Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia linked to CSF1R mutation: A case report

Dear Sir, Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, rapidly progressive neurodegenerative disease affecting the white matter and typically manifests in adulthood with cognitive, behavioral, and motor disturbances. It encompasses hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmented orthochromatic leukodystrophy POLD, which were previously considered distinct but are now recognized as a single disease entity due to shared genetic and pathological features.[1-3] ALSP is characterized by frontal- and parietal-dominant white matter lesions, corpus callosum atrophy, myelin and axon loss, astrocytosis, axonal spheroids, and pigmented macrophages. The neuropathological features of ALSP include widespread myelin and axon loss, astrocytosis, abundant destructive axonal swellings (spheroids in HDLS), and pigmented macrophages (POLD).[3,4] Since the discovery of CSF1R mutations as the underlying cause of ALSP, genetic testing has become a crucial diagnostic tool, distinguishing it from other adult-onset leukodystrophies with overlapping clinical and radiological features.[5,6] Here, we present a genetically confirmed case of ALSP. A 49-year-old right-handed male driver with no significant medical or family history presented with slowness, stiffness while walking, and gait instability for 1.5 years. Initially, he had difficulty operating the clutch and brake due to progressive leg stiffness. His gait became slow with short steps, but he had no difficulty turning. He experienced swaying while walking but managed to maintain his balance. There were no symptoms of headache, loss of consciousness, seizures, behavioral or memory disturbances, urinary incontinence, Parkinsonian features, cranial nerve involvement, sensory complaints, autonomic dysfunction, or drug or toxin exposure. On examination, his vital signs were normal. He was alert and oriented. Neurological examination revealed hypertonia with hyperreflexia in both lower limbs [Video 1] and a spastic gait [Video 2]. Both plantar reflexes were extensor. There was no limb weakness, muscle wasting, fasciculations, or sensory deficits. Cerebellar function was intact, and gait analysis showed a broad-based, spastic pattern with normal arm swing but little swaying while walking and requiring multiple steps while turning [Video 2], Tandem gait was not possible. No meningeal signs were observed. {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"Video 1","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_mzuxe2vj"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"Video 2","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_dnhhosdz"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} Routine laboratory investigations, including complete blood count, electrolytes, lipid profile, liver and renal function tests, syphilis screening, vitamin B12, and thyroid function tests, were all normal. Cerebrospinal fluid analysis was unremarkable. Brain Magnetic resonance Imaging (MRI) revealed T2-weighted and fluid-attenuated inversion recovery (T2/FLAIR) sequences hyperintensities in the bilateral corona radiata, splenium of the corpus callosum, and the peritrigonal and periventricular regions [Figure 1]. Persistent restricted diffusion was noted in these areas and remained unchanged on a follow-up MRI 1 year later [Figure 2]. This pattern of persistent diffusion restriction over time raised suspicion of adult-onset leukodystrophy with pigmented glia, prompting genetic evaluation.Figure 1: T2 and FLAIR images showing discrete and patchy near-symmetrical hyperintensities in the bilateral corona radiata, peritrigonal, and periventricular regions, with persistent restricted diffusion in the bilateral peritrigonal and periventricular white matterFigure 2: T2 and FLAIR images showing discrete and patchy near-symmetrical hyperintensities in the bilateral corona radiata, peritrigonal, and periventricular regions, with persistent restricted diffusion in the bilateral peritrigonal and periventricular white matter on a scan repeated 1 year after the previous scanBased on clinical and imaging findings, leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation, CLCN2-related leukoencephalopathy, and HDLS were considered differential diagnoses. Whole-exome sequencing identified a heterozygous missense variant in exon 20 of the CSF1R gene, confirming the diagnosis of ALSP. It is classified as “likely pathogenic” according to the American College of Medical Genetics and Genomics (ACMG) guidelines. The patient was treated symptomatically. He was initiated on oral baclofen at a dose of 5 mg twice a day, with plans to increase the dose in subsequent follow-up visits. He also started physiotherapy and occupational therapy. The global prevalence of ALSP remains unclear, but estimates suggest approximately 10,000 cases in the United States, with case series reporting 16 cases in France, 122 in Japan, 5 in Taiwan, and about 10 in South Korea.[7] ALSP is exceedingly rare in India, with fewer than 10 genetically confirmed cases published to date.[8-10] To our knowledge, this is the first genetically confirmed case of ALSP with the p.Cys892Phe variant reported from India. The identification of CSF1R mutations has redefined ALSP as a distinct genetic disorder, allowing earlier diagnosis and differentiation from other adult-onset leukoencephalopathies.[5,11] However, cases of pathologically confirmed ALSP without CSF1R mutations have been reported, highlighting the need for a combined genetic and pathological approach in uncertain cases.[4,5,11] The mutation identified in this case (p.Cys892Phe) adds to the growing spectrum of CSF1R-associated pathogenic variants. Since CSF1R mutations underlie both HDLS and POLD, the use of the unified term “ALSP” is recommended for consistency in the medical literature.[6] Given its heterogeneous clinical presentation, ALSP may be underdiagnosed, and genetic testing should be considered in patients presenting with executive dysfunction, personality changes, progressive cognitive decline, motor impairment, and gait abnormalities.[11] Currently, there is no definitive treatment for ALSP.[12] Case reports suggest that selective serotonin reuptake inhibitors may help alleviate depressive symptoms, but carbidopa/levodopa has shown no significant benefit in treating parkinsonian features.[13] The average disease duration is approximately 6.8 years, with a mean age at death of 53 years (range: 23–84 years). Given the progressive nature of ALSP, supportive and symptomatic management remains the mainstay of care.[5,11,14] This case is unique as it represents the first genetically confirmed report from India of ALSP due to a heterozygous missense variant (p.Cys892Phe) in exon 20 of the CSF1R gene. The patient’s presentation was atypical, with progressive spastic paraparesis and gait disturbance rather than the more common behavioral or cognitive symptoms. MRI showed persistent white matter diffusion restriction over a year, a rare imaging feature. The absence of family history suggests a possible de novo mutation or incomplete penetrance, further highlighting the phenotypic and genetic heterogeneity of ALSP. Acknowledgement All authors contributed equally to patient examination, diagnosis, management, data collection, draft preparation, and manuscript writing. Author contribution A. Research project: Conception: Dr Kamalesh Tayade Organization: Dr Kamalesh Tayade Execution: Dr Jivan Morey, Dr Amarnath Chavan, Dr Anarya Karle B. Statistical analysis: Design: Dr Kamalesh Tayade Execution: Dr Jivan Morey, Dr Amarnath Chavan, Dr Anarya Karle Review and Critique: Dr Kamalesh Tayade, Dr Haresh Bharote C. Manuscript preparation: Writing of the first draft: Dr Jivan Morey, Dr Kamalesh Tayade Review and Critique: Dr Kamalesh Tayade, Dr Dnyaneshwar Asole, Dr Anil Venkatachalam Ethical compliance statement Informed patient consent was obtained. Institutional review board or ethics committee approval was not required. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.