Leukoencephalopathy with calcifications and cysts (LCC), also referred to as Labrune syndrome, is a rare disease, which was described for the first time in 1996 (1) and has only recently been genetically characterized (2, 3). LCC is an inherited white matter disease caused by biallelic mutations in SNORD118 (OMIM:616663), encoding the box C/D small nucleolar ribonucleic acid (snoRNA) U8 (3), a non-coding RNA vital for ribosomal RNA homeostasis. While the precise role of SNORD118 in ribosome biogenesis and maturation remains uncertain, the impact of its deficit on brain function is clear (4). From a pathological point of view, LCC is an exclusively brain microangiopathy, where cerebral small blood vessels exhibit angiomatous-like features and Rosenthal fiber deposition with perivascular mineralization and minimal inflammation (5). Macroscopically, neuroimaging studies typically reveal the pathognomonic triad of leukoencephalopathy, calcifications, and cysts. LCC shares a remarkable overlap with the neuroradiological phenotype of Coats plus syndrome, a systemic diffuse microangiopathy affecting not only the brain but also the retina, gastrointestinal tract, and bone, caused by biallelic mutations in CTC1. The molecular pathology and clinical spectrum of 64 LCC patients were recently described, underlining the marked heterogeneity in disease presentation and progression, only partially explained by genotype–phenotype correlations (6). Indeed, in this most recent series, age at presentation varied from 3 weeks to 67 years, and clinical features can range from purely neurological signs to psychiatric manifestations (4, 7).

Although rare, as a slowly progressive chronic illness, LCC represents a major health burden to affected individuals and their families. No standard treatment paradigm for LCC has yet been described, with currently available options aimed at the symptomatic management of disease complications such as motor impairment, epilepsy, and intracranial hypertension. Thus, as one example, in patients with progressive symptoms and/or growing lesions on imaging studies, cystic surgical procedures (cystic puncture, cystic resection, cysto-ventriculoperitoneal shunting) are used to manage intracranial hypertension (8).

Interestingly, starting from the previous application in unilateral Coats disease (9), three reports have described the use in LCC of bevacizumab, a monoclonal antibody that binds to VEGF with high specificity, thereby blocking VEGF-mediated signaling pathways and thus angiogenesis (10–12). Albeit single case reports, a possibly encouraging effect of treatment, both in relation to clinical progression and neuroradiological appearance, has been suggested using this approach. However, due to the rarity of the disease, a knowledge gap exists in relation to the efficacy of this approach. Here, we describe an apparently convincing response to bevacizumab in a patient with typical LCC, on both clinical and neuroradiological features.

To the best of our knowledge, we report the fourth case of LCC treated with bevacizumab, but notably the first to receive repeated cycles of pharmacological treatment. We consider the following as important points of discussion. Firstly, previous reports described a single 12-month period of treatment (10–12), associated with apparent clinical improvement in two patients (10, 12), even if only moderate in one (12). Of note, clinical improvement in these two cases appeared to plateau after 6 months of therapy. Conversely, our patient showed an ongoing clinical improvement, especially in neuropsychological abilities, more prominent during the second cycle of therapy, despite a reduced frequency of administration of bevacizumab compared to the first cycle. These observations lead us to suggest that further studies are warranted to determine if there could be a cumulative effect of therapy, or a therapeutic window-dependent effect. We also speculate that genotype could modulate pharmacological response, noting that the patient homozygous for a n.8G > C mutation in SNORD118, which is rare and can be associated with a more severe clinical phenotype (3), showed no clinical response to treatment (11).

Secondly, evidence of a neuroradiological response to bevacizumab is currently difficult to determine from the cases published to date, with an absence of regression of brain lesions in the single-reported adult patient (12) compared to the two younger subjects (10, 11). Indeed, the age of the treated patients in these reports ranged from 19 months to 53 years, and it can be speculated upon that the initiation of therapy at a younger age might be associated with a better clinical outcome. Consistent with previous reports, we observed a regression in white matter disease but only a slight modification in cyst volume, with calcifications remaining substantially unchanged over time. Possibly of note, we recorded a reabsorption of hemosiderin depositions.

Finally, we observed a recurrent pattern in the topology of bevacizumab responsiveness. Thus, during both cycles of therapy, white matter changes began in the same regions, possibly suggesting a differential sensitivity of LCC brain lesions to VEGF-inhibition. Since LCC is a progressive and multiphasic disease, several stages may be specifically sensitive to pharmacological intervention, differentiating brain areas in a latent or active stage of the disease. Future neuropathological studies should be addressed to understand if there is recurrent pattern in VEGF-response. If so, the therapeutic response may not only be influenced by the age of the patients, but also by the number of cells in a “latent” stage, which enables them to respond to treatment.

Limitations and challenges should be addressed. Firstly, the timeline of neuroradiological follow-up was not strictly homogeneous considering the relative invasiveness of MRI exams. Furthermore, in distinction to leukodystrophies such as Metachromatic Leukodystrophy (15), a more rigorous and standardized scoring system of MRI images is not currently available for LCC in order to properly assess disease severity. Thus, our neuroradiological evaluation is qualitative, with the timeline was based on clinical evolution. To facilitate an interpretation of the MRI pattern as reliable as possible, all assessments were performed by the same neuroradiologist. Of note, an adjustment to the therapeutic protocol that we employed was made during follow-up, in order to meet the needs of the patient and thereby increase compliance. This regimen should be taken into account in future inter-patient assessments. Clearly, further studies are needed to optimize therapeutic protocol.

In conclusion, our report adds significant knowledge about the therapeutic effect of bevacizumab in LCC. Even though a full recovery was not observed, we consider likely that bevacizumab treatment slowed disease progression in our case. We interpret these data to support the further investigation of the efficacy of bevacizumab in the treatment of this devastating disorder, ideally in the context of a controlled clinical trial. Such experimental studies should include a consideration of when to begin therapy, the dosing to be used, and the consequences of drug withdrawal. In terms of future clinical practice and research, we would recommend the collection of data in a centralized registry in order to better determine the natural history of LCC.

The datasets for this article are not publicly available due to concerns regarding participant/patient anonymity. Requests to access the datasets should be directed to the corresponding author.

The studies involving humans were approved by Comitato Etico Pediatrico Regione Toscana Meyer. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

ES and BB: writing-original draft preparation. ES, BB, RP, and PC: writing-review and editing. RP, LB, and RC: elaboration of figure. RB, YC, EM, and FG: supervision. RB and LB: funding acquisition. All authors have participated in conceptualizing the case report, read, and agreed to the published version of the manuscript.

This work was partially supported by the Italian Ministry of Health (Grant RC 2023) to IRCCS Stella Maris Foundation (ES, BB, PC, RC, LB, RP, and RB). YC acknowledges financial support from the MRC (MRC Human Genetics Unit: MC_UU_00035/11).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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