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Oebele F. Brouwer - One of the best experts on this subject based on the ideXlab platform.
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The efficacy of the modified Atkins diet in North Sea Progressive Myoclonus Epilepsy: an observational prospective open-label study.
Orphanet journal of rare diseases, 2017Co-Authors: Martje E. Van Egmond, Amerins Weijenberg, Margreet Van Rijn, Jan Willem J. Elting, Jeannette M. Gelauff, Rodi Zutt, Deborah A Sival, Roald A. Lambrechts, Marina A.j. Tijssen, Oebele F. BrouwerAbstract:North Sea Progressive Myoclonus Epilepsy is a rare and severe disorder caused by mutations in the GOSR2 gene. It is clinically characterized by progressive Myoclonus, seizures, early-onset ataxia and areflexia. As in other progressive Myoclonus epilepsies, the efficacy of antiepileptic drugs is disappointingly limited in North Sea Progressive Myoclonus Epilepsy. The ketogenic diet and the less restrictive modified Atkins diet have been proven to be effective in other drug-resistant Epilepsy syndromes, including those with myoclonic seizures. Our aim was to evaluate the efficacy of the modified Atkins diet in patients with North Sea Progressive Myoclonus Epilepsy. Four North Sea Progressive Myoclonus Epilepsy patients (aged 7–20 years) participated in an observational, prospective, open-label study on the efficacy of the modified Atkins diet. Several clinical parameters were assessed at baseline and again after participants had been on the diet for 3 months. The primary outcome measure was health-related quality of life, with seizure frequency and blinded rated Myoclonus severity as secondary outcome measures. Ketosis was achieved within 2 weeks and all patients completed the 3 months on the modified Atkins diet. The diet was well tolerated by all four patients. Health-related quality of life improved considerably in one patient and showed sustained improvement during long-term follow-up, despite the progressive nature of the disorder. Health-related quality of life remained broadly unchanged in the other three patients and they did not continue the diet. Seizure frequency remained stable and blinded rating of their Myoclonus showed improvement, albeit modest, in all patients. This observational, prospective study shows that some North Sea Progressive Myoclonus Epilepsy patients may benefit from the modified Atkins diet with sustained health-related quality of life improvement. Not all our patients continued on the diet, but nonetheless we show that the modified Atkins diet might be considered as a possible treatment in this devastating disorder.
Akio Ikeda - One of the best experts on this subject based on the ideXlab platform.
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nationwide survey in japan endorsed diagnostic criteria of benign adult familial Myoclonus Epilepsy
Seizure-european Journal of Epilepsy, 2018Co-Authors: Katsuya Kobayashi, Takefumi Hitomi, Riki Matsumoto, Ryosuke Takahashi, Masako Watanabe, Akio IkedaAbstract:Abstract Purpose Benign adult familial Myoclonus Epilepsy (BAFME) is an autosomal dominant disease representing tremulous Myoclonus or cortical tremor and infrequent generalized seizures. We aimed to delineate detailed epidemiological backgrounds in patients with Japanese BAFME and to establish diagnostic criteria based on clinical and electrophysiological findings. Methods After a previous survey on the current nationwide state of Myoclonus Epilepsy of adults in Japan, we conducted this survey to delineate the clinical characteristics of Japanese BAFME patients, using a questionnaire to obtain details for individual patients. Based on clinical diagnostic criteria, we analyzed demographic and clinical characteristics of 101 BAFME patients in 74 families. Results BAFME patients were predominantly female and were widely distributed throughout Japan. Ninety-two patients (91.1%) showed signs of cortical tremor and 84 (83.2%) showed epileptic seizures. Epileptic seizures were infrequent in BAFME patients, but 22.6% of patients had more than one seizure per year at the maximum. Three patients (3.0%) showed cerebellar ataxia, eight (7.9%) showed cognitive impairment, and 13 (12.9%) had psychiatric symptoms. Brain MRI was normal in 74% of patients, and the remaining patients had non-specific abnormal findings. Sodium valproate and clonazepam were the primary drugs used for BAFME patients. The older patients showed significantly more severe and higher rates of abnormal electrophysiological results, which were suggestive of cortical hyperexcitability. Conclusion Our study successfully delineated the overall clinical characteristics of Japanese BAFME. The correlation between the genetic, clinical, and electrophysiological results will be very important to further elucidate the pathophysiology and treatment of BAFME in the future.
