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Imaging Patterns Characterizing Mitochondrial Leukodystrophies

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Imaging Patterns Characterizing Mitochondrial Leukodystrophies Published April 15, 2021 as 10.3174/ajnr.A7097 ORIGINAL RESEARCH PEDIATRICS Imaging Patterns Characterizing Mitochondrial Leukodystrophies S.D. Roosendaal, T. van de Brug, C.A.P.F. Alves, S. Blaser, A. Vanderver, N.I. Wolf, and M.S. van der Knaap ABSTRACT BACKGROUND AND PURPOSE: Achieving a specific diagnosis in leukodystrophies is often difficult due to clinical and genetic heter- ogeneity. Mitochondrial defects cause 5%–10% of leukodystrophies. Our objective was to define MR imaging features commonly shared by mitochondrial leukodystrophies and to distinguish MR imaging patterns related to specific genetic defects. MATERIALS AND METHODS: One hundred thirty-two patients with a mitochondrial leukodystrophy with known genetic defects were identified in the data base of the Amsterdam Leukodystrophy Center. Numerous anatomic structures were systematically assessed on brain MR imaging. Additionally, lesion characteristics were scored. Statistical group analysis was performed for 57 MR imaging features by hierarchic testing on clustered genetic subgroups. RESULTS: MR imaging features indicative of mitochondrial disease that were frequently found included white matter rarefaction (n ¼ 50 patients), well-delineated cysts (n ¼ 20 patients), T2 hyperintensity of the middle blade of the corpus callosum (n ¼ 85 patients), and symmetric abnormalities in deep gray matter structures (n ¼ 42 patients). Several disorders or clusters of disorders had characteristic features. The combination of T2 hyperintensity in the brain stem, middle cerebellar peduncles, and thalami was associated with complex 2 deficiency. Predominantly periventricular localization of T2 hyperintensities and cystic lesions with a dis- tinct border was associated with defects in complexes 3 and 4. T2-hyperintense signal of the cerebellar cortex was specifically associated with variants in the gene NUBPL. T2 hyperintensities predominantly affecting the directly subcortical cerebral white mat- ter, globus pallidus, and substantia nigra were associated with Kearns-Sayre syndrome. CONCLUSIONS: In a large group of patients with a mitochondrial leukodystrophy, general MR imaging features suggestive of mitochon- drial disease were found. Additionally, we identified several MR imaging patterns correlating with specific genotypes. Recognition of these patterns facilitates the diagnosis in future patients. ABBREVIATIONS: KSS ¼ Kearns-Sayre syndrome; SDH ¼ Succinate dehydrogenase; MELAS ¼ mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome; MNGIE ¼ mitochondrial neurogastrointestinal encephalopathy eukodystrophies are genetic disorders predominantly involv- characterized by a specific combination of affected structures on Ling the white matter of the CNS.1 Clinical and genetic hetero- MR imaging, constituting a recognizable pattern. Recent diagnos- geneity complicate establishing a specific molecular diagnosis, tic algorithms for leukodystrophies acknowledge the central role which becomes more effective when clinical, radiologic, and of MR imaging pattern recognition.1,2 genetic parameters are combined.1 Most leukodystrophies are A subset of leukodystrophies, involving 5%–10%, is caused by mitochondrial defects.3,4 Mitochondrial diseases comprise a group Received November 17, 2020; accepted after revision January 14, 2021. of disorders with genetic defects in mitochondrial oxidative energy From the Departments of Radiology (S.D.R.) and Epidemiology and Biostatistics metabolism. Mitochondria are cellular organelles that produce (T.v.d.B.), Amsterdam UMC, Amsterdam, the Netherlands; Division of Neuroradiology (C.A.P.F.A.), and Department of Radiology and Division of energy via oxidative phosphorylation (Online Supplemental Data). Neurology (A.V.), The Children's Hospital of Philadelphia, Philadelphia, The oxidative phosphorylation system consists of 5 respiratory Pennsylvania; Division of Neuroradiology (S.B.), Department of Diagnostic Imaging, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Please address correspondence to Stefan D. Roosendaal, MD, PhD, Amsterdam Department of Pediatric Neurology (M.S.v.d.K., N.I.W.), Emma Children’s Hospital, UMC, Department of Radiology, Meibergdreef 9, 1105 AZ Amsterdam, the Amsterdam Leukodystrophy Center, Amsterdam UMC, Vrije Universiteit and Netherlands: e-mail: [email protected] Amsterdam Neuroscience, Amsterdam, the Netherlands; and Department of Functional Genomics (M.S.v.d.K.), Center for Neurogenomics and Cognitive Indicates open access to non-subscribers at www.ajnr.org Research, VU University, Amsterdam, the Netherlands. The following authors are members of the European Reference Network for Rare