Objective: To describe the first case of Familial adult myoclonic epilepsy 3 (FAME3) due to intermediate intronic expansion of MARCHF6.

Background: FAME is an autosomal dominant syndrome reported under several different names, in over a hundred pedigrees worldwide, clinically characterized by adult-onset of cortical myoclonus with or without epilepsy, due to intronic pentanucleotide repeat expansions, reported in 6 distinct genes (FAME1-4, 6, 7).¹ Expansion of noncoding TTTCA and TTTTA repeats in intron 1 of MARCHF6 was identified as the causative mutation of FAME3.^2-3

Method: Proband was seen at the Fresco Institute for Parkinson’s disease at NYU Langone Health. Subject was enrolled in our ongoing genomic study. Clinical and family history, video recording and blood sample were collected.  Sample of proband’s sister were collected at the University Hospital Center of Toulouse. Samples were tested for FAME1 (proband only) and 3 (both) using long-range PCR amplification, RP-PCR and long-read sequencing with Oxford Nanopore (MinION flow cell R9.4.1) at the University Hospital Essen to describe size, composition and configuration of the expansions.

Results: Proband was a 63‐year-old Caucasian man with an 8‐year history of cortical myoclonus of the upper limbs, triggered by actions, with associated anxiety and obsessive compulsive features (OCD). In his family, originally from France, his father and sister presented similar symptoms, but more severe. There was no personal or family history of seizures. Genomic analysis showed an intermediate pathogenic, intronic expansion TTTTA/TTTCA in MARCHF6, confirmed with RP-PCR and Nanopore sequencing. Intermediate expansion was confirmed also in the affected sister but not found in samples from negative control subjects.

Conclusion: FAME represents a novel non-coding repeat expansion disease model. A growing number of families with FAME have been reported in the literature where disease segregates with intronic expansion in one of the 6 identified genes. Complex genomic rearrangements of intronic repeated expansions have been identified. Here we describe the first family with an intermediate expansion in the MARCHF6 gene, associated with a milder phenotype characterized by cortical myoclonus of varying severity, anxiety, and OCD but no seizures. Our results contribute to the understanding of the phenotypic spectrum of FAME disorders without epilepsy.

References: 1. Latorre A, Rocchi L, Magrinelli F, Mulroy E, Berardelli A, Rothwell J.C., Bhatia K.P. Unravelling the enigma of cortical tremor and other forms of cortical myoclonus. Brain 2020, 143, 2653–2663.

2. Ishiura H, Doi K, Mitsui J, Yoshimura J, Matsukawa M.K, Fujiyama A, Toyoshima Y, Kakita A, Takahashi H, Suzuki Y et al. Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nat. Genet. 2018, 50, 581–590.

3. Mizuguchi T, Toyota T, Miyatake S, Mitsuhashi S, Doi H, Kudo Y, et al. Complete sequencing of expanded SAMD12 repeats by long-read sequencing and Cas9-mediated enrichment. Brain. 2021;144(4):1103–17.

4. Florian RT, Kraft F, Leitão E, Kaya S, Klebe S, Magnin E, van Rootselaar AF, Buratti J, Kühnel T, Schröder C, Giesselmann S, Tschernoster N, Altmueller J, Lamiral A, Keren B, Nava C, Bouteiller D, Forlani S, Jornea L, Kubica R, Ye T, Plassard D, Jost B, Meyer V, Deleuze JF, Delpu Y, Avarello MDM, Vijfhuizen LS, Rudolf G, Hirsch E, Kroes T, Reif PS, Rosenow F, Ganos C, Vidailhet M, Thivard L, Mathieu A, Bourgeron T, Kurth I, Rafehi H, Steenpass L, Horsthemke B; FAME consortium; LeGuern E, Klein KM, Labauge P, Bennett MF, Bahlo M, Gecz J, Corbett MA, Tijssen MAJ, van den Maagdenberg AMJM, Depienne C. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3. Nat Commun. 2019 Oct 29;10(1):4919.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/intermediate-expansion-of-marchf6-causes-fame3-without-epilepsy/