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1 1 04 positive rate of giant somatosensory evoked potential giant sep and c reflex in benign adult familial Myoclonus Epilepsy bafme
Clinical Neurophysiology, 2017Co-Authors: Takefumi Hitomi, Tomohiko Murai, Takeyo Sakurai, Riki Matsumoto, Ryosuke Takahashi, Katsuya Kobayashi, Akio IkedaAbstract:Benign adult familial Myoclonus Epilepsy (BAFME) manifests an autosomal dominant trait, cortical tremor resembling essential tremor and infrequent generalized tonic-clonic seizures. BAFME also shows electrophysiological features of cortical reflex Myoclonus. To clarify the positive rate of giant somatosensory evoked potential (giant SEP) and C reflex in BAFME, we retrospectively analyzed 19 patients in a total of 14 families (5 men and 14 women, age: 51 ± 16 years) about positive rate of giant SEP and C reflex. The positive rates of giant SEP and C reflex were 17/19 (89%) and 16/18 (88%), respectively. Relatively young 3 patients (27, 30, and 34 years old) showed no giant SEP or no C reflex. 1 patient (34 years old) showed neither giant SEP nor C reflex, who was examined within 1 year from the clinical onset. Whereas even 1 patient without cortical tremor showed giant SEP. The positive rate of giant SEP and C reflex is quite high in BAFME. Even presymptomatic patient showed giant SEP. However, some younger patients did not show giant SEP and/or C reflex. Therefore, family history of both clinical and electrophysiological findings is crucial for the diagnosis of BAFME.
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increased clinical anticipation with maternal transmission in benign adult familial Myoclonus Epilepsy in japan
Epileptic Disorders, 2013Co-Authors: Takefumi Hitomi, Riki Matsumoto, Ryosuke Takahashi, Katsuya Kobayashi, Takayuki Kondo, Hisaji Imamura, Naoto Jingami, Tomokazu Nakagawa, Kazuo Chin, Akio IkedaAbstract:We recently reported clinical anticipation in Japanese families with benign adult familial Myoclonus Epilepsy (BAFME). However, it remains unknown whether clinical anticipation is predominantly associated with paternal or maternal transmission. We investigated the relationship between gender of the transmitting parent and clinical anticipation in nine BAFME families. Clinical anticipation regarding either cortical tremor or generalised seizures was observed in all 12 parent/child pairs (8 mother/child pairs and 4 father/child pairs). Moreover, a higher degree of clinical anticipation was associated with maternal transmission than with paternal transmission (p=0.03). Although a causative gene for BAFME still remains unknown, our finding suggests that BAFME and diseases with unstable expanding repeats, including those in non-coding regions, might share a similar molecular mechanism because such diseases often show clinical anticipation with maternal transmission.
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clinical anticipation in japanese families of benign adult familial Myoclonus Epilepsy
Epilepsia, 2012Co-Authors: Takefumi Hitomi, Riki Matsumoto, Ryosuke Takahashi, Katsuya Kobayashi, Takayuki Kondo, Akio IkedaAbstract:Summary The clinical anticipation in Japanese benign adult familial Myoclonus Epilepsy (BAFME), defined as earlier onset age of either cortical tremor or generalized seizures or new appearance of those symptoms in the next generation, remains unknown. The onset age and the degree of both cortical tremor and generalized seizures were investigated in nine patients of four BAFME families (mean age: 46.6 ± 18.7 years). Clinical anticipation in the onset age of cortical tremor or generalized seizures was observed in three families, and generalized seizures newly appeared in the next generation in those two families and in another family. Clinical anticipation was observed in four families, which suggests the clinical progression over generation in Japanese BAFME families.
