Redefining the phenotype of ALSP and AARS2 mutation–related leukodystrophy

摘要

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. Adult-onset leukodystrophies are a rare (estimated prevalence of 2 in 100,000 1 ) and diagnostically challenging group of conditions. 2 MRI is pivotal in identifying the presence of a leukodystrophy; however, MRI findings are commonly etiologically nonspecific. 3 Two leukodystrophies with similar clinical, imaging, and histopathologic 4 phenotypes are adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), the most common adult-onset leukodystrophy, 5 and a novel leukoencephalopathy due to autosomal recessive mutations in the mitochondrial alanyl–transfer RNA (tRNA) synthetase 2 gene ( AARS2 -L). 6 ALSP was previously referred to as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) or pigmentary orthochromatic leukodystrophy (POLD); 7 , 8 however, ALSP is now preferred as the unifying term for leukodystrophies due to autosomal dominant mutations in the colony-stimulating factor receptor 1 ( CSF1R ) gene. 5 Mutations in the CSF1R gene occur in the tyrosine kinase domain of the colony-stimulating factor receptor 1 which is primarily expressed in microglia in the CNS and results in microglial dysfunction in ALSP. 9 , 10 Mutations in the AARS2 gene cause errors in the mitochondrial aminoacyl tRNA synthase gene responsible for encoding alanine onto mitochondrial tRNA during mitochondrial translation 11 and has been recently found to be the cause of an ovario-leukodystrophy 6 and an infantile cardiomyopathy. 11 The aim of this article is to summarize the characteristic imaging appearances of ALSP and AARS2 -L and highlight their phenotypic similarities and discriminating clinical and imaging features.