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Review

Candidate Genes for Eyelid Myoclonia with Absences, Review of the Literature

1
Genetics and Inheritance Research Group, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
2
Department of Genetics, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain
3
Department of Neurology, Division of Pediatric Neurology, Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, 28041 Madrid, Spain
4
Traslational Research in Genetics, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain
5
Genetics Unit, Hospital Universitario y Politecnico La Fe, 46026 Valencia, Spain
6
Department of Neurology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain
7
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
8
Department of Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain
*
Author to whom correspondence should be addressed.
S.M., I.G.-M. and F.J.F.-M. contributed equally to this work and should be considered joint first authors.
A.C., F.M. and J.B.-L. contributed equally to this work and should be considered joint senior authors.
Int. J. Mol. Sci. 2021, 22(11), 5609; https://doi.org/10.3390/ijms22115609
Received: 7 May 2021 / Revised: 19 May 2021 / Accepted: 21 May 2021 / Published: 25 May 2021
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies 3.0)

Abstract

:
Eyelid myoclonia with absences (EMA), also known as Jeavons syndrome (JS) is a childhood onset epileptic syndrome with manifestations involving a clinical triad of absence seizures with eyelid myoclonia (EM), photosensitivity (PS), and seizures or electroencephalogram (EEG) paroxysms induced by eye closure. Although a genetic contribution to this syndrome is likely and some genetic alterations have been defined in several cases, the genes responsible for have not been identified. In this review, patients diagnosed with EMA (or EMA-like phenotype) with a genetic diagnosis are summarized. Based on this, four genes could be associated to this syndrome (SYNGAP1, KIA02022/NEXMIF, RORB, and CHD2). Moreover, although there is not enough evidence yet to consider them as candidate for EMA, three more genes present also different alterations in some patients with clinical diagnosis of the disease (SLC2A1, NAA10, and KCNB1). Therefore, a possible relationship of these genes with the disease is discussed in this review.

1. Introduction

In 1977, Jeavons described something that is now known as Jeavons syndrome (JS): “Eyelid myoclonia and absences show a marked jerking of the eyelids immediately after eye closure and there is associated brief bilateral spike-and-wave activity. The eyelid movement is like rapid blinking and the eyes deviate upwards, in contrast to the very slight flicker of eyelids which may be seen in a typical absence in which the eyes look straight ahead. Brief absences may occur spontaneously and are accompanied by 3 c/s spike-and-wave discharges. The spike-and-wave discharges seen immediately after eye closure do not occur in the dark. Their presence in a routine EEG is a very reliable warning that abnormality will be evoked by photic stimulation” [1].
JS, also known as eyelid myoclonia with absences (EMA), is a childhood onset epileptic syndrome with manifestations involving a clinical triad of absence seizures with eyelid myoclonia (EM), photosensitivity (PS), and seizures or electroencephalogram (EEG) paroxysms induced by eye closure [2].
EMA is considered as a separate entity among genetic generalized epilepsies (GGE) associated with EM and brief absences related to generalized paroxysmal activity on EEG triggered by eye closure or intermittent photic stimulation (IPS) [3,4]. However, epilepsy with eyelid myoclonias has only been recently recognized as a distinct epilepsy syndrome by the International League Against Epilepsy (ILAE) [5].
A family history of seizures or epilepsy is common in those cases (seen in 40–80%) [4,5]. Additionally, reports of affected identical twins suggest its genetic etiology [4,6,7,8]. Despite this, there is actually no known gene accepted as pathogenic for this disease [5,9]. Moreover, different case reports have proposed several candidate genes [2,10,11,12,13].
EMA onset is typically in childhood, with a peak at 6–8 years. However, the time of seizure onset may be difficult to be exactly established, as eyelid jerks are frequently misinterpreted as tics or mannerisms, and absences may be overlooked [3]. The presence of massive myoclonus, intellectual disability (ID), or slowing of the EEG background are not typical features of the syndrome and may also cause delay in making the correct diagnosis [14]. More frequent in females, some patients show resistance to antiepileptic therapy [3,4].
In clinical practice, however, syndromes may overlap and cases may present with unusual manifestations, posing a diagnostic challenge [14]. The phenotypic and genetic heterogeneity may lead to underestimation of the clinical presentation, making the diagnosis more difficult [15]. In this review, based on different reported cases, we present four candidate genes for EMA and three other genes that might also be related to the disease. Moreover, we discuss their possible relation with the disease in order to improve the knowledge of this syndrome.

2. Results and Discussion

2.1. SYNGAP1

SYNGAP1 (MIM *603384) is located on 6p21.32 [16]. This gene encodes a brain-specific synaptic Ras GTPase activating protein that is a member of the N-methyl-D-aspartate receptor complex [17]. Primarily expressed in excitatory neurons, it regulates dendritic spines structure, function, and plasticity, with major consequences for neuronal homeostasis and development, crucial for learning and memory [18]. Heterozygous loss of function variants in SYNGAP1 are associated with developmental delay (DD), ID, epilepsy, and autism spectrum disorder (ASD) (MIM # 612621; ORPHA 544254) [19,20].
In 2011, Klitten et al. described a patient with epilepsy with myoclonic absences and a balanced translocation disrupting SYNGAP1 [12]. This patient presented DD, ID, and ASD, but also eyelid winking and absences associated with eye deviation, being resistant to treatment (Table 1).
Mignot et al. (2016) presented a series of 17 unrelated patients with ID and epilepsy, mainly pharmacoresistant (>55%), carrying 13 different loss-of-function SYNGAP1 mutations [21]. Three of them presented EM and suffered from seizures triggered by PS or EEG alteration after eye closure. Even more, one of them carry the missense alteration c.1685C>T (p.Pro562Leu), which has also been described in another patient diagnosed with EMA with myoclonic-atonic epilepsy (MAE) [22,23] (Table 1). However, this mutation was also recently reported by Lo Barco et al. (2021) in a patient without EM [24].
Vlaskamp et al. (2019) explored the relationship between EMA and MAE [23]. From a cohort of 57 cases with SYNGAP1 mutations or microdeletions, the most common epilepsy phenotype was an overlapping syndrome combining the features of these two epilepsy syndromes (20/57, 35%), followed by the diagnosis of EMA in 13 patients (23%). DD/ID (32/33) and ASD (24/33) were also prevalent in those cases (Table 1). According to the results of Vlaskamp et al., absences with EM and PS were found in more than 50% of the cases with epilepsy and SYNGAP1 alteration. Myoclonic (33%) and atonic (8%) seizures were also recurrent in their patients with EM. Moreover, in those cases, EM has an earlier onset and the cognitive outcome is worse than the classic syndrome of EMA. Therefore, they concluded that the more severe cases of EMA might be explained by SYNGAP1 mutations, especially in those individuals with earlier onset of EM or myoclonic or atonic seizures [23].
In this sense, Kuchenbuch et al. (2020) presented three cases with different de novo mutations in SYNGAP1 and epilepsy [25]. Although not all the clinical data are available, two of these cases presented EM and absences induced by PS or eye closure (Table 1). These two cases presented also myoclonic jerks and the EM onset was before 3 years of age (8 months and 2.5 years, respectively) [25]. In addition, the SYNGAP1 variants of these two cases were also reported by Lo Barco et al. (2021) in two other cases with EMA (p.Glu656*) and EM (p.Arg687*) in a cohort of 15 patients with cognitive disability and pathogenic SYNGAP1 variants, of which 14 were epileptic [24]. According to the clinical and EEG data, five of these patients presented EMA, with an onset age of three years or below, presence of myoclonic (60%) and atonic (40%) seizures in three and two cases respectively, and with uncontrolled seizures despite of the treatment in four cases. Moreover, two more cases of this series also presented EM and absences (Table 1) [24].
Finally, other publications gather more patients with alterations in SYNGAP1 and a phenotype resembling EMA. Okazaki et al. (2017) published a case with a EMA-like phenotype that was carrier of a variant in this gene (p.Val1195Alafs*27) [26]. This alteration was previously identified in a male patient with moderate ID, no speech, psychomotor delay, and behavioral disorders, but without epilepsy [27]. However, this was also later described by Lo Barco et al. in a patient with EMA [24] (Table 1). Von Stülpnagel et al. (2019) published four cases with SYNGAP1 pathogenic variants and EM typically initialed by eye closure [28]. It should be noted that two of them, which were also reported by Vlaskamp et al., were carrier siblings of a variant probably inherited from one of their parents as a result of gonadal mosaicism. Moreover, other variant (p.Leu323Pro) has also been described by Vlaskamp et al. in a patient with a very similar phenotype except for the photosensitivity (Table 1). Furthermore, four more cases of the series from Vlaskamp et al. were previously reported in different publications [22,29,30,31]. Therefore, a total of 49 patients with a phenotype of EMA or EMA-like, carriers of 44 different pathogenic variants in SYNGAP1, have been reported (Table 1).