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increased cortical hyperexcitability and exaggerated Myoclonus with aging in benign adult familial Myoclonus Epilepsy
Movement Disorders, 2011Co-Authors: Takefumi Hitomi, Akio Ikeda, Riki Matsumoto, Takayuki Kondo, Hisaji Imamura, Morito Inouchi, Kiyohito Terada, Masutaro Kanda, Masao Matsuhashi, Takashi NagamineAbstract:The clinical implications of enlarged early cortical components of somatosensory evoked potentials in benign adult familial Myoclonus Epilepsy remain unknown. Somatosensory evoked potentials following electrical stimulation of the median nerve at the wrist were studied in 16 patients with a clinical diagnosis of benign adult familial Myoclonus Epilepsy (7 men and 9 women; mean age, 51 ± 18 years) and 19 age-matched apparently healthy control subjects (11 men and 8 women; mean age, 49 ± 18 years). Giant somatosensory evoked potentials were observed in 13 of the 16 patients. P25 and N35 amplitudes in the patient group were 11.4 ± 6.1 and 19.2 ± 11.5 μV, respectively, and both were significantly larger compared with those in control subjects (P = 0.008 for P25 and P < 0.0001 for N35). There was a significant positive relationship between age at somatosensory evoked potential examination and N20, P25, and N35 amplitudes, both in the patient and in the control groups (P < 0.05). The linear regression gradient of the N35 amplitude with respect to age was significantly larger in the patient group than in the control group (P = 0.04). Furthermore, regression analysis showed a significant positive relationship between the Myoclonus rating scale and age at time of somatosensory evoked potential examination (R = 0.645, P = 0.007). Somatosensory evoked potential amplitude increased with age in patients with benign adult familial Myoclonus Epilepsy to a greater extent than in the control subjects, which suggests a progressive increase in cortical excitability based on progressive pathophysiology in benign adult familial Myoclonus Epilepsy. © 2011 Movement Disorder Society
Takefumi Hitomi - One of the best experts on this subject based on the ideXlab platform.
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Sleep is associated with reduction of epileptiform discharges in benign adult familial Myoclonus Epilepsy
'Elsevier BV', 2019Co-Authors: Takefumi Hitomi, Katsuya Kobayashi, Morito Inouchi, Masao Matsuhashi, Hirofumi Takeyama, Shamima Sultana, Takeshi Inoue, Yuko Nakayama, Akihiro Shimotake, Riki MatsumotoAbstract:To clarify the effects of sleep on cortical irritability in benign adult familial Myoclonus Epilepsy (BAFME), we retrospectively compared epileptiform discharges of electroencephalographies (EEGs) between awake and sleep periods in 5 patients (mean age: 49.6 ± 20.3 years). We also analyzed polysomnography (PSG) of 1 patient. Epileptiform discharges were significantly more frequent during the awake period (1.3 ± 1.2/min) than those during light sleep stages (0.02 ± 0.04/min) (P
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nationwide survey in japan endorsed diagnostic criteria of benign adult familial Myoclonus Epilepsy
Seizure-european Journal of Epilepsy, 2018Co-Authors: Katsuya Kobayashi, Takefumi Hitomi, Riki Matsumoto, Ryosuke Takahashi, Masako Watanabe, Akio IkedaAbstract:Abstract Purpose Benign adult familial Myoclonus Epilepsy (BAFME) is an autosomal dominant disease representing tremulous Myoclonus or cortical tremor and infrequent generalized seizures. We aimed to delineate detailed epidemiological backgrounds in patients with Japanese BAFME and to establish diagnostic criteria based on clinical and electrophysiological findings. Methods After a previous survey on the current nationwide state of Myoclonus Epilepsy of adults in Japan, we conducted this survey to delineate the clinical characteristics of Japanese BAFME patients, using a questionnaire to obtain details for individual patients. Based on clinical diagnostic criteria, we analyzed demographic and clinical characteristics of 101 BAFME patients in 74 families. Results BAFME patients were predominantly female and were widely distributed throughout Japan. Ninety-two patients (91.1%) showed signs of cortical tremor and 84 (83.2%) showed epileptic seizures. Epileptic seizures were infrequent in BAFME patients, but 22.6% of patients had more than one seizure per year at the maximum. Three patients (3.0%) showed cerebellar ataxia, eight (7.9%) showed cognitive impairment, and 13 (12.9%) had psychiatric symptoms. Brain MRI was normal in 74% of patients, and the remaining patients had non-specific abnormal findings. Sodium valproate and clonazepam were the primary drugs used for BAFME patients. The older patients showed significantly more severe and higher rates of abnormal electrophysiological results, which were suggestive of cortical hyperexcitability. Conclusion Our study successfully delineated the overall clinical characteristics of Japanese BAFME. The correlation between the genetic, clinical, and electrophysiological results will be very important to further elucidate the pathophysiology and treatment of BAFME in the future.
