This is a mechanism module, not a disease entry. Disorder files should refer to its nodes via conforms_to using "fame_pentanucleotide_repeat_rna_toxicity#<Node Name>". The module is intentionally conservative: it treats TTTCA-containing repeat RNA toxicity as the shared core mechanism and does not require host-gene loss of function or repeat-associated non-AUG translation.
Pathogenic TTTCA-Containing Pentanucleotide Repeat Expansion
trigger
Pathogenic FAME alleles are intronic pentanucleotide repeat expansions in which elongated TTTTA tracts contain inserted TTTCA segments. TTTTA-only expansions are generally regarded as nonpathogenic, whereas the presence of TTTCA insertions tracks with disease.
Downstream
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UUUCA Repeat RNA Toxicity
Show evidence (1 reference)
"Familial adult myoclonus epilepsy (FAME) is a rare autosomal dominant disorder caused by the same intronic TTTTA/TTTCA repeat expansion in seven distinct genes. TTTTA-only expansions are benign, whereas those containing TTTCA insertions are pathogenic."
Supports the conserved initiating lesion across FAME loci and the pathogenic importance of the inserted TTTCA motif rather than TTTTA-only expansion.
UUUCA Repeat RNA Toxicity
central effector
Transcription of the expanded alleles can produce UUUCA repeat-containing RNA that accumulates in nuclear foci and is thought to drive RNA-mediated toxicity largely independently of the host gene's normal function.
Downstream
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Cerebellocortical Circuit Dysfunction
Show evidence (2 references)
"Current hypotheses include toxicity of the RNA molecules carrying UUUCA repeats, or toxicity of polypeptides encoded by the repeats, a mechanism known as repeat-associated non-AUG translation."
Supports repeat RNA accumulation and RNA-mediated toxicity as the leading shared mechanism, while noting that alternative downstream toxic species remain under investigation.
"CONCLUSIONS: These findings establish a new type of BAFME, BAFME8, in an African family and suggest that haploinsufficiency is unlikely to be the main pathomechanism of BAFME."
Supports a host-gene-independent mechanism and argues against simple haploinsufficiency as the shared explanation for FAME.
Cerebellocortical Circuit Dysfunction
amplifier
Postmortem, neurophysiological, and imaging studies indicate combined dysfunction of the cerebral cortex and cerebellum, especially Purkinje-cell and cerebellar network involvement that may amplify the cortical phenotype.
Downstream
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Cortical Hyperexcitability and Seizure Susceptibility
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"Postmortem and electrophysiological studies have pointed to cortical hyperexcitability as well as dysfunction and neurodegeneration of both the cortex and cerebellum of FAME subjects."
Supports the intermediate circuit-level mechanism involving both cortical and cerebellar compartments rather than an isolated cortical lesion.
"Neuroimaging studies typically show mild cerebellar atrophy or nonspecific structural changes on magnetic resonance imaging."
Provides clinically observed imaging support for cerebellar involvement in the shared FAME phenotype.
Cortical Hyperexcitability and Seizure Susceptibility
effector
The final common network state is cortical hyperexcitability, manifested as cortical-origin myoclonus, enlarged long-loop responses, photosensitivity, and susceptibility to generalized epileptic seizures.
Show evidence (1 reference)
"Electrophysiological examinations are essential in demonstrating cortical hyperexcitability and confirming the cortical origin of myoclonus."
Establishes cortical hyperexcitability as the electrophysiological hallmark of the disease mechanism.