2.2. KIA2022/NEXMIF

NEXMIF (MIM *300524), also known as KIAA2022, is located on Xq13.3 [32]. NEXMIF encodes for the X-linked Intellectual Disability Protein Related to Neurite Extension (XPN) [33]. Highly expressed in the early brain development, it participates in neurite outgrowth and regulates neuronal migration and cellular adhesion, critical for developing neuronal circuits [33,34,35]. Loss of function of NEXMIF causes mental retardation X-linked 98 (MRX98; MIM # 300912) [36]. Like most of X-linked disorders, males tend to be more severely affected than females, whereas carrier females present a wide phenotypic variability and may be unaffected as a result of random X-chromosome inactivation (XCI). MRX98 is a neurodevelopmental disorder characterized in males by delayed motor milestones, lack of language development, moderate to profound ID, behavioral abnormalities such as ASD, hypotonia, postnatal growth restrictions, dysmorphic facial features, and often early-onset seizures [36,37]. Compared with its hemizygous male counterpart, the heterozygous female disease has less severe ID, but is more often associated with a severe and intractable myoclonic epilepsy [38,39].
In 2017, Borlot et al. published the case of a women with EMA syndrome carrier of a de novo NEXMIF deletion of 77Kb, detected by genome-wide oligonucleotide array, within a cohort of 143 adults with unexplained childhood-onset epilepsy and ID [40]. One year later, Myers et al. reported two other sisters diagnosed with MAE with a point mutation at NEXMIF (p.Arg322*) in their search of parental gonadal mosaicism in apparently de novo epileptic encephalopathies [41]. These two cases and their clinical features have recently been reviewed by Stamberger et al. (2021) [42]. Analyzing the phenotype of 87 patients with NEXMIF-related encephalopathy, 10 females were diagnosed with EMA, 2 of them with an earlier onset (one year or younger), and 5 more cases (2 males and 3 females) presented a combination of EMA and MAE syndromes, including the case reported by Myers et al. (2018)) (Table 2) [42]. According to Stamberger et al., there was no correlation between phenotype and XCI status in their series, based on 1) the comparison of females with skewed and random XCI and 2) the families with sisters each presenting skewed and random XCI (families F4 and F7). However, it is interesting that in those families, both cases with a skewed XCI were diagnosed with MAE-EMA syndrome without photosensitivity, and their sister with a random inactivation presented a less severe phenotype. Moreover, XCI testing was performed in blood cells, so that the inactivation rate in neuronal cells is in fact unknown. Additionally, it is remarkable that from the two males, one presented the alteration in a 30% somatic mosaicism, which may lead to clinical repercussions equivalent to XCI in females (Table 2). On the other hand, the majority of patients with NEXMIF-related encephalopathy had drug-resistant epilepsy. Although specific information for each patient was not available, only 16% of the patients from the total cohort were seizure-free. It is outstanding that only 7% of the females, compared to 47% of males, were seizure-free (p = 0.001 Fisher’s exact) [42].
Finally, two more female patients with alterations in the NEXMIF gene and a phenotype resembling EMA have been reported. Wu et al. (2020) described a woman with refractory epilepsy and EEG features similar to those described in EMA who was a carrier of a nonsense variant in NEXMIF (p.Leu355*) (Table 2) [43]. Samanta and Willis (2020) identified a frameshift mutation (p.Asp573Serfs*11) in a girl with intractable seizures diagnosed with EMA [2]. She presented a XCI classified as random (ratio 74:26) (Table 2). Based on the results of Viravan et al. (2011) on occipital lobe relation to eye movements in JS, Samanta and Wills proposed that functional brain mosaicism, as a result of random XCI, causes a cellular interference effect responsible for the variable symptoms, with a predominant involvement of a circuit encompassing the occipital cortex and the cortical/subcortical systems physiologically involved in the motor control of eye closure and eye movements [2,44].
Summarizing, a total of 15 female patients and 2 males (one of which was a mosaic for the alteration) have been reported with pathogenic variants in NEXMIF and clinical features of EMA (Table 2).

2.3. RORB

RORB (MIM * 601972) is located on 9p21.13 [45]. This gene encodes for a nuclear receptor, retinoid-related orphan receptor β (RORβ), involved in neuronal migration and differentiation [46]. Recent evidences have point out that mutations in this gene may contribute to susceptibility to epilepsy (MIM # 618357) [47].
In 2012, Bartnik et al., within a cohort of 102 patients, described a case with epilepsy and EM with generalized tonic-clonic seizures (GTCS), carrier of a 2.57 Mb deletion of 6 genes including RORB [48]. A few years later, Rudolf et al. (2016) described a family with four affected family members of EMA with rare GTCS carriers of a nonsense variant in RORB (p.Arg66*) [49]. Other sporadic cases were also reported by these authors with different alteration on RORB, including two more cases with absences, EM and GTCS (Table 3). Sadleir et al. (2020) identified four novel RORB variants in 11 affected patients from four families with different epileptic syndromes [50]. Of this series, one case was diagnosed with EMA and occipital lobe epilepsy, presenting also GTCS. Moreover, another patient from a different family also presented absences with EM and GTCS, but was diagnosed with juvenile absence epilepsy and idiopathic photosensitive occipital lobe epilepsy (Table 3). Although the predominant epileptic phenotype of this cohort was represented by the overlap of photosensitive generalized and occipital epilepsy, the authors underlined the important role of occipital cortex in starting epileptic discharge in idiopathic generalized epilepsies such as EMA [50]. Finally, Morea et al. (2021) described another case with a RORB variant diagnosed with EMA [11]
Even though only six patients with RORB alterations, from three different families, have been clearly diagnosed with EMA, interestingly, five of them also presented GTCS. Moreover, four more patients presented EM and absences with GTCS.

2.4. CHD2

CHD2 (MIM *602119) is located on 15q26.1 [51]. It encodes a member of the chromodomain helicase DNA-binding (CHD) family of proteins, of which the canonical function is the gene expression regulation by epigenetic changes in chromatin [52]. Loss of function of CHD2 is identified as a cause of developmental epileptic encephalopathy (DEE) [52], being associated with childhood-onset epileptic encephalopathy (EEOC; MIM #615369) and MAE (ORPHA 1942) [53,54]. Usually, it is also characterized by cognitive regression, ID, ASD-like phenotype, and resistance to antiepileptic drugs (AED) treatment [52].
Two publications of 2015 underline the association of CHD2 variants with photosensitivity in epilepsy, with seven patients with EMA between both articles [55,56]. Thomas et al. presented four cases with EMA, out of 10 patients with de novo CHD2 alterations [56]. The four cases also have GTCS; in addition, other common features associated to CHD2 deficiency were present (ID (4/4), ASD (3/4) and regression (3/4)) (Table 4). On the other hand, Galizia et al. presented the results of a CHD2 screening in a series of more than 500 patients with photosensitive epilepsy [55]. From 36 patients with EMA, all with photoparoxysmal response, three cases presented unique variants in CHD2 (Table 4). Based on the highest frequency of alterations among EMA patients compared to the rest of the series (8/544), the authors considered CHD2 as an important contributor to EMA [55].
Although the number of reported cases with EMA and pathogenic variants in CHD2 is low, it should also be considered in the screening for the genetic causes of this pathology.

