CSTB – Unverricht-Lundborg Disease

Unverricht-Lundborg disease (ULD) is an autosomal recessive progressive myoclonic epilepsy characterized by stimulus-sensitive and action myoclonus, tonic-clonic seizures, and variable cognitive impairment (PMID:19170735). The causative gene, CSTB (cystatin B), harbors a characteristic unstable dodecamer repeat expansion in its promoter and a spectrum of point/splice/frameshift mutations, leading to reduced CSTB expression and pathological neurodegeneration.

Over 200 probands worldwide carry CSTB mutations, with the 12- to >80-unit dodecamer expansion accounting for ~90% of alleles and more than 20 non-repeat alleles—including c.218dup (p.His75SerfsTer2), c.202C>T (p.Arg68Ter), c.66G>A (p.Gln22=), and c.67-1G>C—identified in unrelated families across Europe, Asia, and Africa (PMID:14526183; PMID:28378817; PMID:27888502; PMID:22154554). Genetic segregation in multi-affected sibships (e.g., five Finnish compound heterozygotes, two Sri Lankan sisters, and a Serbian pedigree) corroborates AR inheritance with concordant phenotypes.

Founder and population studies reveal a shared haplotype among Reunion Island patients (14 cases, mean 56.3 repeats) and Serbian patients, dating the most recent common ancestor to the 18th century (PMID:14510831; PMID:23883076). Phenotypic variability is evident in Tunisian families presenting a juvenile myoclonic epilepsy–like syndrome despite CSTB expansions (PMID:31368437) and in an Egyptian ULD cohort (14/20 confirmed; 70% expansion frequency; variable cognitive impairment) (PMID:34474241).

Functional investigations demonstrate that 19-unit or greater dodecamer expansions reduce promoter activity ten-fold in vitro and lower CSTB mRNA to 5–10% of control levels (PMID:10721698). Cstb knockout mice recapitulate myoclonus, ataxia, glial activation, apoptosis gene upregulation, and synaptic mitochondrial dysfunction consistent with human pathology (PMID:11555622; PMID:37251643). Patient-derived iPSC neurons retain promoter expansions, exhibit reduced promoter activity, lower CSTB protein, and upregulated cathepsins, underscoring loss-of-function as the pathogenic mechanism (PMID:36359887).

No substantive conflicting reports dispute the CSTB–ULD link. The convergence of extensive AR segregation, recurrent founder expansions, diverse loss-of-function alleles, robust animal models, promoter assays, and patient cell-based systems affirms CSTB as definitively responsible for ULD.

Key Take-home: Genetic testing for CSTB promoter repeat expansions and point/splice/frameshift mutations reliably confirms ULD diagnosis and informs carrier screening in diverse populations, guiding early therapeutic interventions.

References

• Cytogenetic and genome research • 2003 • The epilepsy, the protease inhibitor and the dodecamer: progressive myoclonus epilepsy, cystatin b and a 12-mer repeat expansion. PMID:14526183
• Gene • 2000 • Characterization of the cystatin B gene promoter harboring the dodecamer repeat expanded in progressive myoclonus epilepsy, EPM1. PMID:10721698
• European journal of human genetics: EJHG • 2001 • Cystatin B-deficient mice have increased expression of apoptosis and glial activation genes. PMID:11555622
• European journal of human genetics: EJHG • 2017 • Severe neurodegeneration, progressive cerebral volume loss and diffuse hypomyelination associated with a homozygous frameshift mutation in CSTB. PMID:28378817
• Frontiers in molecular neuroscience • 2023 • Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice. PMID:37251643
• Cells • 2022 • Insights into the Genetic Profile of Two Siblings Affected by Unverricht-Lundborg Disease Using Patient-Derived hiPSCs. PMID:36359887

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