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1 1 04 positive rate of giant somatosensory evoked potential giant sep and c reflex in benign adult familial Myoclonus Epilepsy bafme
Clinical Neurophysiology, 2017Co-Authors: Takefumi Hitomi, Tomohiko Murai, Takeyo Sakurai, Riki Matsumoto, Ryosuke Takahashi, Katsuya Kobayashi, Akio IkedaAbstract:Benign adult familial Myoclonus Epilepsy (BAFME) manifests an autosomal dominant trait, cortical tremor resembling essential tremor and infrequent generalized tonic-clonic seizures. BAFME also shows electrophysiological features of cortical reflex Myoclonus. To clarify the positive rate of giant somatosensory evoked potential (giant SEP) and C reflex in BAFME, we retrospectively analyzed 19 patients in a total of 14 families (5 men and 14 women, age: 51 ± 16 years) about positive rate of giant SEP and C reflex. The positive rates of giant SEP and C reflex were 17/19 (89%) and 16/18 (88%), respectively. Relatively young 3 patients (27, 30, and 34 years old) showed no giant SEP or no C reflex. 1 patient (34 years old) showed neither giant SEP nor C reflex, who was examined within 1 year from the clinical onset. Whereas even 1 patient without cortical tremor showed giant SEP. The positive rate of giant SEP and C reflex is quite high in BAFME. Even presymptomatic patient showed giant SEP. However, some younger patients did not show giant SEP and/or C reflex. Therefore, family history of both clinical and electrophysiological findings is crucial for the diagnosis of BAFME.
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increased clinical anticipation with maternal transmission in benign adult familial Myoclonus Epilepsy in japan
Epileptic Disorders, 2013Co-Authors: Takefumi Hitomi, Riki Matsumoto, Ryosuke Takahashi, Katsuya Kobayashi, Takayuki Kondo, Hisaji Imamura, Naoto Jingami, Tomokazu Nakagawa, Kazuo Chin, Akio IkedaAbstract:We recently reported clinical anticipation in Japanese families with benign adult familial Myoclonus Epilepsy (BAFME). However, it remains unknown whether clinical anticipation is predominantly associated with paternal or maternal transmission. We investigated the relationship between gender of the transmitting parent and clinical anticipation in nine BAFME families. Clinical anticipation regarding either cortical tremor or generalised seizures was observed in all 12 parent/child pairs (8 mother/child pairs and 4 father/child pairs). Moreover, a higher degree of clinical anticipation was associated with maternal transmission than with paternal transmission (p=0.03). Although a causative gene for BAFME still remains unknown, our finding suggests that BAFME and diseases with unstable expanding repeats, including those in non-coding regions, might share a similar molecular mechanism because such diseases often show clinical anticipation with maternal transmission.
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clinical anticipation in japanese families of benign adult familial Myoclonus Epilepsy
Epilepsia, 2012Co-Authors: Takefumi Hitomi, Riki Matsumoto, Ryosuke Takahashi, Katsuya Kobayashi, Takayuki Kondo, Akio IkedaAbstract:Summary The clinical anticipation in Japanese benign adult familial Myoclonus Epilepsy (BAFME), defined as earlier onset age of either cortical tremor or generalized seizures or new appearance of those symptoms in the next generation, remains unknown. The onset age and the degree of both cortical tremor and generalized seizures were investigated in nine patients of four BAFME families (mean age: 46.6 ± 18.7 years). Clinical anticipation in the onset age of cortical tremor or generalized seizures was observed in three families, and generalized seizures newly appeared in the next generation in those two families and in another family. Clinical anticipation was observed in four families, which suggests the clinical progression over generation in Japanese BAFME families.