2.5. Other Genes of Interest

Three publications present different patients with clinical diagnosis of EMA and with a pathogenic variant in three candidate genes for the disease: SLC2A1, KCNB1, and NAA10. The possible implication of these genes in EMA is discussed below.
SLC2A1 (MIM *138140) is located in 1p34.2 and encodes for the major glucose transporter in the brain, GLUT1 [58]. It is responsible for the well-known GLUT1 deficiency syndrome and encephalopathy characterized by a childhood-onset epilepsy refractory to treatment, but with a wide phenotypic variability (MIM #606777; ORPHA 71277) [59,60]. In this sense, Madann et al. reported a pathogenic variant in SLC2A1 in a family with Glut1-deficiency syndrome and JS [13]. The index case was a 9-year-old boy with intractable seizures since 4 months of age, and frequent absences with EM since 3 years of age. EEG showed eye closure sensitivity (eye closure triggered eyelid myoclonia with absences) and photosensitivity suggestive of EMA. He also presented multifocal seizures and paroxysms of intermittent involuntary gaze; sleep EEG showed multifocal interictal discharges and MRI was normal. Moreover, he had DD, mild ID, gait ataxia, scanning speech, and microcephaly. His father had a history of infantile-onset generalized epilepsy with generalized tonic-clonic seizures and ID, and his paternal uncle also had childhood-onset epilepsy. Metabolic results were suggestive of Glut1-deficiency syndrome; therefore, SLC2A1 was sequenced. A pathogenic variant was detected in both the index case and his father (c.376C>T; p.Arg126Cys), in a hotspot located at a transmembrane domain of the GLUT1, that had been previously reported in other cases with the metabolic syndrome and typical absence seizures or myoclonic absences as the most prevalent seizure type but without EM or EMA features [61,62]. After different unsuccessful treatments with AEDs (valproate, phenobarbital, benzodiazepines, phenytoin, and topiramate), once the molecular diagnosis was known, a ketogenic diet allowed complete seizure remission. However, since it was a targeted study, other genetic causes in the index case could contribute to or be responsible for the EMA phenotype. Furthermore, a screening study of SLC2A1 performed at 25 GGE-EM patients, including 8 cases of EMA, did not identify any variant that could confirm the role of SLC2A1 in EMA or other GEE with EM [63]. Based on these cases, although EMA could be included within the wide phenotypic spectrum for non-classic GLUT1 deficiency syndrome, more evidence is required.
KCNB1 (MIM *600397) is located in 20q13.13 [64]. It encodes for a brain potassium channel (Kv2.1) and its alteration causes a developmental epileptic encephalopathy (DEE26) (MIM # 616056) [65]. In 2017, from a cohort of six patients with de novo mutations in KCNB1, Marini et al. described two patients with a phenotype resembling EMA. The first case (patient 3) was carrier of a missense variant and was diagnosed with JS [66]. This patient was a 22-year-old female who had had epilepsy since 6 months of age, with bilateral myoclonic jerks. From 7 years of age, she developed absences with EM, frequently on eye closure or autoinduced, with persistent generalized PS. EEG showed generalized spike- and polyspike-wave discharges with a prominent generalized photoparoxysmal response, several episodes of myoclonia and absences with EM were recorded. She also presented myoclonic and tonic-clonic seizures. Trialed with several AEDs (Carbamazepine, valproic acid, levetiracetam, lamotrigine, ethosuximide, clonazepam, and topiramate), she finally became seizure-free with a combination of three of them. She had a delayed early development, evolving into mild cognitive impairment with motor and verbal dyspraxia, poor coordination, and moderate ID [66]. Her KCNB1 variant (c. 916C>T; p.Arg306Cys) was located in the voltage-sensor domain of the protein, which was previously reported in a patient with DD and infantile-onset seizure refractory to therapy but without EMA [67]. A new case with this mutation was also recently reported by Minardi et al. (2020) in a series of 71 patients with DEE [68]. However, few specific clinical data for this case were provided, and EM or EMA-like features were not included among them. On the other hand, the series reported by Marini et al. included a second case with generalized epilepsy with myoclonic seizures and EM with PS; however, unfortunately, this patient was not clearly identified in the article [66]. Therefore, although the data reported by Marini et al. were promising, stronger evidence and casuistry are required to consider this gene as a candidate for EMA.
Finally, NAA10 (MIM *300013) is located in Xq28 [69]. It encodes for an N-acetyltransferase and it is responsible for the Ogden syndrome in male carriers, a rare syndrome characterized by postnatal growth failure, developmental delay, hypotonia, and variable dysmorphic features (MIM # 300855) [70]. Although epilepsy is not associated to this syndrome, Valentine et al. (2018) describe a case with JS and a de novo variant in this gene [10]. The female patient, at the age of 3 years, presented initial seizures described as eye rolling and blank stares without generalized or focal body twitching. At first, she was diagnosed with absence epilepsy. Her seizures were frequently triggered by light stimulation. EEG showed a photoparoxysmal response, characterized by generalized spike-and-slow wave discharges, and numerous eyelid myoclonias with or without absences were recorded. Moreover, her seizures were intractable despite of the AED treatment (clonazepam, levetiracetam, lamotrigine, valproic acid, topiramate, rufinamide, clobazam, intravenous immunoglobulin, modified Atkins diet, and vagal nerve stimulator). Therefore, her epilepsy was consistent with EMA. She also presented DD, normal growth, self-injurious behavior and stereotypies, mild generalized hypotonia, and mild dysmorphisms (clinodactyly, mild ptosis, down slanting palpebral fissures, and tented upper lip) [10]. This patient’s NAA10 variant (c.346C>T; p.Arg116Trp) was previously reported in a female patient with random XIC and without known seizure activity, but with other clinical features (normal growth, moderate ID, hypotonia, attention deficit hyperactivity disorder (ADHD), and developmental coordination disorder) [71]. This variant was also reported by Popp et al. (2015) in a male patient with a more severe phenotype (postnatal growth retardation, severe ID, truncal hypotonia and hypertonia of extremities, autistic features, and aggressive behavior) [72]. Moreover, EEG under photic stimulation of this reported male showed generalized epileptic form activity. However, the clinical differences might be due to the inactivation pattern of X chromosome in females, as commented for NEXMIF above.
More cases need to be collected to be able to consider these genes as candidates for EMA. However, in the next-generation-sequencing era, the screening for alteration in those genes in EMA-like patients is manageable and will allow to clarify their promising role in the disease.

2.6. General Overview of Genetic Interactions

As mentioned before, the seven genes are expressed in the brain and their function are of great relevance for neuronal development, migration, function, or genetic regulation; however, there is no clear relationship among them. Looking for possible interactions, NEXMIF, highly expressed in fetal and adult brain [73], might be related to RORB, involved in neuronal migration and differentiation [46], and to SLC2A1, essential to provide the requirements of glucose at the brain among other tissues [74] (Figure 1) [75]. However, further studies, including in vitro and animal model assays, would be required to confirm this hypothesis.

2.7. Animal Models

Gene editing techniques have facilitated the generation of mouse models of human diseases; however, very little is known specifically about EMA. SYNGAP1 haploinsufficient young mice showed a reduced fluorothyl-induced seizure threshold and were prone to audiogenic seizures [76]. Furthermore, it is worth noting that in the former study, photostimulation evoked signals originating in the dentate gyrus were dramatically amplified as they spread through the hippocampus, instead of attenuated as it occurs in wild type animals. In addition, germline Syngap1 mutations in mice induced a persistent form of stabilized cortical hyperexcitability that lasted into adulthood, with the seizure threshold remaining reduced [77]. Interestingly, restoration of the gene in adult mice was able to improve behavioral and electrophysiological measures of memory and seizures [78]. Finally, the phenotype of the epileptogenesis in a Syngap1+/− mouse model have been recently described [79]. On the other hand, loss of NEXMIF gene expression in neurons of Knock-out (KO) mice results in a significant decrease in synapse density and synaptic protein expression [80]. These animals presented severe seizures, although further studies are required to characterize the epileptic phenotype in Nexmif KO mouse models.

3. Methods

Systematic literature research of PubMed was performed to identify eligible articles until 31 March 2021 (see Appendix A for complete search terms). The search identified 66 potential articles.
Reviews, clinical trials, and articles in a different language than English were excluded. We screened the titles and abstracts to check if they were within the scope of this review. In some cases, when abstracts were not available or more information was required to decide, a quick review of the whole article was carried out. At this stage, a total of 21 original articles, mainly case reports, containing data dealing with candidate genes for EMA, were obtained (Figure 2). For each of the seven selected genes, a literature research was also performed to look for more cases with an EMA-like phenotype. This selection was based on different number of cases for each gene: 49 for SYNGAP1 (Table 1); 17 for NEXMIF (Table 2); 10 for RORB (Table 3); 7 for CHD2 (Table 4); 2 cases for KCNB1; and 1 case each for SLC2A1 and NAA10. It is also remarkable that some of these cases were reported in different publications (Table 1, Table 2 and Table 4).

4. Conclusions

Loss of function of SYNGAP1, in addition to its association with DD, ID, and ASD, might be considered in epileptic patients with EMA, especially in those cases with earlier onset of EM, pharmacoresistance, or myoclonic or atonic seizures.
The phenotype spectrum of NEXMIF in females (or mosaic males) may also include EMA-like, probably associated with pharmacoresistance. Since this gene is located in the X chromosome, XCI in the brain can causes specific cellular mosaicism that might be responsible for the EMA phenotype in those cases.
In patients with alterations in SYNGAP1 or NEXMIF, clinical features of EMA may overlap with MAE syndrome, presenting manifestations of both pathologies. It is also remarkable that despite the relative low number of cases with pathogenic alteration in those genes, two families presented a probably gonadal mosaicism: one family presented with a frame shift mutation in SYNGAP1 (p.Leu150Valfs*6) and the other with a nonsense variant in NEXMIF (p.Arg322*) (Table 1 and Table 2). The recurrence of gonadal mosaicism is very variable depending on the disease but has to be taken into account for correct genetic counseling [81].
Regarding RORB and CHD2, although the number of cases with EMA is significantly lower, they should be taken into account, especially in those cases with GTCS.
In relation to other genes, a few cases of EMA have been reported with variants in SLC2A1, KCNB1, or NAA10. There is not enough information to establish a clear relationship, but as more and more exome and genome studies in EMA patients are performed, it is expected that their role in the molecular diagnosis of this pathology will be clarified.
It is remarkable that two of the seven genes are located in the X chromosome, NEXMIF and NAA10. Although males show an apparently more severe phenotype, females more often present severe and intractable epilepsy. As mentioned before, random XCI in the brain might lead to cellular interference responsible for the epilepsy and could also explain the higher prevalence of EMA in females.
Finally, an animal model is a great tool to study the pathobiology of complex human disease that affect organs such as the brain. Although mouse models have shown some results regarding SYNGAP1 and NEXMIF haploinsufficiency, no specific data have been collected for EMA. Therefore, to establish the possible interaction between these seven genes, or their direct implication into the pathology, further functional studies are required.

Author Contributions

Conceptualization, S.M. and J.B.-L.; methodology, S.M., I.G.-M., and F.J.F.-M.; resources, S.M. and I.G.-M.; data curation, S.M., A.C., and F.M.; writing—original draft preparation, S.M.; writing, review and editing, F.M. and A.C.; visualization, S.M. and J.B.-L.; supervision, J.B.-L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Mutua Madrileña Foundation (FMM), grant number 2019/0144. S.M. was funded by a postdoctoral “Sara Borell” grant CP20/00154 from the Health Institute Carlos III (Spanish Ministry of Science and Innovation).

