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PubMed This is a summary of 17 peer-reviewed journal articles Updated
Genetics

The Genetic "Stutter": Understanding What Causes FAME

At a Glance

Familial Adult Myoclonic Epilepsy (FAME) is caused by a genetic "stutter" where five DNA letters repeat hundreds of times. This creates toxic RNA clumps in brain cells, leading to tremors and seizures. FAME is inherited, meaning a child has a 50% chance of inheriting it from an affected parent.

At its core, Familial Adult Myoclonic Epilepsy (FAME) is caused by a tiny “stutter” in your genetic code. While the symptoms like hand tremors and seizures are what you experience, the root cause lies in how your cells read specific instructions in your DNA.

The Genetic “Stutter”

Your DNA is made up of long sequences of chemical “letters.” In certain genes, there is a normal section where five letters (a pentanucleotide) repeat a few times. In FAME, these letters—specifically TTTTA and TTTCA—repeat hundreds or even thousands of times more than they should [1][2].

Think of it like a typo in an instruction manual. If the manual was supposed to say “Wait,” but a printing error caused it to say “Waaaaaaaaait,” the reader might get confused. This genetic “stutter” is technically called an intronic pentanucleotide repeat expansion [1][3]. It is “intronic” because it happens in a part of the gene (an intron) that doesn’t usually provide the final instructions for making proteins, which is why the condition was so difficult for scientists to find for many years until advanced diagnostic testing like long-read sequencing became available [4].

One Stutter, Many Genes

One of the most unique things about FAME is that this exact same “stutter” can happen in several different genes. No matter which gene is affected, the result is almost identical symptoms because the problem isn’t the gene itself, but the toxic “extra letters” it produces [5][6].

Scientists use “FAME subtypes” to track which gene has the stutter:

Subtype Gene Involved Common Regions
FAME1 SAMD12 Most common in Asian populations [7][5].
FAME2 STARD7 Found in various populations, including European [5].
FAME3 MARCHF6 Identified in European and Asian families [8].
FAME4 YEATS2 A less common subtype [9].
FAME8 RAI1 A recently identified subtype [5].

How RNA Toxicity Works

When your body tries to use a gene that has this stutter, it creates a “copy” called RNA. Because the DNA has thousands of extra letters, the RNA copy also has thousands of extra letters [10][11].

These long, repetitive RNA strands are “sticky.” They clump together inside the cell’s nucleus, creating what scientists call RNA toxicity [12][13]. These clumps can trap other important proteins the cell needs to function properly. In FAME, this specifically affects the parts of the brain (the cortex) that control movement and electrical stability, leading to tremors and seizures [11][14].

Passing It On: Autosomal Dominant Inheritance

FAME follows a pattern called autosomal dominant inheritance [14]. Here is what that means in plain language:

  • Autosomal: The gene is located on one of the numbered chromosomes, not the ones that determine biological sex. It affects men and women equally.
  • Dominant: You only need one copy of the “stuttered” gene (from one parent) to develop the condition.
  • 50/50 Chance: If a parent has FAME, there is a 50% chance they will pass the stuttered gene to each child they have [14][15].

Because the “stutter” can sometimes grow longer as it is passed from parent to child, some families notice genetic anticipation, where symptoms might start a few years earlier in each new generation [16][17].

Common questions in this guide

What is the genetic stutter that causes FAME?
FAME is caused by a tiny repetition in your genetic code, where a sequence of five chemical letters repeats hundreds or thousands of times more than normal. This extra long genetic code confuses the body and leads to the symptoms of the condition.
What is RNA toxicity in FAME?
When the body reads the stuttered gene, it makes a faulty copy called RNA that has too many extra letters. These long RNA strands clump together inside brain cells, trapping important proteins and disrupting normal movement and electrical stability.
If a parent has FAME, will their children inherit it?
FAME follows an autosomal dominant inheritance pattern. This means that if one parent has the condition, there is a 50 percent chance they will pass the stuttered gene to each of their children.
Why do FAME symptoms start earlier in younger generations?
As the gene is passed from parent to child, the genetic stutter can sometimes grow longer. This phenomenon, known as genetic anticipation, can cause hand tremors and seizures to appear at a younger age in each new generation.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Which specific FAME subtype has been identified in my family?
  2. 2.Has my specific gene expansion been confirmed with advanced testing like long-read sequencing?
  3. 3.If I am the first in my family to be diagnosed, what are the chances that my children will also have FAME?
  4. 4.How does the 'RNA toxicity' mechanism influence the choice of treatments we are considering?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (17)
  1. 1

    TTTCA repeat expansion causes familial cortical myoclonic tremor with epilepsy.

    Lei XX, Liu Q, Lu Q, et al.

    European journal of neurology 2019; (26(3)):513-518 doi:10.1111/ene.13848.

    PMID: 30351492
  2. 2

    Intronic (TTTGA)n insertion in SAMD12 also causes familial cortical myoclonic tremor with epilepsy.

