HEPACAM – Megalencephalic leukoencephalopathy with subcortical cysts

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy characterized by early-onset macrocephaly, subcortical cysts and variable neurological decline. HEPACAM (also known as GLIALCAM) encodes the GlialCAM adhesion molecule, a binding partner of MLC1, and is implicated in both recessive (MLC2A) and dominant (MLC2B) forms of MLC (HEPACAM; Megalencephalic leukoencephalopathy with subcortical cysts).

Clinical Validity

Definitive: Bi-allelic and heterozygous HEPACAM variants have been reported in >100 unrelated probands across multiple populations, with autosomal recessive segregation in classical MLC and autosomal dominant segregation in remitting MLC, and concordant functional studies demonstrating disrupted GlialCAM–MLC1 complexes (PMID:21419380, PMID:29661901).

Genetic Evidence

Inheritance mode: Both autosomal recessive (MLC2A) and autosomal dominant (MLC2B).
Segregation: 18 affected relatives with macrocephaly segregating HEPACAM variants in dominant families (PMID:21419380).
Case series: >100 MLC patients with 29 unique HEPACAM variants including missense, frameshift, splice-site and deep intronic changes. A recurrent missense variant c.274C>T (p.Arg92Trp) has been observed in multiple cohorts (PMID:21419380, PMID:31372844).

Functional / Experimental Evidence

Mechanism: Loss of GlialCAM homo- and hetero-complex formation at astrocytic junctions leads to mislocalization of the GlialCAM–MLC1 complex, impaired ion and water flux regulation, and white matter vacuolation. Key assays include proteomic identification of the MLC1–GlialCAM interaction, trafficking studies in cell lines, structural modelling of Ig-domain interfaces, and mouse knock-in models recapitulating vacuolization and disease progression (PMID:21419380, PMID:25044933, PMID:31960914, PMID:31372844). AAV-mediated MLC1 delivery ameliorates myelin vacuolation in Mlc1 knockout mice, underscoring therapeutic potential (PMID:33551753).

Integration & Conclusion

Extensive genetic and functional data provide definitive evidence that HEPACAM variants cause both classical (recessive) and remitting (dominant) forms of MLC by disrupting astrocytic junctional complexes essential for ion and water homeostasis. HEPACAM testing should be included in diagnostic panels for MLC, and functional insights support future gene-based or molecular therapies.

References

• American journal of human genetics • 2011 • Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism PMID:21419380
• Neurology • 2018 • Megalencephalic leukoencephalopathy with subcortical cysts: Characterization of disease variants PMID:29661901
• Human mutation • 2014 • Functional analyses of mutations in HEPACAM causing megalencephalic leukoencephalopathy PMID:25044933
• Human molecular genetics • 2020 • Structural basis for the dominant or recessive character of GLIALCAM mutations found in leukodystrophies PMID:31960914
• World journal of pediatrics : WJP • 2019 • Identification in Chinese patients with GLIALCAM mutations of megalencephalic leukoencephalopathy with subcortical cysts and brain pathological study on Glialcam knock-in mouse models PMID:31372844
• Frontiers in cellular neuroscience • 2020 • Megalencephalic Leukoencephalopathy: Insights Into Pathophysiology and Perspectives for Therapy PMID:33551753

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