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

PubMed search terms:
  • ((Jeavons Syndrome) OR (epilepsy with eyelid myoclonias)) AND (genetic OR gene OR genes)
  • (“Eyelid myoclonia with absences”) AND (genetic OR gene OR genes)

Abbreviations

ADHDAttention deficit hyperactivity disorder
AEDAntiepileptic drugs
ASDAutism spectrum disorder
CHDChromodomain helicase DNA-binding
DDDevelopmental delay
DEEDevelopmental epileptic encephalopathy
EEOCChildhood-onset epileptic encephalopathy
EEGElectroencephalogram
EMEyelid myoclonia
EMAEyelid myoclonia with absences
GGEGenetic generalized epilepsies
GTCSGeneralized tonic-clonic seizures
IDIntellectual disability
ILAEInternational League Against Epilepsy
IPSIntermittent photic stimulation
JSJeavons syndrome
KOKnock-out
MAEMyoclonic-atonic epilepsy
MRX98Mental retardation X-linked 98
PSPhotosensitivity
XCIX-Chromosome Inactivation
XPNX-linked Intellectual Disability Protein Related to Neurite Extension

References

  1. Jeavons, P.M. Nosological Problems of Myoclonic Epilepsies in Childhood and Adolescence. Dev. Med. Child Neurol. 1977, 19, 3–8. [Google Scholar] [CrossRef]
  2. Samanta, D.; Willis, E. KIAA2022-related disorders can cause Jeavons (eyelid myoclonia with absence) syndrome. Acta Neurol. Belg. 2020, 120, 205–207. [Google Scholar] [CrossRef] [PubMed]
  3. Striano, S.; Capovilla, G.; Sofia, V.; Romeo, A.; Rubboli, G.; Striano, P.; Trenité, D.K.N. Eyelid myoclonia with absences (Jeavons syndrome): A well-defined idiopathic generalized epilepsy syndrome or a spectrum of photosensitive conditions? Epilepsia 2009, 50, 15–19. [Google Scholar] [CrossRef]
  4. Striano, S. Eyelid myoclonia with absences: An overlooked epileptic syndrome?Les myoclonies des paupières avec absences: Un syndrome épileptique sous-estimé ? Neurophysiol. Clin. Neurophysiol. 2002, 32, 287–296. [Google Scholar] [CrossRef]
  5. International League against Epilepsy. Epilepsy with Eyelid Myoclonias. Available online: https://www.epilepsydiagnosis.org/syndrome/emwa-overview.html (accessed on 1 April 2021).
  6. Parker, A.; Gardiner, R.; Panayiotopoulos, C.P.; Agathonikou, A.; Ferrie, C.D. Observations on families with eyelid myoclonia with absences. In Eyelid Myoclonia with Absences; Duncan, J.S., Panayiotopoulos, C.P., Eds.; John Libbey Ltd.: London, UK, 1996; pp. 107–115. [Google Scholar]
  7. Demarco, P. Eyelid Myoclonia with Absences (EMA) in Two Monovular Twins. Clin. EEG Neurosci. 1989, 20, 193–195. [Google Scholar] [CrossRef] [PubMed]
  8. Adachi, M.; Inoue, T.; Tsuneishi, S.; Takada, S.; Nakamura, H. Eyelid myoclonia with absences in monozygotic twins. Pediatr. Int. 2005, 47, 343–347. [Google Scholar] [CrossRef] [PubMed]
  9. Striano, P. Orphanet Encyclopedia Jeavons Syndrome. Available online: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=139431#:~:text=Disease (accessed on 1 April 2021).
  10. Valentine, V.; Sogawa, Y.; Rajan, D.; Ortiz, D. A case of de novo NAA10 mutation presenting with eyelid myoclonias (AKA Jeavons syndrome). Seizure 2018, 60, 120–122. [Google Scholar] [CrossRef] [PubMed][Green Version]
  11. Morea, A.; Boero, G.; Demaio, V.; Francavilla, T.; La Neve, A. Eyelid myoclonia with absences, intellectual disability and attention deficit hyperactivity disorder: A clinical phenotype of the RORB gene mutation. Neurol. Sci. 2021, 42, 2059–2062. [Google Scholar] [CrossRef] [PubMed]
  12. Klitten, L.L.; Møller, R.S.; Nikanorova, M.; Silahtaroglu, A.; Hjalgrim, H.; Tommerup, N. A balanced translocation disrupts SYNGAP1 in a patient with intellectual disability, speech impairment, and epilepsy with myoclonic absences (EMA). Epilepsia 2011, 52, 190–193. [Google Scholar] [CrossRef]
  13. Madaan, P.; Jauhari, P.; Chakrabarty, B.; Gulati, S. Jeavons syndrome in a family with GLUT1-deficiency syndrome. Seizure 2019, 71, 158–160. [Google Scholar] [CrossRef] [PubMed]
  14. Dragoumi, P.; Emery, J.; Chivers, F.; Brady, M.; Desurkar, A.; Cross, J.H.; Das, K.B. Crossing the lines between epilepsy syndromes: A myoclonic epilepsy variant with prominent eyelid myoclonia and atonic components. Epileptic Disord. 2018, 20, 35–41. [Google Scholar] [CrossRef] [PubMed]
  15. Reyhani, A.; Özkara, Ç. Pitfalls in the diagnosis of Jeavons syndrome: A study of 32 cases and review of the literature. Epileptic Disord. 2020, 22, 281–290. [Google Scholar] [CrossRef] [PubMed]
  16. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, M.D. SYNAPTIC RAS-GTPase-ACTIVATING PROTEIN 1; SYNGAP1. Number: * 603384. Available online: https://www.omim.org/entry/603384 (accessed on 1 April 2021).
  17. Gene [Internet]. Bethesda (MD): National Library of Medicine (US) National Center for Biotechnology Information. SYNGAP1 Synaptic Ras GTPase Activating Protein 1 [Homo Sapiens (Human)] Gene ID: 8831. Available online: https://www.ncbi.nlm.nih.gov/gene/8831 (accessed on 1 April 2021).
  18. Jeyabalan, N.; Clement, J.P. SYNGAP1: Mind the gap. Front. Cell. Neurosci. 2016, 10, 1–16. [Google Scholar] [CrossRef] [PubMed][Green Version]
  19. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, M.D. MENTAL RETARDATION, AUTOSOMAL DOMINANT 5; MRD5. Number: # 612621. Available online: https://www.omim.org/entry/612621 (accessed on 1 April 2021).
  20. Matricardi, S. Orphanet Encyclopedia SYNGAP1-Related Developmental and Epileptic Encephalopathy. Available online: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=28070&Disease_Disease_Search_diseaseGroup=SYNGAP1&Disease_Disease_Search_diseaseType=Gen&Disease (accessed on 1 April 2021).
  21. Mignot, C.; von Stülpnagel, C.; Nava, C.; Ville, D.; Sanlaville, D.; Lesca, G.; Rastetter, A.; Gachet, B.; Marie, Y.; Korenke, G.C.; et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. J. Med. Genet. 2016, 53, 511–522. [Google Scholar] [CrossRef][Green Version]
  22. Berryer, M.H.; Hamdan, F.F.; Klitten, L.L.; Møller, R.S.; Carmant, L.; Schwartzentruber, J.; Patry, L.; Dobrzeniecka, S.; Rochefort, D.; Neugnot-Cerioli, M.; et al. Mutations in SYNGAP1 Cause Intellectual Disability, Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency. Hum. Mutat. 2013, 34, 385–394. [Google Scholar] [CrossRef][Green Version]
  23. Vlaskamp, D.R.M.; Shaw, B.J.; Burgess, R.; Mei, D.; Montomoli, M.; Xie, H.; Myers, C.T.; Bennett, M.F.; Xiangwei, W.; Williams, D.; et al. SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy. Neurology 2019, 92, E96–E107. [Google Scholar] [CrossRef][Green Version]
  24. Lo Barco, T.; Kaminska, A.; Solazzi, R.; Cancés, C.; Barcia, G.; Chemaly, N.; Fontana, E.; Desguerre, I.; Canafoglia, L.; Hachon Le Camus, C.; et al. Syngap1-Dee: A visual sensitive epilepsy. Clin. Neurophysiol. 2021, 132, 841–850. [Google Scholar] [CrossRef]
  25. Kuchenbuch, M.; D’Onofrio, G.; Chemaly, N.; Barcia, G.; Teng, T.; Nabbout, R. Add-on cannabidiol significantly decreases seizures in 3 patients with SYNGAP1 developmental and epileptic encephalopathy. Epilepsia Open 2020, 5, 496–500. [Google Scholar] [CrossRef]
  26. Okazaki, T.; Saito, Y.; Hiraiwa, R.; Saitoh, S.; Kai, M.; Adachi, K.; Nishimura, Y.; Nanba, E.; Maegaki, Y. Pharmacoresistant epileptic eyelid twitching in a child with a mutation in SYNGAP1. Epileptic Disord. 2017, 19, 339–344. [Google Scholar] [CrossRef]
  27. Redin, C.; Gérard, B.; Lauer, J.; Herenger, Y.; Muller, J.; Quartier, A.; Masurel-Paulet, A.; Willems, M.; Lesca, G.; El-Chehadeh, S.; et al. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. J. Med. Genet. 2014, 51, 724–736. [Google Scholar] [CrossRef]
  28. von Stülpnagel, C.; Hartlieb, T.; Borggräfe, I.; Coppola, A.; Gennaro, E.; Eschermann, K.; Kiwull, L.; Kluger, F.; Krois, I.; Møller, R.S.; et al. Chewing induced reflex seizures (“eating epilepsy”) and eye closure sensitivity as a common feature in pediatric patients with SYNGAP1 mutations: Review of literature and report of 8 cases. Seizure 2019, 65, 131–137. [Google Scholar] [CrossRef] [PubMed][Green Version]