Berge A. Minassian - One of the best experts on this subject based on the ideXlab platform.
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ketogenic diet reduces lafora bodies in murine lafora disease
Neurology Genetics, 2020Co-Authors: Lori Israelian, Peixiang Wang, Xiaochu Zhao, Shoghig Gabrielian, Berge A. MinassianAbstract:Lafora disease (LD) is a teenage-onset fatal progressive Myoclonus Epilepsy caused by loss-of-function mutations in the EPM2A gene encoding the glycogen phosphatase laforin or EPM2B encoding the laforin-interacting ubiquitin E3 ligase malin. Concerted actions of glycogen synthase (GS) and branching enzyme generate normal short-branched soluble glycogen. In LD, some glycogen molecules develop long branches, precipitate, and accumulate into pathognomonic and pathogenic Lafora bodies (LBs). The precise mechanism by which the laforin-malin complex mitigates this is unknown, but thought to involve GS downregulation. In fact, transgenic GS downregulation in LD mouse models reduces LB formation and rescues the disease.1,2
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lafora disease seizures and sugars
Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology edited by the Gaetano Conte Academy for th, 2007Co-Authors: Danielle M Andrade, Julie Turnbull, Berge A. MinassianAbstract:Lafora disease (LD) is the most severe form of Progressive Myoclonus Epilepsy with teenage onset. It has an autosomal recessive mode of inheritance and is almost universally fatal by the second or third decade of life. To date, there is no prevention or cure. In the last decade, with the identification of the genes responsible for this disease, much knowledge has been gained with the potential for the future development of effective treatment. This review will briefly address clinical issues and will focus on the molecular aspects of the disease.
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novel glycogen synthase kinase 3 and ubiquitination pathways in progressive Myoclonus Epilepsy
Human Molecular Genetics, 2005Co-Authors: Hannes Lohi, Julie Turnbull, Stephen W. Scherer, Elayne M Chan, Leonarda Ianzano, Xiaochu Zhao, Cameron A Ackerley, Berge A. MinassianAbstract:Lafora progressive Myoclonus Epilepsy, caused by defective laforin or malin, insidiously present in normal teenagers with cognitive decline, followed by rapidly intractable Epilepsy, dementia and death. Pathology reveals neurodegeneration with neurofibrillary tangle formation and Lafora bodies (LBs). LBs are deposits of starch-like polyglucosans, insufficiently branched and hence insoluble glycogen molecules resulting from glycogen synthase (GS) overactivity relative to glycogen branching enzyme activity. We previously made the unexpected observation that laforin, in the absence of which polyglucosans accumulate, specifically binds polyglucosans. This suggested that laforin’s role is to detect polyglucosan appearances during glycogen synthesis and to initiate mechanisms to downregulate GS. Glycogen synthase kinase 3 (GSK3) is the principal inhibitor of GS. Dephosphorylation of GSK3 at Ser 9 activates GSK3 to inhibit GS through phosphorylation at multiple sites. Glucose-6-phosphate is a potent allosteric activator of GS. Glucose-6-phosphate levels are high when the amount of glucose increases and its activation of GS overrides any phospho-inhibition. Here, we show that laforin is a GSK3 Ser 9 phosphatase, and therefore capable of inactivating GS through GSK3. We also show that laforin interacts with malin and that malin is an E3 ubiquitin ligase that binds GS. We propose that laforin, in response to appearance of polyglucosans, directs two negative feedback pathways: polyglucosan‐laforin‐GSK3‐GS to inhibit GS activity and polyglucosan‐ laforin‐malin‐GS to remove GS through proteasomal degradation.
