MLC1 – Megalencephalic Leukoencephalopathy with Subcortical Cysts

Megalencephalic leukoencephalopathy with subcortical cysts (Megalencephalic Leukoencephalopathy with Subcortical Cysts, MLC) is a rare autosomal recessive leukodystrophy characterized by early-onset macrocephaly, diffuse cerebral white matter edema, subcortical cysts, and progressive motor and cognitive decline. Biallelic pathogenic variants in the gene MLC1 were first linked to MLC via linkage and mutation screening of 11 families, achieving a maximum LOD score of 6.6 (PMID:11254442).

Genetic replication over two decades includes reports of recessive MLC1 variants in over 500 patients across diverse populations, with 151 unique variants described to date (PMID:38487253). Recessive segregation of pathogenic alleles has been documented in 11 families, confirming autosomal recessive inheritance and fulfilling segregation criteria (PMID:11254442; PMID:38487253). A recurrent founder variant in Japanese patients, c.278C>T (p.Ser93Leu), accounts for ~85% of alleles in that group (PMID:12850517).

The spectrum of MLC1 variants encompasses missense (~24%), protein-truncating (nonsense, frameshift), canonical splice-site, deep intronic (e.g., c.895-226T>G), and small in-frame indels. Population-specific founder alleles have been identified, including p.Gly59Glu in Libyan Jews (carrier rate 1/40) and p.Pro92Ser in Agarwal Indians, underscoring allelic heterogeneity and diagnostic utility of targeted screening (PMID:12189496).

Clinically, MLC manifests with macrocephaly (HP:0000256), spasticity (HP:0001257), cerebellar ataxia (HP:0001251), seizures (HP:0001250), and mild to moderate cognitive decline. Head trauma or fever may trigger transient worsened motor function or coma in children, with some patients showing partial recovery (PMID:38487253).

Functional studies reveal that MLC1 encodes a membrane protein enriched in astrocyte end-feet and Bergmann glia, forming a complex with GlialCAM, Na,K-ATPase, and the TRPV4 cation channel. Pathogenic variants disrupt MLC1 folding, trafficking, endosomal pH regulation, and osmolyte flux, and can be partially rescued by chemical chaperones or adeno-associated viral gene delivery in Mlc1 knockout mice, reducing vacuolation and improving motor phenotypes (PMID:15367490; PMID:22328087; PMID:33551753).

Integration of robust genetic and experimental evidence supports a Definitive gene–disease relationship for MLC1 and MLC. Comprehensive MLC1 variant screening is recommended for accurate diagnosis, carrier detection in high-risk populations, prenatal counseling, and stratification for emerging therapies targeting astrocyte volume regulation.

References

• American Journal of Human Genetics • 2001 • Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts PMID:11254442
• Frontiers in Genetics • 2024 • Megalencephalic leukoencephalopathy with subcortical cysts: a variant update and review of the literature PMID:38487253
• Brain & Development • 2003 • A case of megalencephalic leukoencephalopathy with subcortical cysts (van der Knaap disease): molecular genetic study. PMID:12850517
• Human Molecular Genetics • 2004 • Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts PMID:15367490
• Human Molecular Genetics • 2012 • Megalencephalic leukoencephalopathy with subcortical cysts protein 1 functionally cooperates with the TRPV4 cation channel to activate the response of astrocytes to osmotic stress: dysregulation by pathological mutations PMID:22328087
• Frontiers in Cellular Neuroscience • 2020 • Megalencephalic leukoencephalopathy: insights into pathophysiology and perspectives for therapy PMID:33551753

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