  29. Carvill, G.L.; Heavin, S.B.; Yendle, S.C.; McMahon, J.M.; O’Roak, B.J.; Cook, J.; Khan, A.; Dorschner, M.O.; Weaver, M.; Calvert, S.; et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat. Genet. 2013, 45, 825–830. [Google Scholar] [CrossRef][Green Version]
  30. Parrini, E.; Marini, C.; Mei, D.; Galuppi, A.; Cellini, E.; Chiti, L.; Rutigliano, D.; Bianchini, C.; Virdò, S.; De, D.; et al. Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes. Hum. Mutat. 2017, 38, 216–225. [Google Scholar] [CrossRef] [PubMed][Green Version]
  31. Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature 2017, 542, 433–438. [Google Scholar] [CrossRef] [PubMed]
  32. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, M.D. NEURITE EXTENSION AND MIGRATION FACTOR; NEXMIF. Number: * 300524. Available online: https://www.omim.org/entry/300524 (accessed on 1 April 2021).
  33. Cantagrel, V.; Haddad, M.R.; Ciofi, P.; Andrieu, D.; Lossi, A.M.; van Maldergem, L.; Roux, J.C.; Villard, L. Spatiotemporal expression in mouse brain of Kiaa2022, a gene disrupted in two patients with severe mental retardation. Gene Expr. Patterns 2009, 9, 423–429. [Google Scholar] [CrossRef] [PubMed]
  34. Ishikawa, T.; Miyata, S.; Koyama, Y.; Yoshikawa, K.; Hattori, T.; Kumamoto, N.; Shingaki, K.; Katayama, T.; Tohyama, M. Transient expression of Xpn, an XLMR protein related to neurite extension, during brain development and participation in neurite outgrowth. Neuroscience 2012, 214, 181–191. [Google Scholar] [CrossRef] [PubMed]
  35. Magome, T.; Hattori, T.; Taniguchi, M.; Ishikawa, T.; Miyata, S.; Yamada, K.; Takamura, H.; Matsuzaki, S.; Ito, A.; Tohyama, M.; et al. XLMR protein related to neurite extension (Xpn/KIAA2022) regulates cell-cell and cell-matrix adhesion and migration. Neurochem. Int. 2013, 63, 561–569. [Google Scholar] [CrossRef] [PubMed]
  36. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, M.D. MENTAL RETARDATION, X-LINKED 98; MRX98. Number: # 300912. Available online: https://www.omim.org/entry/300912 (accessed on 1 April 2021).
  37. Lorenzo, M.; Stolte-Dijkstra, I.; van Rheenen, P.; Smith, R.G.; Scheers, T.; Walia, J.S. Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with KIAA2022 pathogenic variants and review of the literature. Am. J. Med. Genet. Part A 2018, 176, 1455–1462. [Google Scholar] [CrossRef]
  38. de Lange, I.M.; Helbig, K.L.; Weckhuysen, S.; Møller, R.S.; Velinov, M.; Dolzhanskaya, N.; Marsh, E.; Helbig, I.; Devinsky, O.; Tang, S.; et al. De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy. J. Med. Genet. 2016, 53, 850–858. [Google Scholar] [CrossRef][Green Version]
  39. Webster, R.; Cho, M.T.; Retterer, K.; Millan, F.; Nowak, C.; Douglas, J.; Ahmad, A.; Raymond, G.V.; Johnson, M.R.; Pujol, A.; et al. De novo loss of function mutations in KIAA2022 are associated with epilepsy and neurodevelopmental delay in females. Clin. Genet. 2017, 91, 756–763. [Google Scholar] [CrossRef]
  40. Borlot, F.; Regan, B.M.; Bassett, A.S.; Stavropoulos, D.J.; Andrade, D.M. Prevalence of pathogenic copy number variation in adults with pediatric-onset epilepsy and intellectual disability. JAMA Neurol. 2017, 74, 1301–1311. [Google Scholar] [CrossRef] [PubMed]
  41. Myers, C.T.; Hollingsworth, G.; Muir, A.M.; Schneider, A.L.; Thuesmunn, Z.; Knupp, A.; King, C.; Lacroix, A.; Mehaffey, M.G.; Berkovic, S.F.; et al. Parental Mosaicism in “De Novo” Epileptic Encephalopathies. N. Engl. J. Med. 2018, 378, 1646–1648. [Google Scholar] [CrossRef] [PubMed]
  42. Stamberger, H.; Hammer, T.B.; Gardella, E.; Vlaskamp, D.R.M.; Bertelsen, B.; Mandelstam, S.; de Lange, I.; Zhang, J.; Myers, C.T.; Fenger, C.; et al. NEXMIF encephalopathy: An X-linked disorder with male and female phenotypic patterns. Genet. Med. 2021, 23, 363–373. [Google Scholar] [CrossRef] [PubMed]
  43. Wu, D.; Ji, C.; Chen, Z.; Wang, K. Novel NEXMIF gene pathogenic variant in a female patient with refractory epilepsy and intellectual disability. Am. J. Med. Genet. Part A 2020, 182, 2765–2772. [Google Scholar] [CrossRef] [PubMed]
  44. Viravan, S.; Go, C.; Ochi, A.; Akiyama, T.; Carter Snead, O.; Otsubo, H. Jeavons syndrome existing as occipital cortex initiating generalized epilepsy. Epilepsia 2011, 52, 1273–1279. [Google Scholar] [CrossRef]
  45. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, M.D. RAR-RELATED ORPHAN RECEPTOR B; RORB. Number: * 601972. Available online: https://www.omim.org/entry/601972 (accessed on 1 April 2021).
  46. Liu, H.; Aramaki, M.; Fu, Y.; Forrest, D. Retinoid-Related Orphan Receptor β and Transcriptional Control of Neuronal Differentiation, 1st ed.; Elsevier Inc.: New York, NY, USA, 2017; Volume 125. [Google Scholar]
  47. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, M.D. EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 15; EIG15. Number: # 618357. Available online: https://www.omim.org/entry/618357 (accessed on 1 April 2021).
  48. Bartnik, M.; Szczepanik, E.; Derwińska, K.; Wiśniowiecka-Kowalnik, B.; Gambin, T.; Sykulski, M.; Ziemkiewicz, K.; Keogonekdzior, M.; Gos, M.; Hoffman-Zacharska, D.; et al. Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 2012, 159, 760–771. [Google Scholar] [CrossRef]
  49. Rudolf, G.; Lesca, G.; Mehrjouy, M.M.; Labalme, A.; Salmi, M.; Bache, I.; Bruneau, N.; Pendziwiat, M.; Fluss, J.; De Bellescize, J.; et al. Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy. Eur. J. Hum. Genet. 2016, 24, 1761–1770. [Google Scholar] [CrossRef][Green Version]
  50. Sadleir, L.G.; de Valles-Ibáñez, G.; King, C.; Coleman, M.; Mossman, S.; Paterson, S.; Nguyen, J.; Berkovic, S.F.; Mullen, S.; Bahlo, M.; et al. Inherited RORB pathogenic variants: Overlap of photosensitive genetic generalized and occipital lobe epilepsy. Epilepsia 2020, 61, e23–e29. [Google Scholar] [CrossRef]
  51. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, M.D. CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 2; CHD2. Number: * 602119. Available online: https://www.omim.org/entry/602119 (accessed on 1 April 2021).
  52. Wilson, M.M.; Henshall, D.C.; Byrne, S.M.; Brennan, G.P. Chd2-related cns pathologies. Int. J. Mol. Sci. 2021, 22, 588. [Google Scholar] [CrossRef] [PubMed]
  53. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, M.D. EPILEPTIC ENCEPHALOPATHY, CHILDHOOD-ONSET; EEOC. Number: # 615369. Available online: https://www.omim.org/entry/615369 (accessed on 1 April 2021).
  54. Helbig, I. Orphanet Encyclopedia Myoclonic-Astatic Epilepsy. Available online: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=891&Disease_Disease_Search_diseaseGroup=CHD2&Disease_Disease_Search_diseaseType=Gen&Enfermedad(es) (accessed on 1 April 2021).
  55. Galizia, E.C.; Myers, C.T.; Leu, C.; De Kovel, C.G.F.; Afrikanova, T.; Cordero-Maldonado, M.L.; Martins, T.G.; Jacmin, M.; Drury, S.; Chinthapalli, V.K.; et al. CHD2 variants are a risk factor for photosensitivity in epilepsy. Brain 2015, 138, 1198–1207. [Google Scholar] [CrossRef][Green Version]
  56. Thomas, R.H.; Zhang, L.M.; Carvill, G.L.; Archer, J.S.; Heavin, S.B.; Mandelstam, S.A.; Craiu, D.; Berkovic, S.F.; Gill, D.S.; Mefford, H.C.; et al. CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures. Neurology 2015, 84, 951–958. [Google Scholar] [CrossRef] [PubMed][Green Version]
  57. Mullen, S.A.; Carvill, G.L.; Bellows, S.; Bayly, M.A.; Berkovic, S.F.; Dibbens, L.M.; Scheffer, I.E.; Mefford, H.C. Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology 2013, 81, 1507–1514. [Google Scholar] [CrossRef] [PubMed][Green Version]
  58. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, M.D. SOLUTE CARRIER FAMILY 2 (FACILITATED GLUCOSE TRANSPORTER), MEMBER 1; SLC2A1. Number: * 138140. Available online: https://www.omim.org/entry/138140 (accessed on 1 April 2021).
