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Observational Study
. 2018 Apr 17;90(16):e1395-e1403.
doi: 10.1212/WNL.0000000000005334. Epub 2018 Mar 21.

Megalencephalic Leukoencephalopathy With Subcortical Cysts: Characterization of Disease Variants

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Free PMC article
Observational Study

Megalencephalic Leukoencephalopathy With Subcortical Cysts: Characterization of Disease Variants

Eline M C Hamilton et al. Neurology. .
Free PMC article

Abstract

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.

Figures

Figure 1
Figure 1. Disease course
Kaplan-Meier plots on (A) onset of motor deterioration, (B) loss of walking without support, (C) loss of walking with or without support (full wheelchair dependency), (D) onset of seizures, and (E) survival, grouped by disease variant. Censored patients (absence of motor deterioration, still walking without support, still walking with or without support, absence of seizures, or still alive at last follow-up) are indicated by crosses. MLC1 = classic megalencephalic leukoencephalopathy with subcortical cysts caused by recessive MLC1 mutations; MLC2A = classic megalencephalic leukoencephalopathy with subcortical cysts caused by recessive GLIALCAM mutations; MLC2B = remitting megalencephalic leukoencephalopathy with subcortical cysts caused by dominant GLIALCAM mutations.
Figure 2
Figure 2. Function levels
Overview of megalencephalic leukoencephalopathy with subcortical cysts (MLC) patients' scores on (A) the Gross Motor Function Classification System (GMFCS), (B) Manual Ability Classification System (MACS), and (C) Communication Function Classification System (CFCS) in relation to age, grouped by disease variant: MLC1 (classic MLC caused by recessive MLC1 mutations; blue circles), MLC2A (classic MLC caused by recessive GLIALCAM mutations; red squares) and MLC2B (remitting MLC caused by dominant GLIALCAM mutations; green triangles). Scores range from I (no limitations) to V (severe limitations; table e-1, links.lww.com/WNL/A356).
Figure 3
Figure 3. MRI characteristics
MRI findings in a patient with megalencephalic leukoencephalopathy with subcortical cysts (MLC) caused by recessive MLC1 mutations (MLC1) at age 3 years (top), a patient with MLC caused by recessive GLIALCAM mutations (MLC2A) at age 6 years (middle), and a patient with MLC caused by dominant GLIALCAM mutations (MLC2B) at age 10 months (bottom). Sagittal T1-weighted images show anterior-temporal and frontoparietal cysts in the patient with MLC1 (A), an anterior-temporal cyst in the patient with MLC2A (D), and some near-cystic rarefaction in the anterior-temporal region in the patient with MLC2B (G). The T2-weighted axial images of the hemispheres show diffuse white matter abnormalities with some swelling (B, E, H). The sagittal images show some sparing of the subcortical white matter in all patients, especially in the occipital region (A, D, G); in the patient with MLC2B, the white matter is relatively preserved in the occipital region (G). The patients with classic MLC have a double-line-shaped abnormal signal of the posterior limb of the internal capsule (B, E), while the signal is normal in the patient with MLC2B (H). The T2-weighted axial images of the cerebellum show a mildly hyperintense signal of the cerebellar white matter in the patients with classic MLC (C, F) and a normal signal in the patient with MLC2B (I).

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