Single Large-Scale Mitochondrial Deletion Syndromes: Neuroimaging Phenotypes and Longitudinal Progression in Pediatric Patients

DISCUSSION

Here, we describe the results of a multicenter study of 40 pediatric-onset individuals with SLSMDs to provide novel insights into the occurrence and longitudinal progression of neuroimaging features of specific SLSMD disorders. While the largest proportion of patients had clinically defined KSS, several individuals exhibited variable clinical features of different SLSMDs, including CPEO-plus and PS, as well as patients with progressive clinical transition from PS→KSS, and 1 NOS patient. Interestingly, 1 individual manifested both KSS and genetically confirmed Neurofibromatosis type 1 (NF-1), which is consistent with approximately 5% of patients with suspected monogenic disease having more than 1 etiology.¹⁹ As distinct brain areas were commonly affected in patients with KSS, neuroimaging is recommended as part of diagnostic criteria for this disorder in addition to clinical, genetic, and laboratory analyses. Specifically, based on our results, diagnostic neuroimaging should assess for involvement of 1) upper brainstem nuclei and tegmental tracts; 2) basal ganglia lesions with discrete involvement of the globus pallidus, and 3) supratentorial white matter changes displaying selective involvement of the subcortical regions.

When comparing the neuroimaging features of patients with KSS with those with KSS who had a preceding history of PS or those with CPEO-plus, no significant differences of the brain MRI lesions were found, suggesting that the neuroimaging phenotype is relatively stable among these SLSMD phenotypes regardless of clinical features and initial syndromic classification. However, neuroimaging features of individuals with PS who had not transitioned to KSS were notably different, characterized by either normal brain MRI studies or with nonspecific diffuse leukodystrophy patterns without significant brainstem involvement. This finding suggests that this neuroimaging feature may be used for differentiating those who will from those who will not progress to KSS. Further investigation, including prospective neuroimaging follow-up over time, is needed to further differentiate PS from PS→KSS in the early stages. Overall, the detection of characteristic early imaging abnormalities of KSS in patients with PS (brainstem involvement) suggests that these individuals are at high risk of transitioning later into KSS. This result highlights the importance of correlating clinical subtypes with neuroimaging features to delineate their expected progression and neurodevelopmental outcomes accurately.

Novel imaging characteristics of brain lesions were observed in patients with KSS, including selective preservation of the affected subcortical white matter in the perivenular regions, giving a coral-reef snake appearance of these changes. This feature has not previously been considered in the differential diagnosis of leukodystrophies with selective subcortical white matter involvement. It is similar to a so-called tigroid skin pattern described for other neurometabolic leukodystrophies (lysosomal disorders), though those disorders involve the deep rather than superficial white matter, such as in metachromatic leukodystrophy and Krabbe disease.²⁰ This finding may provide some degree of specificity for KSS diagnosis, helping to differentiate it from some leukodystrophies that present with predominant subcortical white matter involvement, such as L2-hydroxyglutaric aciduria²¹ and other recently described rare mitochondrial disorders.²²

In contrast to many mitochondrial lesions, most of our SLSMD cases did not show lesions with reduced diffusivity but rather manifested mostly with T2-shinethrough (78%). This distinction may have important clinical implications not only in evaluating disease activity in natural history and treatment response but also in investigating the pathophysiology of different cellular insults. The exact reason for this difference when compared with other mitochondrial syndromes is not known. However, a speculation based on this imaging phenotype, which may reflect a different lesional mechanism/and degree of cellular injury compared with other mitochondrial disorders, should be considered, and factors including the specific characteristics of the cellular components along the selective structures frequently affected may have an important role on this. One of the common characteristics of mitochondrial disorders with restricted diffusion is direct involvement and deficiencies of cellular respiratory chain structural and functional components often resulting in areas of necrosis. Lesions in SLSMD frequently do not follow this pattern (cystic areas or areas of necrosis by imaging) but tend to be more homogeneous and without cavitations. It has been proposed that DWI restriction in patients with KSS could be related to postmortem findings of vacuolization in the neuritic processes finally leading to the postmortem finding of spongiform degeneration.^23,24 It is possible that diffusion pseudorestriction (T2 shinethrough-ADC maps demonstrating persistent iso- or subtle hyperintense signal) could indeed reflect variable degree of progressive spongiform degeneration of the white matter following vacuolization without necessary association with large necrotic areas. Of course, this hypothesis should be supported by longitudinal quantitative analysis of diffusion imaging over time and postmortem pathologic correlations.

