Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Feb 15;3(2):e135.
doi: 10.1212/NXG.0000000000000135. eCollection 2017 Apr.

Redefining the phenotype of ALSP and AARS2 mutation-related leukodystrophy

Rahul Lakshmanan  1 , Matthew E Adams  1 , David S Lynch  1 , Justin A Kinsella  1 , Rahul Phadke  1 , Jonathan M Schott  1 , Elaine Murphy  1 , Jonathan D Rohrer  1 , Jeremy Chataway  1 , Henry Houlden  1 , Nick C Fox  1 , Indran Davagnanam  1
Affiliations
Review

Redefining the phenotype of ALSP and AARS2 mutation-related leukodystrophy

Rahul Lakshmanan et al. Neurol Genet. .

Abstract

Objective: To provide an overview of the phenotype of 2 clinically, radiologically, and pathologically similar leukodystrophies, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and alanyl-transfer RNA synthetase 2 mutation-related leukodystrophy (AARS2-L), and highlight key differentiating features.

Methods: ALSP and AARS2-L cases were identified from the adult-onset leukodystrophy database at our institution. In addition, cases with imaging findings were identified from a literature review. The phenotypic features were determined by combining published cases with those from our database.

Results: A combined total of 74 cases of ALSP and 10 cases of AARS2-L with neuroimaging data were identified. The mean age at onset was 42 years in ALSP and 26 years in AARS2-L. Cognitive and motor symptoms were the most common symptoms overall in both. Ovarian failure was exclusive to AARS2-L, present in all known female cases. Both ALSP and AARS2-L showed a confluent, asymmetric, predominantly frontoparietal, periventricular pattern of white matter disease with subcortical U-fiber sparing; pyramidal tract and corpus callosum involvement; and diffusion changes in the white matter which we have termed "deep white matter diffusion dots." Central atrophy and corpus callosal thinning were prominent in ALSP and disproportionately mild in AARS2-L when present. ALSP also occasionally showed ventricular abnormalities and calcifications in the frontal periventricular white matter, features not seen in AARS2-L. AARS2-L demonstrates white matter rarefaction which suppresses on fluid-attenuated inversion recovery MRI sequences, a feature not seen in ALSP.

Conclusions: ALSP and AARS2-L share similar clinical, imaging, and pathologic characteristics with key differentiating features that we have highlighted.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Imaging similarities between ALSP and AARS2-L
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) MRI findings are shown in upper image panels A–D. AARS2-L MRI findings are shown in lower image panels E–H. (A and E) Axial T2-w MRI sequence in ALSP case 8, table 1, and AARS2-L case 1, table 1, respectively, showing similar confluent slightly asymmetric frontoparietal predominant white matter T2-w hyperintensity, with more atrophy in ALSP. (B and F) Axial diffusion-weighted imaging b1000 trace image in ALSP case 1, table 1, and AARS2-L case 4, table 1, respectively, illustrating near-identical linearly arranged punctate and partly confluent hyperintense “deep white matter diffusion dots”. (C and G) Coronal fluid-attenuated inversion recovery sequence in ALSP case 8, table 1, and AARS2-L case 3, table 1, respectively, both showing hyperintense involvement of the left corticospinal tract (white arrows). (D and H) Sagittal T1-w sequence in case 8, table 1, and AARS2-L case 1, table 1, illustrating focal low-signal corpus callosum involvement with more marked thinning of the corpus callosum in ALSP.
Figure 2
Figure 2. Imaging differences between ALSP and AARS2-L
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) MRI findings are shown in upper image panels A–C. AARS2-L MRI findings are shown in lower image panels D–F. (A and D) Axial T2-w MRI sequence in ALSP case 8, table 1, and AARS2-L case 1, table 1, respectively, showing more severe atrophy in ALSP, despite a similar degree of white matter signal abnormality in both. Image panel (A) also shows a cavum septum pelludicum with a septal perforation (black arrows). (B) Axial unenhanced CT in ALSP case 4, table 1, illustrating frontal periventricular calcifications (white arrows). (C) Coronal fluid-attenuated inversion recovery (FLAIR) MRI image in ALSP case 7, table 1, showing linear septations in the frontal horn of the right lateral ventricle (compound white arrow). (E) Axial FLAIR MRI in AARS2-L case 1, table 1, showing suppression of white matter signal adjacent to the frontal horns and trigones of the lateral ventricles (dotted white arrows). (F) Axial FLAIR MRI in AARS2-L case 2, table 1, shows hyperintense signal in the heads of the caudate nuclei (black dotted arrows).
Figure 3
Figure 3. “Deep white matter diffusion dots” in ALSP and AARS2-L
Axial diffusion-weighted imaging b1000 trace sequences (top row) and axial apparent diffusion coefficient sequences (bottom row) in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) (A) and AARS2-L (B) showing linearly arranged, punctate, and partly confluent deep white matter areas of restricted diffusion arranged parallel to the ependymal surface.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Heim P, Claussen M, Hoffmann B, et al. . Leukodystrophy incidence in Germany. Am J Med Genet 1997;71:475–478. - PubMed
    1. Ahmed R, Murphy E, Davagnanam I, et al. . A practical approach to diagnosing adult onset leukodystrophies. J Neurol Neurosurg Psychiatry 2013;85:770–781. - PubMed
    1. Parikh S, Bernard G, Leventer RJ, et al. . A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies. Mol Genet Metab 2015;114:501–515. - PMC - PubMed
    1. Lynch D, Zhang WJ, Lakshmanan R, et al. . Adult onset leukoencephalopathy with axonal spheroids and pigmented glia: recessive mutations in AARS2 identified in a series of CSF1R negative patients. JAMA Neurol 2016;73:1433–1439. - PubMed
    1. Rademakers R, Baker M, Nicholson A, et al. . Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet 2012;44:200–205. - PMC - PubMed

LinkOut - more resources