PT  - JOURNAL ARTICLE
AU  - Alves, Cesar A.P.F.
AU  - Rossi-Espagnet, Maria Camilla
AU  - Perez, Francisco
AU  - Manteghinejad, Amirreza
AU  - Peterson, James T.
AU  - Ganetzky, Rebecca
AU  - Napolitano, Antonio
AU  - Grassi, Francesco
AU  - George-Sankoh, Ibrahim
AU  - Yildiz, Harun
AU  - Muraresku, Colleen
AU  - Falk, Marni J.
AU  - Martinelli, Diego
AU  - Longo, Daniela
AU  - Vanderver, Adeline
AU  - Gandolfo, Carlo
AU  - Saneto, Russell P.
AU  - Goldstein, Amy
AU  - Vossough, Arastoo
TI  - Single Large-Scale Mitochondrial Deletion Syndromes: Neuroimaging Phenotypes and Longitudinal Progression in Pediatric Patients
AID  - 10.3174/ajnr.A8670
DP  - 2025 Apr 10
TA  - American Journal of Neuroradiology
4099  - http://www.ajnr.org/content/early/2025/05/02/ajnr.A8670.short
4100  - http://www.ajnr.org/content/early/2025/05/02/ajnr.A8670.full
AB  - BACKGROUND AND PURPOSE: Single large-scale mitochondrial deletion syndrome (SLSMD) comprises devastating mitochondrial diseases often classified into 3 major clinical syndromes: Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), and Pearson syndrome (PS). Nevertheless, there remains large clinical variability and overlap among these SLSMD groups. Therefore, further stratification is required for more precise prognostication and clinical management. Through detailed description and analysis of longitudinal neuroimaging changes, we sought to determine the neuroradiologic hallmarks of SLSMDs and define their expected imaging progression to further delineate their natural history.MATERIALS AND METHODS: A retrospective, longitudinal study of 40 children with SLSMDs at 3 mitochondrial disease centers was performed. MRI review assessed the prevalence and progression of brain lesions in different regions with statistical significance testing and Kaplan-Meier analysis. Hierarchical cluster analysis was performed for involved brain regions to stratify findings into imaging phenotype groups.RESULTS: Among 40 patients with SLSMD (median age 9.26 years; interquartile range: 5.16–13.1), 67.5% had KSS, 15% had KSS with a prior history of PS (PS→KSS), and 10% had PS only. A well-delineated phenotype could not be specified for 1 (2.5%) and 2 (5%) individuals who had CPEO-plus (CPEO + extraocular symptoms). Regardless of presentation, initial MRI of patients with KSS revealed lesions within selective areas of the upper brainstem tegmentum. Follow-up MRIs in 26 patients showed well-defined progression along other select brainstem and white matter regions. Log-rank tests demonstrated varying onset times by lesion type. Cluster analysis revealed 2 distinct neuroimaging groups: 1) KSS, CPEO-plus, and PS→KSS versus 2) PS and not otherwise specified individuals. KSS, CPEO-plus, and PS→KSS showed indistinguishable neuroimaging features regardless of the initial clinical presentation.CONCLUSIONS: We describe the first comprehensive longitudinal neuroimaging pattern analysis in a multicenter, international SLSMDs disease pediatric cohort, delineating a predictable progression of brain lesions, regardless of clinical phenotype.CPEOchronic progressive external ophthalmoplegiaGPglobus pallidusIQRinterquartile rangeKSSKearns-Sayre syndromeNOSnot otherwise specifiedmtDNAmitrochondrial DNAPSPearson syndromePS→KSSindividuals with initial presentation of PS converting to KSS during the progression of the diseaseSLSMDsingle large-scale mitochondrial deletion syndrome