Selective involvement of midbrain structures and the tegmentum of the pons were shown to be a common feature in individuals with KSS, CPEO-plus, and PS→KSS, regardless of the timeframe in the disease (early versus late). Differences between the baseline and follow-up MRIs were more striking with an evaluation of white matter changes. The olivary bodies were curiously preserved in patients with SLSMDs even though olivary involvement can be seen in a variety of other mitochondrial or metabolic disorders. Again, the cause of this selective preservation is not clear and further investigation is recommended. Superficial white matter changes were noted to be either absent in a significant portion of patients with KSS on baseline MRI or only present concurrently with the brainstem changes. Interestingly, isolated supratentorial subcortical white matter changes without brainstem findings were not found. Thus, the distinct pattern of lesion distribution in the brainstem appears to be a landmark for the imaging diagnosis in the early stage of KSS, facilitating the earlier recognition of this disorder. White matter changes tend to become more evident upon clinical disease progression. Early white matter changes, when present, were selectively noted along the perirolandic region, with follow-up studies showing progressive extension in a centripetal fashion into the deeper white matter areas. Of note, the periventricular white matter was relatively spared in these subsets of patients, even in advanced stages. Understanding the unique pattern of lesion locations in SLSMDs provides insights into the underlying pathology of the disease, where we observe disease progression in KSS to follow an ascending trend of lesion distribution, starting from the brainstem region, particularly in the upper tegmentum of the brainstem and basal ganglia, before more extensively affecting the superficial white matter.

Spinal MRI lesions showed variable findings, including most frequently the involvement of the posterior columns of the cervical spine. These findings further underscore the importance of including spinal cord examinations as part of the imaging protocol of patients with mitochondrial disorder. Spinal cord involvement in KSS correlates with higher levels of disability, as previously reported.^18,25

Comprehending the natural history of a disease is critical to facilitate early diagnosis and design clinical trials that evaluate therapeutic interventions on disease initiation and progression. However, studying the natural history of mitochondrial disorders is a complex task due to the numerous variables that can influence disease presentation and progression. These variables include the specific SLSMD site, size, heteroplasmy level,⁹ and multiple additional genetic and environmental factors affecting presentation that are difficult to control. Additionally, the same SLSMD may cause different disease phenotypes depending on the age and organ affected.^1,9 This fact may partly explain the limitations of implementing effective drugs to treat mitochondrial disorders and the paucity of high-level scientific evidence in this field.²⁶ To help mitigate these challenges, neuroimaging has emerged as a valuable noninvasive adjunctive tool to classify mitochondrial disorders objectively. Brain MRI can provide detailed information on lesion distribution, spatial extent, and degree of severity based on signal change by using standard and advanced sequences.^{16,27⇓–29} Furthermore, it can be used to exclude many other acute insults from different causes²⁸ and aid in the assessment of disease progression.

Clinical implications of this study include the ability to facilitate early detection and diagnosis of SLSMDs, which can potentially lead to better management and ultimately improved outcomes for patients. Although this study is indeed a large imaging study of very rare disorders, a limitation is its retrospective nature. This prevented the performance or analysis of MR follow-up studies at standardized regular intervals throughout the disease course for all patients. Another limitation is the presence of ascertainment bias in our cohort because only patients with childhood disease onset were included. Additionally, medical devices including cochlear implants or pacemakers prevented acquisition of follow-up MR studies for some of our patients.