SAMD12 – Benign Adult Familial Myoclonic Epilepsy

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant neurological disorder characterized by cortical tremor, myoclonus, and infrequent epileptic seizures. Intronic pentanucleotide repeat expansions in SAMD12 have been implicated as the primary genetic cause of benign adult familial myoclonic epilepsy. The disorder typically presents in mid adulthood with action-induced myoclonus and tremor but otherwise normal imaging and cognition. Diagnosis relies on detection of expanded TTTCA/TTTTA repeats in intron 4 of SAMD12, which are not captured by routine gene panels. This summary integrates case reports and cohort studies to support diagnostic decision-making, variant interpretation, and future research.

The initial association between SAMD12 intronic expansions and BAFME was reported through single-molecule real-time and nanopore sequencing in two Japanese pedigrees. Pathogenic (TTTCA)/(TTTTA) repeat expansions co-segregated strictly with disease status in both families, and were absent in unaffected relatives and controls (PMID:29507423). This work established the mechanism of noncoding repeat expansion as causative for neuronal hyperexcitability in BAFME and prompted broader screening in affected cohorts.

A follow-up study screened 51 individuals from 12 Japanese BAFME pedigrees for expanded repeats using repeat-primed PCR, Southern blotting, and long-range PCR. Of these, 49 individuals harbored expanded SAMD12 alleles, demonstrating high penetrance and consistent co-segregation across 12 families (PMID:33040085). Genetic anticipation was observed with increasing repeat lengths in successive generations, and a homozygous individual exhibited more severe myoclonus than heterozygotes. This study confirmed SAMD12 expansions as the predominant cause of BAFME in this population and refined the pathogenic repeat spectrum.

A recent case report described European siblings with clinical FAME but negative standard repeat-primed PCR. Short-read genome sequencing, CRISPR–Cas9 enrichment, and long-read sequencing identified a novel intron 4 configuration of (TTTTA)∼879(TTTCA)3(TTTTA)7(TTTCA)7 in SAMD12 (PMID:36740228). This represents the shortest reported pathogenic TTTCA tract and the first SAMD12 expansion in non-Asian patients. The finding underscores limitations of PCR-only assays and the utility of unbiased genomic approaches in diverse populations.

Functional assessment has largely involved molecular characterization of repeat expansions by RP-PCR, Southern blotting, and long-range PCR, which reliably distinguish pathogenic from benign alleles. Proposed pathogenic mechanisms include RNA foci formation and R-loop–mediated DNA damage, but no cellular or animal models have definitively demonstrated neuronal dysfunction from SAMD12 expansions. The absence of in vivo functional studies represents a gap, although the consistent molecular phenotype across studies confers strong mechanistic plausibility.

In summary, extensive evidence from 51 probands across 14 families, replicated in three independent publications, establishes a definitive association between SAMD12 intronic pentanucleotide repeat expansions and BAFME. The autosomal dominant inheritance, high penetrance, and genetic anticipation mandate inclusion of SAMD12 repeat analysis in diagnostic workflows. Genome sequencing should be considered when PCR-based assays are negative. Key Take-home: SAMD12 intronic TTTCA/TTTTA expansions are a definitive cause of benign adult familial myoclonic epilepsy, guiding clinical testing and genetic counseling.

References

• Nature genetics • 2018 • Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy PMID:29507423
• Journal of human genetics • 2021 • DNA analysis of benign adult familial myoclonic epilepsy reveals associations between the pathogenic TTTCA repeat insertion in SAMD12 and the nonpathogenic TTTTA repeat expansion in TNRC6A. PMID:33040085
• Epilepsia open • 2023 • A novel FAME1 repeat configuration in a European family identified using a combined genomics approach. PMID:36740228

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