Objective: To report a family with Familial Cortical Myoclonic Tremor with Epilepsy(FAME) type 3 diagnosed through long-read sequencing and presenting a progressive disease course and cognitive decline

Background: FAME is a rare, highly penetrant autosomal dominant disorder characterized by cortical myoclonic tremor and seizures[1][2] Different subtypes of FAME have been identified, all caused by non-coding intronic TTTTA/TTTCA repeat expansions in different genes not detectable by traditional next-generation sequencing[3]. FAME3 is caused by the TTTTA/TTTCA repeat expansion in MARCH6 gene[4][5]. FAME has historically been viewed as a benign condition, distinguishable from progressive myoclonic epilepsies due to its typically non-refractory epilepsy, absence of cognitive decline and mild disease progression. However, cognitive dysfunction and intractable seizures have been occasionally reported in FAME2[6]

Method: Clinical, radiological and genetic assessments were performed using Bionano Optical Mapping and Oxford Nanopore sequencing

Results: Pedigree of the family is shown in [figure1]. The sister (III:4) had tonic-clonic seizures from 20, with myoclonic tremor, gait difficulties, and cognitive decline by 52. Despite medication, her seizures were only partially controlled. She passed away at 62.MRI showed T2 hyperintensity in the pyramidal tract and mild cerebellar atrophy.The proband (III:3) had seizures from 20 and developed generalized myoclonic tremor and cognitive decline by 64, requiring a wheelchair by 50.The nephew (IV:7) and the daughter (IV:6) had controlled seizures with mild EEG abnormalities. Genetic testing in III:3, IV:7 and IV:6 showed a TTTTA/TTTCA repeat expansion in MARCH6.

Conclusion: FAME3, increasingly diagnosed with the advent of long read sequencing, can present with a more aggressive course than historically recognized. Cognitive impairment and only partially controlled seizures, though rare, highlight the need for reevaluating FAME3’s clinical course as potentially more severe than previously assumed

Pedigree of family with MARCH6 expansion

Cerebellar atrophy and T2-hyperintensity in pons

References: 1 Cuccurullo, C.; Striano, P.; Coppola, A. Familial Adult Myoclonus Epilepsy: A Non-Coding Repeat Expansion Disorder of Cerebellar–Thalamic -Cortical Loop. Cells 2023, 12, 1617.
2 Vegezzi E, Ishiura H, Bragg DC, Pellerin D, Magrinelli F, Currò R, Facchini S, Tucci A, Hardy J, Sharma N, Danzi MC, Zuchner S, Brais B, Reilly MM, Tsuji S, Houlden H, Cortese A. Neurological disorders caused by novel non-coding repeat expansions: clinical features and differential diagnosis. Lancet Neurol. 2024 Jul;23(7):725-739.
3 Logsdon, G.A., Vollger, M.R. & Eichler, E.E. Long-read human genome sequencing and its applications. Nat Rev Genet 21, 597–614 (2020).
4 Depienne, C.; Magnin, E.; Bouteiller, D.; Stevanin, G.; Saint-Martin, C.; Vidailhet, M.; Apartis, E.; Hirsch, E.; LeGuern, E.; Labauge, P.; et al. Familial cortical myoclonic tremor with epilepsy: The third locus (FCMTE3) maps to 5p. Neurology 2010, 74, 2000–2003.
5 Florian, R.T.; Kraft, F.; Leitão, E.; Kaya, S.; Klebe, S.; Magnin, E.; van Rootselaar, A.F.; Buratti, J.; Kühnel, T.; Schröder, C.; et al. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3. Nat. Commun. 2019, 10, 4919.
6 Lagorio I, Zara F, Striano S, Striano P. Familial adult myoclonic epilepsy: A new expansion repeats disorder. Seizure. 2019 Apr;67:73-77.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/beyond-benign-tremor-and-epilepsy-in-fame3-a-new-family-report-with-progressive-course-and-cognitive-impairment/