Indicates article with online supplemental data. Neurological Disorders, project ID 739510: M.S. van der Knaap and N.I. Wolf. http://dx.doi.org/10.3174/ajnr.A7097 AJNR Am J Neuroradiol :2021 www.ajnr.org 1 Copyright 2021 by American Society of Neuroradiology. chain complexes in the mitochondrial membrane. Human cells deficiency was present in 10 patients, all with variants in LYRM7. possess 2 different genomes: the nuclear genome, containing Some were part of a previous study on LYRM7.14 Complex 4 defi- approximately 20,000 genes, and the mitochondrial genome, con- ciency was present in 9 patients: 7 with variants in APOPT1,1 taining 37 genes. Although mitochondria have functions in addi- with variants in COX6B,and1withvariantsinCOX10.Most tion to energy metabolism, mitochondrial diseases are typically patients with APOPT1 variants were part of a previous study on regarded as disorders of oxidative phosphorylation.5 They are APOPT1.12 Iron-sulfur cluster assembly pathway variants were caused by variants in either mitochondrial genes or, much more present in 33 patients: 9 with variants in NUBPL, 8inIBA57,7in frequently, nuclear genes encoding proteins necessary for mito- ISCA2,5inFDX1L,3inBOLA3,and1inCDK5RAP1. chondrial function.5 Concerning the high number of associated Descriptions of some of the patients with NUBPL,11 IBA57,20 and gene defects, it is not surprising that mitochondrial disorders have a FDX1L21 variants were published before. A large mitochondrial striking clinical heterogeneity;5 the high energy demand of the CNS DNA deletion was present in 6 patients, all presenting with the explains it being the most commonly affected organ.5 KSS phenotype. Additionally, 4 patients had TYMP variants, in- Some mitochondrial encephalopathies predominantly manifest dicative of MNGIE, and 5 patients had CLPP variants; descrip- with lesions of gray matter structures (eg, mitochondrial encephal- tions of some of the latter have been published before.13 opathy, lactic acidosis, and stroke-like episodes syndrome (MELAS); Alpers syndrome; and Leigh syndrome).6 Another category mani- MR Imaging Evaluation festsasleukodystrophy.7 The leukoencephalopathy in Kearns-Sayre At least 1 brain MR imaging was available for each patient. syndrome (KSS)8 and mitochondrial neurogastrointestinal ence- When multiple MRIs were available, the first was used for phalopathy syndrome (MNGIE)9 has been known for a long time, analysis. MR sequences and image quality were variable but more recently, next-generation genetic sequencing techniques because the MRIs were acquired at multiple institutions. T2- have revealed that numerous unsolved cases of leukodystrophy have weighted and nonenhanced T1-weighted sequences were a mitochondrial cause, and MR imaging patterns of new mitochon- available for every patient; FLAIR was available for 115 drial leukodystrophies were added.10 Patient selection by specific MR patients. These images were used to systematically score imaging patterns was pivotal in the detection of the novel leukody- numerous white and gray matter structures as normal or strophies caused by defects in the genes LYRM7, APOPT1, NUBPL, abnormal, and specific features of the abnormalities were and CLPP.11-14 However, systematic studies on MR imaging patterns scored, as described in van der Knaap et al.22 More salient in larger groups of patients with different mitochondrial leukodystro- features of this scoring system were as follows: The white phies are lacking, and information on the associated MR imaging matter was divided into 3 zones—directly subcortical white patterns is lacking in recent leukodystrophy diagnostic algorithms.1,2 matter (ie, arcuate fibers), deep white matter, and periven- In the current study, we systematically analyzed MRIs of a tricular white matter. The corpus callosum was divided into large group of patients with mitochondrial leukodystrophy. In all inner, middle, and outer blades (or layers) and anterior, mid- patients, the causative gene defect was known. The study aims dle, and posterior parts. Cysts were strictly scored as lesions were to describe MR imaging features suggesting a mitochondrial with a signal intensity identical to that of CSF on FLAIR leukodystrophy in general and to distinguish MR imaging pat- images, whereas lesions having a signal intensity on FLAIR terns related to particular gene defects. intermediate between normal white matter and CSF were defined as rarefaction. The caudate nucleus, putamen, globus MATERIALS AND METHODS pallidus, thalamus, dentate nucleus, substantia nigra, cerebral Patients cortex, and cerebellar cortex were individually evaluated. In the MR imaging data base of the Amsterdam Leukodystrophy Center, comprising more than 4000 patients, 132 patients with a Statistical Analysis mitochondrial leukodystrophy and a known gene defect
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