Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
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Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD), refers to a rare inherited autosomal dominant disease characterized by an adult-onset leukodystrophy that usually leads to death in around 5-7 years. It is considered to belong to the microgliopathies.
For many years hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD) were considered to be two separate hereditary leukoencephalopathies. Sometimes HDLS was also called neuroaxonal leukodystrophy. The striking similarities in clinical presentation and histology suggested a link between the two diseases for a long time and HDLS and POLD are now considered to be part of the same disease spectrum, which researchers have recommended calling adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) 1.
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is considered a rare disease, typically manifesting between ages 30 and 50 years. Its exact prevalence is unknown, as it has been previously mistaken for many other diseases and it might thus continue to be underdiagnosed.
While it is usually an inherited disease, there exist case reports of proven de novo mutations and mutation carriers without clinical symptoms currently up to the age of over 70 years 2.
Patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) can have a wide variety of symptoms that usually exhibit a rapid progression and lead to death within a couple of years due to progressive motor impairment.
Typical symptoms are:
- depression, which might precede the other symptoms
- neuropsychiatric symptoms, progressing to dementia
- motor impairment, with extrapyramidal and pyramidal symptoms that usually lead to tetraparesis
- apraxia and rarely ataxia
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by autosomal dominantly inherited mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. The mutations can be proven by genetic testing of blood samples. Before the identification of the underlying genetic cause of the disease, a brain biopsy was needed to establish the diagnosis. Neuropathologic findings usually show gliosis, white matter destruction with pigmented glia and/or axonal spheroids and macrophages.
Small periventricular calcifications, often only seen on thin sagittal reconstructions with a bone kernel are a typical imaging finding. Affected areas show a low attenuation and no contrast enhancement.
Presymptomatic mutation carriers
Mutation carriers usually show non-specific T2 hyperintense lesions of the white matter that are pronounced for the age of the patient. MR spectroscopy in these lesions is usually normal without characteristic findings.
Characterized by bilateral, asymmetric patchy or confluent areas of subcortical and deep white matter signal change, usually most pronounced in the frontal lobe followed by the parietal lobe with a relative sparing of the temporal lobe. The corticospinal tract is usually affected late in the disease course. Progression leads to a severe atrophy of the supratentorial white matter. The cerebellum and brainstem are usually spared 3,4.
- T1: affected areas are low in signal
- T1 C+ (Gd): no enhancement is visible
- T2/FLAIR: hyperintense
- DWI: small spots of diffusion restriction, that can be visible over months have been described as a characteristic finding 3
- MR spectroscopy: (in symptomatic patients)
Treatment and prognosis
Currently, there exists no accepted specific therapy and the disease is inevitably fatal within a couple of years. In a few cases, hematopoietic stem cell transplantation was attempted as an individual cure, leading to clinical stabilization in some cases but also therapy associated death in one case10.
The main differential for ALSP is leukoencephalopathy due to autosomal recessive mutations in the mitochondrial alanyl-transfer RNA (tRNA) synthetase gene (AARS2-L), another adult-onset leukodystrophy with similar pathologic findings. The clinical presentation and imaging findings in AARS2-L strongly resemble those of ALSP, but there are subtle differences 8,9.
General imaging differential considerations include 2-6:
Clinical differential considerations include 2-6:
- 1. ALSP - Genetics Home Reference - NIH Webpage
- 2. Karle KN, Biskup S, Schüle R, et-al. De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS). Neurology 2013;81(23): 2039-44 Neurology (full text)-Pubmed citation
- 3. Bender B, Klose U, Lindig T, et-al.Imaging features in conventional MRI, spectroscopy and diffusion weighted images of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS). J Neurol. 2014;261(12):2351-9doi: 10.1007/s00415-014-7509-2 (full text)-Pubmed citation
- 4. Sundal C, van Gerpen JA, Nicholson AM, et-al. MRI characteristics and scoring in HDLS due to CSF1R gene mutations.Neurology 2012;79(6):566-74free full text (PMC)-Pubmed citation
- 5. Sundal C, Lash J, Aasly J, et-al. Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): a misdiagnosed disease entity. J Neurol Sci 2012;314(1-2):130-7. free full text (PMC)-Pubmed citation
- 6. Mascalchia M, Gavazzia C, Morbinc M, et-al. CT and MR Imaging of Neuroaxonal Leukodystrophy Presenting as Early-Onset Frontal Dementia. AJNR 2006;27: 1037-1039. URL http://www.ajnr.org/content/27/5/1037.full.pdf
- 7. Freeman SH,Hyman BT, Sims KB, et-al. Adult onset leukodystrophy with neuroaxonal spheroids: Clinical, neuroimaging and neuropathologic observations. Brain Pathol 2009; 19(1): 39–47. URL http://onlinelibrary.wiley.com/doi/10.1111/j.1750-3639.2008.00163.x/epdf
- 8. Lakshmanan R, Adams ME, Lynch DS, Kinsella JA, Phadke R, Schott JM, Murphy E, Rohrer JD, Chataway J, Houlden H, Fox NC, Davagnanam I. Redefining the phenotype of ALSP and AARS2 mutation-related leukodystrophy. Neurol Genet. 2017 Feb 15;3(2):e135. doi: 10.1212/NXG.0000000000000135. PMID: 28243630; PMCID: PMC5312114.
- 9. De Cocker LJL, Castillo M. Distinctive diffusion-weighted imaging features in late-onset genetic leukoencephalopathies. Neuroradiology. 2020 Sep 3. doi: 10.1007/s00234-020-02543-4. Epub ahead of print. PMID: 32879996.
- 10. Papapetropoulos S, Pontius A, Finger E, Karrenbauer V, Lynch DS, Brennan M, Zappia S, Koehler W, Schoels L, Hayer SN, Konno T, Ikeuchi T, Lund T, Orthmann-Murphy J, Eichler F, Wszolek ZK. Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development. Front Neurol. 2022;12:788168. 35185751, PMCID: PMC8850408.