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Background <p>Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited white matter disorder. Initially, a “classic” phenotype has been characterized, presenting early-onset macrocephaly, cerebellar ataxia, mild spasticity, and a distinctive neuroimaging pattern of diffuse white matter abnormalities with subcortical cysts. An “improving” phenotype has also been described, featuring milder or absent neurological signs and a remitting pattern on neuroimaging. Mutations in four genes, <i>MLC1</i>, <i>HEPACAM</i>, <i>GPRC5B</i> and <i>AQP4</i> have been associated with MLC. We describe clinical and genetic features of a cohort of genetically confirmed Italian MLC patients, representing the largest Italian cohort reported to date.</p> Materials and methods <p>We conducted a retrospective, multicenter, observational study. Patients were included based on clinical and neuroimaging features consistent with MLC, along with a confirmed genetic diagnosis. Data were collected using a standardized database and included demographic, clinical, neuroimaging, neurophysiological, and genetic information.</p> Results <p>Thirty-three patients from eight Italian centers were enrolled. Twenty-seven harbored biallelic <i>MLC1</i> variants (23 distinct mutations, including three novel variants), while six had three distinct heterozygous <i>HEPACAM</i> variants. All <i>MLC1</i>-mutated patients exhibited the “classic” phenotype, frequently accompanied by orthopedic, gastrointestinal, and respiratory comorbidities. <i>HEPACAM-</i>mutated patients were consistent with the “improving” phenotype. No patients harbored mutations in <i>GPRC5B</i> or <i>AQP4</i>.</p> Conclusions <p>Our findings expand the mutational spectrum of <i>MLC1</i>, further characterize the disease phenotype, and provide valuable insights into its presence in Italy. They also underscore management needs of individuals with MLC, highlighting the importance of multidisciplinary care.</p>

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Megalencephalic leukoencephalopathy with subcortical cysts: a multicenter Italian experience

  • 期刊论文

  • 发表日期：

    2026年1月2日

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  • Jacopo Sartorelli,
  • Davide Tonduti,
  • Elena Ambrosini,
  • Eleonora Bonaventura,
  • Luisa Vercellino,
  • Ylenia Vaia,
  • Fabio Bruschi,
  • Francesca Pochiero,
  • Elena Procopio,
  • Alessandro Simonati,
  • Isabella Moroni,
  • Federica Rachele Danti,
  • Mariasavina Severino,
  • Marina Martinez Popple,
  • Salvatore Rossi,
  • Gabriella Silvestri,
  • Livia Garavelli,
  • Simona Madeo,
  • Enrico Bertini,
  • Francesco Nicita

摘要

Background

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited white matter disorder. Initially, a “classic” phenotype has been characterized, presenting early-onset macrocephaly, cerebellar ataxia, mild spasticity, and a distinctive neuroimaging pattern of diffuse white matter abnormalities with subcortical cysts. An “improving” phenotype has also been described, featuring milder or absent neurological signs and a remitting pattern on neuroimaging. Mutations in four genes, MLC1, HEPACAM, GPRC5B and AQP4 have been associated with MLC. We describe clinical and genetic features of a cohort of genetically confirmed Italian MLC patients, representing the largest Italian cohort reported to date.

Materials and methods

We conducted a retrospective, multicenter, observational study. Patients were included based on clinical and neuroimaging features consistent with MLC, along with a confirmed genetic diagnosis. Data were collected using a standardized database and included demographic, clinical, neuroimaging, neurophysiological, and genetic information.

Results

Thirty-three patients from eight Italian centers were enrolled. Twenty-seven harbored biallelic MLC1 variants (23 distinct mutations, including three novel variants), while six had three distinct heterozygous HEPACAM variants. All MLC1-mutated patients exhibited the “classic” phenotype, frequently accompanied by orthopedic, gastrointestinal, and respiratory comorbidities. HEPACAM-mutated patients were consistent with the “improving” phenotype. No patients harbored mutations in GPRC5B or AQP4.

Conclusions

Our findings expand the mutational spectrum of MLC1, further characterize the disease phenotype, and provide valuable insights into its presence in Italy. They also underscore management needs of individuals with MLC, highlighting the importance of multidisciplinary care.