  59. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, M.D. GLUT1 DEFICIENCY SYNDROME 1; GLUT1DS1. Number: # 606777. Available online: https://omim.org/entry/606777 (accessed on 1 April 2021).
  60. De Lonlay, P.P. Orphanet Encyclopedia Classic Glucose Transporter Type 1 Deficiency Syndrome. Available online: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=10999&Disease_Disease_Search_diseaseGroup=GLUt1&Disease_Disease_Search_diseaseType=Pat&Disease (accessed on 1 April 2021).
  61. Gökben, S.; Yilmaz, S.; Klepper, J.; Serdaroǧlu, G.; Tekgül, H. Video/EEG recording of myoclonic absences in GLUT1 deficiency syndrome with a hot-spot R126C mutation in the SLC2A1 gene. Epilepsy Behav. 2011, 21, 200–202. [Google Scholar] [CrossRef] [PubMed]
  62. Diomedi, M.; Gan-Or, Z.; Placidi, F.; Dion, P.A.; Szuto, A.; Bengala, M.; Rouleau, G.A.; Gigli, G.L. A 23 years follow-up study identifies GLUT1 deficiency syndrome initially diagnosed as complicated hereditary spastic paraplegia. Eur. J. Med. Genet. 2016, 59, 564–568. [Google Scholar] [CrossRef][Green Version]
  63. Altıokka-Uzun, G.; Özdemir, Ö.; Uğur-İşeri, S.; Bebek, N.; Gürses, C.; Özbek, U.; Baykan, B. Investigation of SLC2A1 gene variants in genetic generalized epilepsy patients with eyelid myoclonia. Epileptic Disord. 2018, 20, 396–400. [Google Scholar] [CrossRef]
  64. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, M.D. POTASSIUM CHANNEL, VOLTAGE-GATED, SHAB-RELATED SUBFAMILY, MEMBER 1; KCNB1. Number: * 600397. Available online: https://www.omim.org/entry/600397 (accessed on 1 April 2021).
  65. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, M.D. DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 26; DEE26. Number: # 616056. Available online: https://www.omim.org/entry/616056 (accessed on 1 April 2021).
  66. Marini, C.; Romoli, M.; Parrini, E.; Costa, C.; Mei, D.; Mari, F.; Parmeggiani, L.; Procopio, E.; Metitieri, T.; Cellini, E.; et al. Clinical features and outcome of 6 new patients carrying de novo KCNB1 gene mutations. Neurol. Genet. 2017, 3, e206. [Google Scholar] [CrossRef][Green Version]
  67. Saitsu, H.; Akita, T.; Tohyama, J.; Goldberg-Stern, H.; Kobayashi, Y.; Cohen, R.; Kato, M.; Ohba, C.; Miyatake, S.; Tsurusaki, Y.; et al. De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing. Sci. Rep. 2015, 5, 1–14. [Google Scholar] [CrossRef][Green Version]
  68. Minardi, R.; Licchetta, L.; Baroni, M.C.; Pippucci, T.; Stipa, C.; Mostacci, B.; Severi, G.; Toni, F.; Bergonzini, L.; Carelli, V.; et al. Whole-exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late. Clin. Genet. 2020, 98, 477–485. [Google Scholar] [CrossRef]
  69. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, M.D. N-ALPHA-ACETYLTRANSFERASE 10, NatA CATALYTIC SUBUNIT; NAA10. Number: * 300013. Available online: https://www.omim.org/entry/300013 (accessed on 1 April 2021).
  70. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, M.D. OGDEN SYNDROME. Number: # 300855. Available online: https://www.omim.org/entry/300855 (accessed on 1 April 2021).
  71. Saunier, C.; Støve, S.I.; Popp, B.; Gérard, B.; Blenski, M.; AhMew, N.; de Bie, C.; Goldenberg, P.; Isidor, B.; Keren, B.; et al. Expanding the Phenotype Associated with NAA10-Related N-Terminal Acetylation Deficiency. Hum. Mutat. 2016, 37, 755–764. [Google Scholar] [CrossRef] [PubMed][Green Version]
  72. Popp, B.; Støve, S.I.; Endele, S.; Myklebust, L.M.; Hoyer, J.; Sticht, H.; Azzarello-Burri, S.; Rauch, A.; Arnesen, T.; Reis, A. De novo missense mutations in the NAA10 gene cause severe non-syndromic developmental delay in males and females. Eur. J. Hum. Genet. 2015, 23, 602–609. [Google Scholar] [CrossRef][Green Version]
  73. Cantagrel, V.; Lossi, A.M.; Boulanger, S.; Depetris, D.; Mattei, M.G.; Gecz, J.; Schwartz, C.E.; Van Maldergem, L.; Villard, L. Disruption of a new X linked gene highly expressed in brain in a family with two mentally retarded males. J. Med. Genet. 2004, 41, 736–742. [Google Scholar] [CrossRef] [PubMed][Green Version]
  74. Xiuli, G.; Meiyu, G.; Guanhua, D. Glucose transporter 1, distribution in the brain and in neural disorders: Its relationship with transport of neuroactive drugs through the blood-brain barrier. Biochem. Genet. 2005, 43, 175–187. [Google Scholar] [CrossRef] [PubMed]
  75. Warde-Farley, D.; Donaldson, S.L.; Comes, O.; Zuberi, K.; Badrawi, R.; Chao, P.; Franz, M.; Grouios, C.; Kazi, F.; Lopes, C.T.; et al. The GeneMANIA prediction server: Biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 2010, 38, 214–220. [Google Scholar] [CrossRef] [PubMed]
  76. Clement, J.P.; Aceti, M.; Creson, T.K.; Ozkan, E.D.; Shi, Y.; Reish, N.J.; Almonte, A.G.; Miller, B.H.; Wiltgen, B.J.; Miller, C.A.; et al. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 2012, 151, 709–723. [Google Scholar] [CrossRef][Green Version]
  77. Ozkan, E.D.; Creson, T.K.; Kramár, E.A.; Rojas, C.; Seese, R.R.; Babyan, A.H.; Shi, Y.; Lucero, R.; Xu, X.; Noebels, J.L.; et al. Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons. Neuron 2014, 82, 1317–1333. [Google Scholar] [CrossRef][Green Version]
  78. Creson, T.K.; Rojas, C.; Hwaun, E.; Vaissiere, T.; Kilinc, M.; Jimenez-Gomez, A.; Holder, J.L.; Tang, J.; Colgin, L.L.; Miller, C.A.; et al. Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior. Elife 2019, 8, e46752. [Google Scholar] [CrossRef] [PubMed]
  79. Sullivan, B.J.; Ammanuel, S.; Kipnis, P.A.; Araki, Y.; Huganir, R.L.; Kadam, S.D. Low-Dose Perampanel Rescues Cortical Gamma Dysregulation Associated With Parvalbumin Interneuron GluA2 Upregulation in Epileptic Syngap1 +/− Mice. Biol Psychiatry 2020, 87, 829–842. [Google Scholar] [CrossRef] [PubMed][Green Version]
  80. Gilbert, J.; O’Connor, M.; Templet, S.; Moghaddam, M.; Di Via Ioschpe, A.; Sinclair, A.; Zhu, L.Q.; Xu, W.; Man, H.Y. NExMIF/Kidlia knock-out mouse demonstrates autism-like behaviors, memory deficits, and impairments in synapse formation and function. J. Neurosci. 2020, 40, 237–254. [Google Scholar] [CrossRef] [PubMed]
  81. Zlotogora, J. Germ line mosaicism. Hum. Genet. 1998, 102, 381–386. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Prediction of the genetic interactions performed by Genemania (http://genemania.org/ (accessed on 15 April 2021) [75].
Figure 1. Prediction of the genetic interactions performed by Genemania (http://genemania.org/ (accessed on 15 April 2021) [75].
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Figure 2. Flow diagram summarizing the systematic search, screening, and studies selection for this review.
Figure 2. Flow diagram summarizing the systematic search, screening, and studies selection for this review.
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Table 1. Summary of the cases reported with pathogenic (or probably pathogenic) alteration in SYNGAP1 (NM_006772) and an EMA/EMA-like phenotype.
Table 1. Summary of the cases reported with pathogenic (or probably pathogenic) alteration in SYNGAP1 (NM_006772) and an EMA/EMA-like phenotype.
A
ReferenceKlitten 2011 1Mingot 2016 aMingot 2016Mingot 2016Okazaki 2017 bVlaskamp 2019 1Vlaskamp 2019 1Vlaskamp 2019 1,2Vlaskamp 2019 1,2
Patient 111214 1457
Clinical featuresgenderMaleMaleFemaleFemaleMaleMaleFemaleMaleMale
Age25 yr3 yr22 yr8 yr4 yr3 yr 10 months8 yr 3 months11 yr 2 months17
DD/ID+ (Severe)+ (Severe)+ (Severe)+ (Mild)+- (FSIQ: 80, low average)+ (Mild)+ (Moderate)+ (Severe)
Behavioral featuresASD traits, anxious behaviorRepetitive behaviours, stereotypiesStereotypiesASD, stereotypiesNR-ASD traits, mild tantrums, aggression, high pain thresholds, sleeping problems-ASD, regression severe tantrums, self-injury, aggression, high pain threshold, sleeping problems
Other parametresAbsence of languageAbsence of language, truncal hypotonia, swallowing difficultiesAbsence of language, mild gait ataxia, flexion deformity of left hip, hyperlordotic lumbar spine, microcephalyMotor slowness and moderate akinesia, ataxic gait, truncal hypotonia, dystonic postures of hands and feet, plastic hypertoniaHypotonia, hypersalivation-Hypotonia -Hypotonia, unsteady gait, reflux, obstipation, eating difficulties, benign bone tumor
