Megalencephalic leukoencephalopathy with subcortical cysts: a multicenter Italian experience.

Area of Science:

• Neurology
• Genetics
• Rare Diseases

Background:

• Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited white matter disorder.
• Characterized by macrocephaly, ataxia, and white matter abnormalities, MLC presents with classic or improving phenotypes.
• Mutations in MLC1, HEPACAM, GPRC5B, and AQP4 genes are associated with MLC.

Purpose of the Study:

• To describe the clinical and genetic features of a genetically confirmed Italian cohort of MLC patients.
• To expand the known mutational spectrum of MLC genes.
• To provide insights into the prevalence and characteristics of MLC in Italy.

Main Methods:

• Retrospective, multicenter, observational study.
• Inclusion criteria: clinical and neuroimaging features consistent with MLC and confirmed genetic diagnosis.
• Data collection included demographic, clinical, neuroimaging, neurophysiological, and genetic information.

Main Results:

• Thirty-three Italian patients from eight centers were enrolled.
• Twenty-seven patients had biallelic MLC1 variants (including three novel mutations); six had heterozygous HEPACAM variants.
• MLC1 mutations correlated with the classic phenotype, while HEPACAM mutations aligned with the improving phenotype. GPRC5B and AQP4 mutations were not found.

Conclusions:

• The study expands the MLC1 mutational spectrum and further characterizes MLC phenotypes.
• Findings offer insights into MLC in Italy and emphasize the need for multidisciplinary care.
• Genetic confirmation and comprehensive management are crucial for individuals with MLC.