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Progressive Myoclonus Epilepsy with polyglucosans (Lafora disease): evidence for a third locus.
Neurology, 2004Co-Authors: Elayne Chan, Salah Omer, Mushtaq Ahmed, L. R. Bridges, Christopher P. Bennett, Stephen W. Scherer, Berge A. MinassianAbstract:Lafora disease (LD) is the most common teenage-onset progressive Myoclonus Epilepsy. It is caused by recessive mutations in the EPM2A or EPM2B genes. The authors describe a family with three affected members with no mutations in either gene. Linkage and haplotype analyses exclude both loci from causative involvement in this family. Therefore, a third LD locus is predicted. Its identification will be a crucial element in the understanding of the biochemical pathway underlying the generation of Lafora bodies and LD.
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lafora s disease towards a clinical pathologic and molecular synthesis
Pediatric Neurology, 2001Co-Authors: Berge A. MinassianAbstract:Lafora's disease is one of five inherited progressive Myoclonus Epilepsy syndromes. It is an autosomal-recessive disorder with onset in late childhood or adolescence. Characteristic seizures include myoclonic and occipital lobe seizures with visual hallucinations, scotomata, and photoconvulsions. The course of the disease consists of worsening seizures and an inexorable decline in mental and other neurologic functions that result in dementia and death within 10 years of onset. Pathology reveals pathognomonic polyglucosan inclusions that are not seen in any other progressive Myoclonus Epilepsy. Lafora's disease is one of several neurologic conditions associated with brain polyglucosan bodies. Why Lafora's polyglucosan bodies alone are associated with Epilepsy is unknown and is discussed in this article. Up to 80% of patients with Lafora's disease have mutations in the EPM2A gene. Although common mutations are rare, simple genetic tests to identify most mutations have been established. At least one other still-unknown gene causes Lafora's disease. The EPM2A gene codes for the protein laforin, which localizes at the plasma membrane and the rough endoplasmic reticulum and functions as a dual-specificity phosphatase. Work toward establishing the connection between laforin and Lafora's disease polyglucosans is underway, as are attempts to replace it into the central nervous system of patients with Lafora's disease.
Birgitta Söderfeldt - One of the best experts on this subject based on the ideXlab platform.
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unstable insertion in the 5 flanking region of the cystatin b gene is the most common mutation in progressive Myoclonus Epilepsy type 1 epm1
Nature Genetics, 1997Co-Authors: Ronald G. Lafrenière, Reetta Kälviäinen, Daniel Rochefort, Nathalie Chretien, Johanna M. Rommens, Jeffrey I. Cochius, Unto Nousiainen, George Patry, Kevin Farrell, Birgitta SöderfeldtAbstract:Progressive Myoclonus Epilepsy type 1 (EPM1, also known as Unverricht-Lundborg disease) is an autosomal recessive disorder characterized by progressively worsening myoclonic jerks, frequent generalized tonic-clonic seizures, and a slowly progressive decline in cognition1. Recently, two mutations in the cystatin B gene (also known as stefin B, STFB) mapping to 21q22.3 have been implicated in the EPM1 phenotype: a G→C substitution in the last nucleotide of intron 1 that was predicted to cause a splicing defect in one family, and a C→T substitution that would change an Arg codon (CGA) to a stop codon (TGA) at amino acid position 68, resulting in a truncated cystatin B protein in two other families2. A fourth family showed undetectable amounts of STFB mRNA by northern blot analysis in an affected individual. We present haplotype and mutational analyses of our collection of 20 unrelated EPM1 patients and families from different ethnic groups. We identify four different mutations, the most common of which consists of an unstable ∼600–900 bp insertion which is resistant to PCR amplification. This insertion maps to a 12-bp polymorphic tandem repeat located in the 5' flanking region of the STFB gene, in the region of the promoter. The size of the insertion varies between different EPM1 chromosomes sharing a common haplotype and a common origin, suggesting some level of meiotic instability over the course of many generations. This dynamic mutation, which appears distinct from conventional trinucleotide repeat expansions, may arise via a novel mechanism related to the instability of tandemly repeated sequences.