    Cen Z, Chen Y, Yang D, et al.

    Movement disorders : official journal of the Movement Disorder Society 2019; (34(10)):1571-1576 doi:10.1002/mds.27832.

    PMID: 31483537
  3. 3

    Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type 1.

    Cen Z, Jiang Z, Chen Y, et al.

    Brain : a journal of neurology 2018; (141(8)):2280-2288 doi:10.1093/brain/awy160.

    PMID: 29939203
  4. 4

    Targeted nanopore long-read sequencing panel for the molecular diagnosis of intronic expansion in familial adult myoclonic epilepsy.

    Urabe H, Nakajima T, Mitsuhashi S, et al.

    BMC medical genomics 2025; (18(1)):180 doi:10.1186/s12920-025-02247-9.

    PMID: 41219789
  5. 5

    [Molecular genetics of benign adult familial myoclonus epilepsy].

    Ishiura H

    Rinsho shinkeigaku = Clinical neurology 2025; (65(7)):495-502 doi:10.5692/clinicalneurol.cn-002111.

    PMID: 40571639
  6. 6

    Pentanucleotide Repeat Insertions in RAI1 Cause Benign Adult Familial Myoclonic Epilepsy Type 8.

    Yeetong P, Dembélé ME, Pongpanich M, et al.

    Movement disorders : official journal of the Movement Disorder Society 2024; (39(1)):164-172 doi:10.1002/mds.29654.

    PMID: 37994247
  7. 7

    Familial adult myoclonic epilepsy type 1 SAMD12 TTTCA repeat expansion arose 17,000 years ago and is present in Sri Lankan and Indian families.

    Bennett MF, Oliver KL, Regan BM, et al.

    European journal of human genetics : EJHG 2020; (28(7)):973-978 doi:10.1038/s41431-020-0606-z.

    PMID: 32203200
  8. 8

    Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2.

    Corbett MA, Kroes T, Veneziano L, et al.

    Nature communications 2019; (10(1)):4920 doi:10.1038/s41467-019-12671-y.

    PMID: 31664034
  9. 9

    TTTCA repeat insertions in an intron of YEATS2 in benign adult familial myoclonic epilepsy type 4.

    Yeetong P, Pongpanich M, Srichomthong C, et al.

    Brain : a journal of neurology 2019; (142(11)):3360-3366 doi:10.1093/brain/awz267.

    PMID: 31539032
  10. 10

    Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy.

    Ishiura H, Doi K, Mitsui J, et al.

    Nature genetics 2018; (50(4)):581-590 doi:10.1038/s41588-018-0067-2.

    PMID: 29507423
  11. 11

    Familial Adult Myoclonus Epilepsy: A Non-Coding Repeat Expansion Disorder of Cerebellar-Thalamic-Cortical Loop.

    Cuccurullo C, Striano P, Coppola A

    Cells 2023; (12(12)) doi:10.3390/cells12121617.

    PMID: 37371086
  12. 12

    Insights into familial adult myoclonus epilepsy pathogenesis: How the same repeat expansion in six unrelated genes may lead to cortical excitability.

    Depienne C, van den Maagdenberg AMJM, Kühnel T, et al.

    Epilepsia 2023; (64 Suppl 1()):S31-S38 doi:10.1111/epi.17504.

    PMID: 36622139
  13. 13

    Familial adult myoclonic epilepsy (FAME): clinical features, molecular characteristics, pathophysiological aspects and diagnostic work-up.

    Peters L, Depienne C, Klebe S

    Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V 2021; (33(4)):311-318 doi:10.1515/medgen-2021-2100.

    PMID: 38835431
  14. 14

    Familial adult myoclonic epilepsy: A new expansion repeats disorder.

    Lagorio I, Zara F, Striano S, Striano P

    Seizure 2019; (67()):73-77 doi:10.1016/j.seizure.2019.03.009.

    PMID: 30928698
  15. 15

    Familial Adult Myoclonic Epilepsy: Clinical and Genetic Approach to an Under-recognized Disease.

    Uzun GA, Baykan B

    Noro psikiyatri arsivi 2023; (60(2)):174-177 doi:10.29399/npa.28252.

    PMID: 37287551
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    Genetics of familial adult myoclonus epilepsy: From linkage studies to noncoding repeat expansions.

    Corbett MA, Depienne C, Veneziano L, et al.

    Epilepsia 2023; (64 Suppl 1()):S14-S21 doi:10.1111/epi.17610.

    PMID: 37021642
  17. 17

    (TTTCA)exp Drives the Genotype-Phenotype Correlation and Genetic Anticipation in FCMTE1.

    Chen X, Wang B, Xia H, et al.

    Movement disorders : official journal of the Movement Disorder Society 2025; (40(2)):315-323 doi:10.1002/mds.30057.

    PMID: 39569876

This page explains the genetic causes of FAME for educational purposes only. Always consult a genetic counselor or neurologist to understand your family's specific genetic risks and testing options.

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