Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic disorder belonging to the group of vacuolating leukodystrophies. It is characterized by megalencephaly, loss of motor functions, epilepsy, and mild mental decline. In brain biopsies of MLC patients, vacuoles were observed in myelin and in astrocytes surrounding blood vessels. It is mainly caused by recessive mutations in MLC1 and HEPACAM (also called GLIALCAM) genes. These disease variants are called MLC1 and MLC2A with both types of patients sharing the same clinical phenotype. Besides, dominant mutations in HEPACAM were also identified in a subtype of MLC patients (MLC2B) with a remitting phenotype. MLC1 and GlialCAM proteins form a complex mainly expressed in brain astrocytes at the gliovascular interface and in Bergmann glia at the cerebellum. Both proteins regulate several ion channels and transporters involved in the control of ion and water fluxes in glial cells, either directly influencing their location and function, or indirectly regulating associated signal transduction pathways. However, the MLC1/GLIALCAM complex function and the related pathological mechanisms leading to MLC are still unknown. It has been hypothesized that, in MLC, the role of glial cells in brain ion homeostasis is altered in both physiological and inflammatory conditions. There is no therapy for MLC patients, only supportive treatment. As MLC2B patients show an MLC reversible phenotype, we speculated that the phenotype of MLC1 and MLC2A patients could also be mitigated by the re-introduction of the correct gene even at later stages. To prove this hypothesis, we injected in the cerebellar subarachnoid space of Mlc1 knockout mice an adeno-associated virus (AAV) coding for human MLC1 under the control of the glial-fibrillary acidic protein promoter. MLC1 expression in the cerebellum extremely reduced myelin vacuolation at all ages in a dose-dependent manner. This study could be considered as the first preclinical approach for MLC. We also suggest other potential therapeutic strategies in this review.

患有皮层下囊肿的大脑白质脑病（MLC）是一种罕见的遗传性疾病，属于空泡性白细胞奖杯。它的特征是巨头畸形，运动功能丧失，癫痫和轻度智力下降。在MLC患者的脑活检中，在髓磷脂和血管周围的星形胶质细胞中观察到液泡。它主要是由隐性突变引起的MLC1 和 HEPACAM （也被称为 胶体）基因。这些疾病变体称为MLC1和MLC2A，两种类型的患者共享相同的临床表型。此外，在HEPACAM还发现了MLC患者亚型（MLC2B）具有表型。MLC1和GlialCAM蛋白形成复合物，主要在神经胶质血管界面的脑星形胶质细胞和小脑的Bergmann胶质细胞中表达。两种蛋白质均调节神经胶质细胞中离子和水通量控制中涉及的几个离子通道和转运蛋白，它们直接影响其位置和功能，或间接调节相关的信号转导途径。然而，MLC1 / GLIALCAM复杂功能和导致MLC的相关病理机制仍是未知的。据推测，在MLC中，神经胶质细胞在脑离子稳态中的作用在生理和炎症条件下均改变。MLC患者没有疗法，只有支持疗法。由于MLC2B患者表现出MLC可逆表型，我们推测即使在以后的阶段，也可以通过重新引入正确的基因来缓解MLC1和MLC2A患者的表型。为了证明这一假设，我们向小脑蛛网膜下腔注入Mlc1基因敲除小鼠，在神经胶质纤维酸性蛋白启动子的控制下，编码人MLC1的腺相关病毒（AAV）。在所有年龄的小脑中，MLC1的表达均以剂量依赖性方式极大地降低了髓鞘空泡形成。该研究可被认为是MLC的首个临床前方法。我们还建议在这篇评论中其他潜在的治疗策略。