Familial cortical myoclonic tremor with epilepsy: TTTCA/TTTTA repeat expansions and expanding phenotype in two Chinese families

Zhang, Yingying; Xiong, Weixi; Lu, Lu; Zhou, Dong

doi:10.1016/j.brainres.2020.146796

Cited by 5 publications

(6 citation statements)

References 32 publications

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“…It is notable that a subgroup of patients with FAME has concomitant psychiatric disorders, such as depression and anxiety, which require diagnosis and appropriate management. 4,20 Similarly, several studies have confirmed an increased incidence of psychiatric comorbidities (26.5%-47%), mostly anxiety and mood disorders in patients with JME. 21 However, a higher prevalence of state anxiety and depression was reported in patients with FAME (ADCME) in comparison to patients with JME.…”

Section: Other Differential Diagnosesmentioning

confidence: 89%

“…In these cases, a psychogenic basis for the symptoms needs to be excluded, to enable a diagnosis of FAME. It is notable that a subgroup of patients with FAME has concomitant psychiatric disorders, such as depression and anxiety, which require diagnosis and appropriate management 4,20 . Similarly, several studies have confirmed an increased incidence of psychiatric comorbidities (26.5%–47%), mostly anxiety and mood disorders in patients with JME 21 .…”

Section: Differential Diagnosis Of Famementioning

confidence: 99%

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Differential diagnosis of familial adult myoclonic epilepsy

et al. 2023

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Objective Familial adult myoclonic epilepsy (FAME) is an under‐recognized disorder characterized by cortical myoclonus, generalized tonic–clonic seizures, and additional clinical symptoms, which vary depending on the FAME subtype. FAME is caused by pentanucleotide repeat expansions of intronic TTTCA/TTTTA in different genes. FAME should be distinguished from a range of differential diagnoses. Methods The differential diagnoses and frequent presentations leading to misdiagnosis of FAME were investigated from the available literature and reported based on an expert opinion survey. Results The phenotypic features of FAME, including generalized tonic–clonic and myoclonic seizures, are also seen in other epilepsy syndromes, such as juvenile myoclonic epilepsy, with a resultant risk of misdiagnosis and lack of identification of the underlying cause. Cortical myoclonus may mimic essential tremor or drug‐induced tremor. In younger individuals, the differential diagnosis includes progressive myoclonus epilepsies (PMEs), such as Unverricht‐Lundborg disease, whereas, in adulthood, late‐onset variants of PMEs, such as sialidoses, myoclonus epilepsy, and ataxia due to potassium channel pathogenic variants should be considered. PMEs may also be suggested by cognitive impairment, cerebellar signs, or psychiatric disorders. Electroencephalography (EEG) may show similarities to other idiopathic generalized epilepsies or PMEs, with generalized spike–wave activity. Signs of cortical hyperexcitability may be seen, such as an increased amplitude of somatosensory evoked potentials or enhanced cortical reflex to sensory stimuli, together with the neurophysiological pattern of the movement disorder. Significance Recognition of FAME will inform prognostic and genetic counseling and diagnosis of the insidious progression, which may occur in older individuals who show mild cognitive deterioration. Distinguishing FAME from other disorders in individuals or families with this constellation of symptoms is essential to allow the identification of underlying etiology.

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Section: Other Differential Diagnosesmentioning

confidence: 89%

Section: Differential Diagnosis Of Famementioning

confidence: 99%

Differential diagnosis of familial adult myoclonic epilepsy

et al. 2023

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“…When TTTTA and TTTCA expansions were identified, Ishiura et al also showed that the length of the expanded repeats tended to be unstable over consecutive generations and appeared inversely correlated to the age at cortical tremor or seizure onset [82]. This correlation has been further confirmed in other pedigrees and the other FAME genes, supporting that progressive increase in the TTTCA/TTTTA repeat length over successive generations provides a molecular explanation for the anticipation observed in FAME [83][84][85]92,93].…”

