathy with axonal spheroids and pigmented glia diagnostic criteria. Eur J Neurol 2022;29:329–334.PubMed
• 7. Konno T, Kasanuki K, Ikeuchi T, Dickson DW, Wszolek ZK. CSF1R-related leukoencephalopathy: a major player in primary microgliopathies. Neurology 2018;91:1092–1104.ArticlePubMedPMC
• 8. Wu J, Cheng X, Ji D, Niu H, Yao S, Lv X, et al. The phenotypic and genotypic spectrum of CSF1R-related disorder in China. Mov Disord 2024;39:798–813.PubMed
• 9. Sundal C, Fujioka S, Van Gerpen JA, Wider C, Nicholson AM, Baker M, et al. Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations. Parkinsonism Relat Disord 2013;19:869–877.ArticlePubMedPMC
• 10. Mickeviciute GC, Valiuskyte M, Plattén M, Wszolek ZK, Andersen O, Danylaité Karrenbauer V, et al. Neuroimaging phenotypes of CSF1R-related leukoencephalopathy: systematic review, meta-analysis, and imaging recommendations. J Intern Med 2022;291:269–282.ArticlePubMedPDF
• 11. Tsai PC, Fuh JL, Yang CC, Chang A, Lien LM, Wang PN, et al. Clinical and genetic characterization of adult-onset leukoencephalopathy caused by CSF1R mutations. Ann Clin Transl Neurol 2021;8:2121–2131.ArticlePubMedPMCPDF
• 12. Kim EJ, Shin JH, Lee JH, Kim JH, Na DL, Suh YL, et al. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia linked CSF1R mutation: report of four Korean cases. J Neurol Sci 2015;349:232–238.ArticlePubMed
• 13. Reddy Tallapalli AV, Nashi S, Kamath SD, Srijithesh PR, Kulkarni GB, Alladi S. A rare genetic cause of young onset rapidly progressive dementia-first report from India. Neurol India 2022;70:781–783.ArticlePubMed
• 14. Sriram N, Padmanabha H, Chandra SR, Mahale R, Nandeesh B, Bhat MD, et al. CSF1R related leukoencephalopathy - rare childhood presentation of an autosomal dominant microgliopathy! Ann Indian Acad Neurol 2022;25:311–314.ArticlePubMedPMC
• 15. Arshad F, Vengalil S, Maskomani S, Kamath SD, Kulanthaivelu K, Mundlamuri RC, et al. Novel CSF1R variant in adult-onset leukoencephalopathy masquerading as frontotemporal dementia: a follow-up study. Neurocase 2021;27:484–489.ArticlePubMed
• 16. Rudrabhatla P, Sabarish S, Ramachandran H, Nair SS. Teaching neuroImages: rare adult-onset genetic leukoencephalopathy. Neurology 2021;96:e2561–e2562.ArticlePubMed
• 17. Goyal S, Darshini KJ, Sharma D, Nashi S, Arshad F, Vandana VP, et al. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) masquerading primary progressive aphasia. Ann Indian Acad Neurol 2022;25:777–779.ArticlePubMedPMC
• 18. Dulski J, Baker M, Banks SA, Bayat M, Bruffaerts R, Ortiz Cruz G, et al. Global presence and penetrance of CSF1R-related disorder. Neurol Genet 2024;10:e200187.ArticlePubMedPMC
• 19. Ramakrishnan S, Arshad F, Bs K, Pon AG, Bosco S, Kumar S, et al. Primary microgliopathy presenting as degenerative dementias: a case series of novel gene mutations from India. Dement Geriatr Cogn Dis Extra 2024;14:14–28.ArticlePubMedPMCPDF

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