EpilepsyAge of onset13 months2 yr1 yr5 yr1 yr and 5 months16 months2.5 yr11 months2 yr
Abscence seizures+ (MA, AA)NR+ (AA)+ (MA)NR+ (MA)NRNRNR
Eyelid myoclonia+ (eyelid winking)+++NR++++
PhotosensitivityNR+NR++++++
Other seizuresDA with MJFSFS, MJ NRUpward eye deviation, motion arrest, loss of consciousness, and eyelid twitching. Triggered by crying and photosensivilityMS. Triggered by PS, sounds, sleep deprivation and fatigueMSFS, MAt, bilateral TCS. Triggered by PS, sleep deprivation and fatigueBilateral TCS, MS, FIAS, DA. Triggered by PS, eye closure and eating
EEGothersInterictal: generalized synchronous 3–7 Hz (P)SWAbnormal BG, generalized slowing, EM, and generalized seizure patterns. Triggered by photosensivilityBursts of spikes and slow waves in the occipital region after eye closure. Triggered by FOSIctal: bursts of diffuse PSW with posterior predominance after eyes closer and photic stimulation. Triggered by FOS and PSIctal: diffuseslow or SW activity with occipitalto central predominance. Interictal: bilateral frontal spikes. Sleep: rhythmic, generalized 2–3-Hz delta activity, without visible seizures. Normal BGIctal: GSW (myoclonic). Interictal: GSWBG slow. Interrictal: Frequent 2.5–4 Hz GSW, after eye closure in trains, MFDInterictal: GPWsleep: frequent seizures while falling asleep
Cranial MRI NRNormalNormalNormalNormalNormalNormalNormalNR
AED TreatmentVPA, LTG, CLB VPALEV, TPMLEV, ETXCBZ, VPA, LEV, ETX, LTGVPAVPA, LEV, LTG, ETX, CBDVPAVPA, CLZ, CBZ
GeneticinformationGenetic testkaryotypegene panel NGSWESWESNGS panelNRNRNRNR
Genomic change (Hg19)NRchr6:33406650; C>C/Tchr6:33408514; C>C/Tchr6:33409458_
33409461delAGCG
chr6:33414346; G>G/Achr6:33391277; C>C/Tchr6:33399974; CA>CA/Cchr6:333400498_
33400501delAAAC
chr6:33400501; C>C/T
cDNA/aa change(truncate gene) ish, 46,XY, t(6;22)(p21.32;q11.21)dnc.1630C>T, p.Arg544*c.1685C>T, p.Pro562Leuc.2214_2217delAGCG, p.Glu739Glyfs*20c.3583-6G>A, p.Val1195Alafs*27c.91C>T, p.Arg31*c.333delA, p.Lys114Serfs*20c.424_
427delAAAC, p.Lys142Glufs*31
c.427C>T, p.Arg143*
Inheritancede novode novode novode novo(parent not tested)de novode novode novode novo
Others informationFISH (probe RP11.497A24)VUS inherited from the mother: SCN9A: c.4282G>A and c.5624G>A; ARX: c.1462A>G--Karyotype and anlysis for AS with normal results. CSF glucose normal
Family History- (epilepsy)---- (epilepsy or ID)- (seizures, ID or ASD)- (seizures, ID or ASD)- (seizures, ID or ASD)Sister, father, and many paternal relatives with learning difficulties. Maternal cousin ASD
B
ReferenceVlaskamp 2019 1,2/Von Stülpnagel 2019Vlaskamp 2019 1,2/Von Stülpnagel 2019Vlaskamp 2019 1,2Vlaskamp 2019 1,2Vlaskamp 2019 1,2/The DDD Study 2017Vlaskamp 2019 1,2Vlaskamp 2019 1Vlaskamp 2019 1Vlaskamp 2019 1,2Vlaskamp 2019 1,2
Patient8/79/8111213/2411517182021
Clinical featuresgenderfemalefemalemalefemalemalefemalefemalemalefemalefemale
Age8 yr6 yr6 yr4 yr 8 months7 yr 10 months9.5 yr5 yr 2 months5 yr 10 months15 yr 1 months10 yr 5 months
DD/ID+ (moderate-severe)+ (moderate-severe)+ (severe)+ (severe)+ (severe)+ (severe)+ (severe)+ (severe)+ (moderate)+ (moderate)
Behavioral featuresregression, tantrums, self-injury, tichotillomania, high pain threshold, eating disorder, sleeping problems ASD, echolalia, high pain threshold, eating disorder, sleeping problemsaggression, high pain thresholdregression, ASD, tantrums, self-injury, aggression. high pain threshold, sleep problemsTantrums, aggression, high pain threshold, sleep problemsASD traits, stereotypes, odontoprisis, high pain thresholdodontoprisis, high pain thresholdregression, obsession, self-injury, aggression, high pain threshold, sleep problems, eating disorderASD, self-injury, aggression, sleep problems, high pain threshold, oral hypersensitivityregression, ASD, severe tantrums, self-injury, aggression, sleep problems, high pain threshold, oral hypersensitivity
Other parametreshypotonia, hyperlaxity, 2 café au lait spots, small capillary hemangioma, constipation, hearing loss after infection/ataxia, problems in fine motor skillshypotonia, hyperlaxity, hearing loss after recurrent otitis/ataxia hypotonia, ataxia, constipation, reflux, absence of languagepes planus, strabismus, constipation, hearing lossnystagmusCongenital hipdyslocation, absence of languagehypotonia, poor balance and coordination, absence of languagehypotonia, hypermobility, scoliosos, constipationcongenital nystagmus, hypotonia, a few cafe au lait macules, constipation
EpilepsyAge of onset8/16 months12–13 months4 yr23 months2 yr2 yr3.5 yr3 yr12–14 months2 yrs
Abscence seizures++NR+ (AA)NRNRNRNR+ (MA)
Eyelid myoclonia++++++++++
Photosensitivity++NRNRNRNR+NR++
Other seizuresMS, MAt. Triggered by touch and thinking of eating/GS, MJ, atonic drops. Reflex seizures while chewingMS, MAt. Triggered by thinking of eating/GS, MJ, atonic drops. Reflex seizures while chewingMS, DA. Triggered by fever and infectionMS, ASMS, AS, bilateral TCS. Triggered by eating (chocolate), fever and fatigueBi- and unilateral TCSMJ, MSTriggered by fatigueatonic DA, nocturnal TS. Triggered by PS and eatingMJ, bilateral TCS
EEGothersIntal: 3 Hz GSW (EM-MAt). Interictal:G(P)SW Intal: 2.5–3.5 Hz GSW (EM-MAt).
Inerictal: 2.5–3.5 Hz GSW
BG poor. Ictal: Bilateral occipital sharps, followed by MFD (EM). Interictal: MFDBG: slow. Ictal: GPSW (MS), 1.5–2 Hz GSW (AA). Interictal: GSW facilited by eye closureInterictal: GSWBG: slow. Ictal: FD (unilateral TCS). Interictal: 3–4 Hz GSW, MFDBG: slow. Interictal: 1.5–3 Hz GSW, MFDInterictal: 3 Hz GSW, bifrotal SWBG: slow. Ictal: GSE (MA). Inerictal: MFDBG: slow. Interictal: 3 Hz GSW, also following eye closure, FD
MRICranialNormalNormalNormalNormalNormalNormalNormalNormalNormal (discrete hippocampal tissue loss, not progressive and without sclerosis)Normal
TreatmentAEDVPA, LEV, TPM, CLB, LTG, ETX, LCM, ZNS, CLZ, CBD, PHTCLB, LCM, ZNS, CLZ, CBDVPA, LEV, TPMCLB, TPM, NZP, LTG, VPA, CLZVPA, CLBVPA, CLZ, LEV, TPMVPA, CLZ, LEV, CLBVPAVPA, LEV, LTGVPA
OtherKDKD, mAD Vitamin B6
Genetic informationGenomic change (Hg19)chr6:33400509_33400521dupchr6:33403058delCchr6:33403318dupCchr6:33403367; C>C/Tchr6:33405511_33405512insCchr6:33406048; C>C/Tchr6:33406202delCchr6:33406324;C>C/Gchr6:33408547G>GGCTGC
cDNA/aa changec.435_447dup, p.Leu150Valfs*6c.639delC, p.Ile214Trpfs*9c.690dupC, p.Phe231Leufs*14c.739C>T, p.Gln247*c.822_823insC, p.Lys277Glnfs*7c.1366C>T, p.Gln456*c.1393delC, p.Leu465Phefs*9c.1515C>G, p.Tyr505*c.1718_1719insGCTGC, p.Glu578Alafs*74
Inheritancede novo/mosaic parentde novode novode novode novode novode novode novode novo
Family Historysisters- (seizures, ID or ASD)- (seizures, ID or ASD)Maternal aunt and distant relative epilepsy, other distant relatives ASD- (seizures, ID or ASD)- (seizures, ID or ASD)Maternal grandfather post-stroke epilepsyPaternal uncle moderate ID - (seizures, ID or ASD)
C
ReferenceVlaskamp 2019 1,2Vlaskamp 2019 1,2Vlaskamp 2019 1Vlaskamp 2019 1/Carvill 2013Vlaskamp 2019 1Vlaskamp 2019 1Vlaskamp 2019 1,2Vlaskamp 2019 1Vlaskamp 2019 1Vlaskamp 2019 1
Patient23242526/T2528273031323335
Clinical featuresgenderfemalefemalemalemalemalefemalemalefemalemalemale
Age11 yr 11 months7 yr11 yr 7 months30/26 yr6 yr3 yr 11 months11 yr 2 months33 yr15 yr 3 months4 yr 9 months
DD/ID+ (severe)+ (severe)+ (moderate)+ (moderate)+ (severe)+ (severe)+ (severe)+ (moderate-severe)+ (severe)+ (moderate-severe)
