Megalencephalic leukoencephalopathy with subcortical cysts: Characterization of disease variants.

OBJECTIVE: To provide an overview of clinical and MRI characteristics of the different variants of the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC) and identify possible differentiating features. METHODS: We performed an international multi-institutional, cross-sectional observational study of the clinical and MRI characteristics in patients with genetically confirmed MLC. Clinical information was obtained by questionnaires for physicians and retrospective chart review. RESULTS: We included 204 patients with classic MLC, 187 of whom had recessive mutations in MLC1 (MLC1 variant) and 17 in GLIALCAM (MLC2A variant) and 38 patients with remitting MLC caused by dominant GLIALCAM mutations (MLC2B variant). We observed a relatively wide variability in neurologic disability among patients with classic MLC. No clinical differences could be identified between patients with MLC1 and MLC2A. Patients with MLC2B invariably had a milder phenotype with preservation of motor function, while intellectual disability and autism were relatively frequent. Systematic MRI review revealed no MRI features that distinguish between MLC1 and MLC2A. Radiologic improvement was observed in all patients with MLC2B and also in 2 patients with MLC1. In MRIs obtained in the early disease stage, absence of signal abnormalities of the posterior limb of the internal capsule and cerebellar white matter and presence of only rarefied subcortical white matter instead of true subcortical cysts were suggestive of MLC2B. CONCLUSION: Clinical and MRI features did not distinguish between classic MLC with MLC1 or GLIALCAM mutations. Absence of signal abnormalities of the internal capsule and cerebellar white matter are MRI findings that point to the remitting phenotype.

Eight novel mutations in MLC1 from 18 Iranian patients with megalencephalic leukoencephalopathy with subcortical cysts.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) (MIM #604004) is a rare autosomal recessive neurological disorder characterized by macrocephaly, motor and cognitive decline, ataxia, spasticity and occasional seizures. Magnetic resonance imaging (MRI) shows diffusely abnormal and swollen white matter of the cerebral hemispheres and subcortical cysts in the anterior temporal and frontoparietal region. Mutations in MLC1(22q13.33) and GLIALCAM have been identified in patients with MLC. Mutations in MLC1 account for approximately 75% of the cases. MLC was suspected in eighteen Iranian patients from sixteen families based on positive clinical findings including macrocephaly beginning in the first year, neurocognitive deterioration, seizure or loss of consciousness after minor head trauma. All except two were born to consanguineous parents. Brain MRI images were compatible with MLC and confirmed the diagnosis. Sequencing of entire coding region of MLC1 was performed for seventeen patients and mutations in MLC1 were detected in all of them. Eight novel mutations and seven previously reported mutations were identified. This report shows that MLC is relatively common in Iranian population, as expected for rare diseases with high inbreeding, with a surprisingly high frequency of novel mutations.