Section: Genotype-phenotype Correlationmentioning

confidence: 90%

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

Cuccurullo

Rinaldi

Coppola

2023

Cells

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Familial adult myoclonus Epilepsy (FAME) is a non-coding repeat expansion disorder that has been reported under different acronyms and initially linked to four main loci: FAME1 (8q23.3–q24.1), FAME 2 (2p11.1–q12.1), FAME3 (5p15.31–p15.1), and FAME4 (3q26.32–3q28). To date, it is known that the genetic mechanism underlying FAME consists of the expansion of similar non-coding pentanucleotide repeats, TTTCA and TTTTA, in different genes. FAME is characterized by cortical tremor and myoclonus usually manifesting within the second decade of life, and infrequent seizures by the third or fourth decade. Cortical tremor is the core feature of FAME and is considered part of a spectrum of cortical myoclonus. Neurophysiological investigations as jerk-locked back averaging (JLBA) and corticomuscular coherence analysis, giant somatosensory evoked potentials (SEPs), and the presence of long-latency reflex I (or C reflex) at rest support cortical tremor as the result of the sensorimotor cortex hyperexcitability. Furthermore, the application of transcranial magnetic stimulation (TMS) protocols in FAME patients has recently shown that inhibitory circuits are also altered within the primary somatosensory cortex and the concomitant involvement of subcortical networks. Moreover, neuroimaging studies and postmortem autoptic studies indicate cerebellar alterations and abnormal functional connectivity between the cerebellum and cerebrum in FAME. Accordingly, the pathophysiological mechanism underlying FAME has been hypothesized to reside in decreased sensorimotor cortical inhibition through dysfunction of the cerebellar–thalamic–cortical loop, secondary to primary cerebellar pathology. In this context, the non-coding pentameric expansions have been proposed to cause cerebellar damage through an RNA-mediated toxicity mechanism. The elucidation of the underlying pathological mechanisms of FAME paves the way to novel therapeutic possibilities, such as RNA-targeting treatments, possibly applicable to other neurodegenerative non-coding disorders.

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“… 32 Individuals in >200 families have now had a confirmed genetic diagnosis of a TTTTA and inserted TTTCA repeat expansion within one of the FAME genes since the genetic cause of FAME1 was discovered. The pathogenic FAME1 repeat expansion has since been discovered in Chinese, 26 , 33 , 34 , 35 , 36 , 37 , 38 Japanese, 39 Indian, 40 , 41 Sri Lankan, 41 and Thai 42 families, all likely arising from one founder. The FAME1 repeat expansion was estimated to be approximately 16 800 years old and predicted to have arrived in Japan approximately 4300 years ago.…”

Section: The Hunt For the Genetic Cause Of Famementioning

confidence: 99%

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

Corbett

Depienne²,

Veneziano

et al. 2023

Epilepsia

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Familial adult myoclonus epilepsy (FAME) is a genetic epilepsy syndrome that for many years has resisted understanding of its underlying molecular cause. This review covers the history of FAME genetic studies worldwide, starting with linkage and culminating in the discovery of noncoding TTTTA and inserted TTTCA pentanucleotide repeat expansions within six different genes to date (SAMD12, STARD7, MARCHF6, YEATS2, TNRC6A, and RAPGEF2). FAME occurs worldwide; however, repeat expansions in particular genes have regional geographical distributions. FAME repeat expansions are dynamic in nature, changing in length and structure within germline and somatic tissues. This variation poses challenges for molecular diagnosis such that molecular methods used to identify FAME repeat expansions typically require a trade‐off between cost and efficiency. A rigorous evaluation of the sensitivity and specificity of each molecular approach remains to be performed. The origin of FAME repeat expansions and the genetic and environmental factors that modulate repeat variability are not well defined. Longer repeats and particular arrangements of the TTTTA and TTTCA motifs within an expansion are correlated with earlier onset and increased severity of disease. Other factors such as maternal or paternal inheritance, parental age, and repeat length alone have been suggested to influence repeat variation; however, further research is required to confirm this. The history of FAME genetics to the present is a chronicle of perseverance and predominantly collaborative efforts that yielded a successful outcome. The discovery of FAME repeats will spark progress toward a deeper understanding of the molecular pathogenesis of FAME, discovery of new loci, and development of cell and animal models.

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Familial cortical myoclonic tremor with epilepsy: TTTCA/TTTTA repeat expansions and expanding phenotype in two Chinese families

Cited by 5 publications

References 32 publications

Differential diagnosis of familial adult myoclonic epilepsy

Differential diagnosis of familial adult myoclonic epilepsy

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

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

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