SCARB2 – Unverricht-Lundborg syndrome

SCARB2 encodes the lysosomal integral membrane protein-2 (LIMP-2), which is critical for mannose 6-phosphate–independent targeting of beta-glucosidase to lysosomes. Biallelic SCARB2 variants disrupt lysosomal enzyme trafficking, leading to progressive myoclonus epilepsy resembling Unverricht-Lundborg syndrome (ULD).

Autosomal recessive inheritance has been established through multiple reports. The initial description involved six unrelated families presenting with progressive myoclonic epilepsy and renal failure, including a c.1087C>A (p.His363Asn) missense variant demonstrating beta-glucosidase mistargeting in one patient ([PMID:19454373]). Subsequent segregation in three sibships confirmed loss-of-function alleles.

Screening of 71 unsolved PME cases without renal involvement identified five individuals with SCARB2 mutations, underscoring the gene’s role in ULD-like presentations ([PMID:19847901]). These cases had disease onset between ages 14 and 26 years and no renal impairment over long-term follow-up.

Further genetic studies reported novel homozygous splice-site variants in diverse populations: c.995-1G>A in two Chinese brothers ([PMID:29941711]), c.423+1G>A in an Iranian sibling pair ([PMID:33772352]), and a homozygous truncating p.Asn45MetfsTer88 in a Turkish kindred ([PMID:35346091]). Each variant segregated with disease and was absent from controls.

Functional assays in patient-derived and transfected cells demonstrate that mutant LIMP-2 fails to localize to lysosomes, leading to impaired autophagosome processing and accumulation of immature vesicles in lymphocytes ([PMID:23515316]). This loss-of-function mechanism is consistent with the clinical phenotype.

Integration of genetic and experimental data supports a Strong gene–disease association: biallelic SCARB2 variants cause ULD-like PME through haploinsufficiency. Routine SCARB2 testing is recommended in patients with PME even in the absence of renal failure. Key Take-home: SCARB2 analysis enables definitive diagnosis and informs genetic counseling in Unverricht-Lundborg syndrome.

References

• Molecular genetics and metabolism • 2009 • Biochemical and molecular findings in a patient with myoclonic epilepsy due to a mistarget of the beta-glucosidase enzyme. PMID:19454373
• Annals of neurology • 2009 • SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure. PMID:19847901
• BioResearch open access • 2013 • Abnormal Processing of Autophagosomes in Transformed B Lymphocytes from SCARB2-Deficient Subjects. PMID:23515316
• Chinese medical journal • 2018 • Identification of a Novel Homozygous Splice-Site Mutation in SCARB2 that Causes Progressive Myoclonus Epilepsy with or without Renal Failure. PMID:29941711
• Neurological sciences • 2021 • A novel homozygous splice-site mutation in SCARB2 is associated with progressive myoclonic epilepsy with renal failure. PMID:33772352
• BMC neurology • 2022 • Genotype-Phenotype correlations of SCARB2 associated clinical presentation: a case report and in-depth literature review. PMID:35346091

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