Behavioral featuresregression, ASD, tantrums, self-injury, aggression. Sleep problems, high pain threshold, eating difficultiesregression, ASD, aggression, sleep problems, high pain thresholdASD, self injury, aggression, sleep problems, high pain thresholdregression, OCD symptoms, tantrums, aggressionregression, ASD, high pain thresholdASD, tantrums, self-injury, aggression, sleep problems, high pain threshold, oral hypersensibilityregression, ASD, tantrums, aggressive, sleep problems, high pain threshold, eating difficultiesregression, ASD, self-injury, aggression, poor concentration, high pain thresholdregression, ASD, aggression, sleep problems, high pain thresholds, eating difficultiesASD, aggression, sleep problems, high pain threshold
Other parametreshypotonia, constipationcongenital hisdysplasia, hypotonia, ataxic gaitpes planus, hypotonia, unsteady gait, constipationmild two/three syndactyly, irregular tremor upper extremities, osteopeniaUnsteady gaithypotyonia, unsteady gait, constipation, chronic idiopathic tromnocytopenic purpura, absence of languagemicrocephaly, short stature, borderline hypotonia, ataxia, Hemangioma nasal cavityHypotonia, coordination disoder/ataxiaright pes planus, left pes caves, hypotonia, bilateral pyramidal syndrome, unsteady gait, orthothics, hyperflexibilitymild hypotonia
EpilepsyAge of onset2 yr6 months9.5 yr18 months2 yr18 months2 yr 3 months8 months18 months2 yr 1 month
Abscence seizuresNRNRNR+NRNRNRNRNRNR
Eyelid myoclonia++++++++++
PhotosensitivityNRNRNR+NRNRNR+NRNR
Other seizuresFS, bilateral TCS (with fiver)bilateral TCS (with fiver), atonic DA. Triggered by fatigue and illnessTriggered by eatingFS, aura, FIAS, MJ, NCSE, bi- and unilateral TCS, MS. Triggered by PSTriggered by hunger, self-induced with hyperventilation, fatigue and stressTCS (with fiver)Atonic DA. Triggered by sounds, fatigue, and drop in emperatureGTCS. Triggered by PS-Triggered by eating
EEGothersIBG: Slow. Ictal: 2–3 Hz GSW with frontal maximum, (EM-AS). Interictal: MFDInterictal: 2.5 Hz GSWNRBG: slow. Interictal: occipital 2 Hz GSW, occipital FD/bi-occipital ED, DS, SSWBG: iregular. Ictal: GSW (EM). Interictal: 2–3 Hz GSW, irregular GPSW, MFDinterictal: epileptiform dischargeIctal: irregular GSW followed by slower discharges (EM), GPSW (EM). Interictal: G(P)SW, bifrotal SW, FDNRBG: slow Ictal: GSW (EM). Interictal: temporo-occipital SW, 10% generalized activity in 24 hours.BG: right occipital slowing. Ictal: eyeblink without ictal correlate. Interictal: only in sleep: right occipital slowing, focal sharp waves
Cranial MRINormalNormalNormalNormalPatent cavus vergaeAtypical WM abnormalitiesNormal NREnlarged ventriclesNormal
TreatmentAEDVPA, LEVVPA, LEV-VPA, LTG, CLBVPA, LEV, ETX, ZNS, CBD, LTG-VPA, CLB, TPM, LTGVPA, CBZ, TPMVPA, LEV, LTG-
Other KD KD
Genetic informationGenetic testNRNRNRNGS panelNRNRNRNRNRNR
Genomic change (Hg19)chr6:33409006;G>G/Achr6:33409095;C>C/Tchr6:33409095;C>C/Tchr6:33409140;C>C/Tchr6:33409419_3349422delchr6:33411265_
33411267delinsCA
chr6:33411735dupCchr6:33412317;G>G/Tchr6:33414426;T>T/Gchr6:33393573;A>A/G
cDNA/aa changec.1970G>A, p.Trp657*c.2059C>T, p.Arg687*c.2059C>T, p.Arg687*c.2104C>T, p.Gln702*c.2177_2180delGGAA, p.Arg726Thrfs*33c.2936_
2938delinsCA, p.Phe979Serfs*98
c.3406dupC, p.Gln1136Profs*17c.3505G>T, p.Glu1169*c.3657T>G, p.Tyr1219*c.190-2A>G, (splice acceptor site)
Inheritanceunknowde novode novode novode novode novode novode novode novode novo
Family HistoryDistant relative ASDPaternal grandmother GTCS 16–20 y. Distant relative ASD- (seizures, ID or ASD)Distant relative epilepsy- (seizures, ID or ASD)Maternal aunt ID. Paternal first cousin post-traumatic epilepsyMaternal uncle ID post-meningitis. Distant relative epilepsyMaternal and paternal first cousins learning difficultiesDistant relative ASD- (seizures, ID or ASD)
D
ReferenceVlaskamp 2019 1,2Vlaskamp 2019 1/Parrini 2017Vlaskamp 2019 1Vlaskamp 2019 1,2,cVlaskamp 2019 1,2Vlaskamp 2019 1,2Vlaskamp 2019 1,2,a/Berryer 2013 aVlaskamp 2019 1,2Vlaskamp 2019 1,2Von Stülpnagel 2019 2,cVon Stülpnagel 2019
Patient3639/1190N4145465051/3525312
Clinical featuresgenderfemalefemalefemalemalemalemalefemalefemalefemalemalemale
Age8 yr 11 months16.4/17 yr6 yr 8 months3 yr 2 months10 yr15 yr 1 month9.1/4.2 yr8 yr 3 months7 yr months5 yr14 yr
DD/ID+ (mild)+ (moderate-severe)+ (moderate-severe)+ (severe)+ (moderate)+ (severe)+ (moderate/mild)+ (severe)+ (mild)+ (moderate)+ (moderate-severe)
Behavioral featuresregression, ASD traits, tantrums, self-injury, aggresiveregression, Aggressive, REM sleep behavioral disorder, ASDregression, ASD, sleep problems, high pain thresholdregression, ASD traitsregression, ASD, tantrums, OCD, echolalia, high pain threshold, eating dificultiesregression, ASD, eating disorderregression, ASD, OCD, tantrums, self-injury, sleep problems, high pain threshold, eating disorderregression, ASD, tantrums, self-injury, sleep problems, high pain thresholdtantrums, aggressive, sleep problemsregression, ASDASD
Other parametresFew café au lait maculespronated foot, coordinarition disorder, ataxic gaithypotoniahypospadie, 6th toe, hypotonia, nystagmusMild cerebral palsy, pes planus, mild musle weakness, clinodactyly toes, hypotonia, constipation, coeliac diseaseobesity, ataxia with wide-based gaitHypotonia, unsteady gait with poor balance, gross and fine motor dyspraxiamacrocephaly, knee hyperextension, pes planus, pronated feet, hypotonia, wide-based gait with poor balance, constipationpes caves, hypotonia, balance issuesHeight <3p. Tongue hypotonia and horizontal nystagmus. Postaxial hexadactylia and hypospadiaAbnormal gait; poor coordination; dysarthria. Abnormal facial shape (triangular), large anteverted, ears, wide mouth, thin lips, pointed chin
EpilepsyAge of onset<2 yr6.7/5 yr4.5 ys2.5 yr2.8 yr2.5 yr18 months18 months 2.5 yr2.5 yr20 months
Abscence seizuresNRNR+ (typical)NRNR+ (typical)NRNRNR
Eyelid myoclonia+++++++++++
PhotosensitivityNR+++-+-NR--+
Other seizuresTriggered by eye closure, hunger and fatigueTriggered by PS-MAt, MS, atonic DA. Triggered by eating and stressTriggered by visual patternsbilateral TCS (with fiver). Triggered by PS and noisebilateral TCS, myoclonic DA. Triggered by eatingTriggered by eating, eye closure and fatigueTriggered by illness and fatigueAtonic head dropping FS, GTCS, episodes characterized by loss of consciousness, backward eyeball rolling, MS; generalized with head atonia and EM; status epilepticus.
EEGothersIctal: GD (EM-MAt). Interictal:2–3 Hz GSW, frequent GD, induced by eye closureIctal: G(P)SW (EM)Interictal: G(P)SWIctal: G(P)SW (EM)NRBG: slowing. Interictal: GPS, 3.5–4 GSP, FDInterictal: GD, MFD, spikes, G(P)SW BG slowInterictal: GSWBG: gegeralized slowing. Interictal: MFD1–3 s lasting high amplitude 3/s SW complexes with bilateral initiation and occipital predominance but never lateralized. Triggered by heat, fatigue, stress, and orofacial stimulislowed BG activity (theta); spikes and polyspikes over the occipital regions; abnormalities are worsened by sleep. Triggered by PS, autoinduced, and eating.
MRICranialNormalNormalMega cisterna magna fossa posteriorNormalNormalNormalSmall hyperintens subcortical WM lesions (bi-frontal, peri-ventricular), possibly post-anoxic leukopathyStable mild enlarged ventricles and pineal cystNormalSlight frontal dilatation of the external spaces of cerebrospinal fluid and an age-appropriate myelinationNormal
TreatmentAEDVPA, CLB, LTGLZP, RUF, VPALEV, ZNS, RUF, VPAVPA, LTGVPAHydrocortison, VGB, NZPVPAVPA, LEV, ETX, CLZ, LTG, CBDVPA, ZNS, LEV, PER, CBDVPA, LTGVPA, LTG, LEV, CLB
OtherNRNRNRNRNRNRNRNRKDNRNR
Genetic informationGenetic testNRNGS panel (95 genes)NRNRNRNRNRNRNRgene panel NGSNR
Genomic change (Hg19)chr6:33400029;G>G/Achr6:33400583; G>G/Achr6:33408504_
33408514delAGCGTGTTCCC
chr6:33405650;T>T/Cchr6:33405712; G>G/Achr6:33406199;T>T/
TTCC
chr6:33408514;C>C/Tchr6:33408626;C>C/Gchr6:33408718;T>T/Achr6:33405650;T>T/Cchr6:33400462;C>C/T
cDNA/aa changec.387G>A, p.Ser129Ser (splice donor site)c.509G>A, p.
Arg170Gln
c.1677-2_1685del, (splice acceptor site)c.968T>C, p.Leu323Proc.1030G>A, p.Gly344Serc.
1390delinsTTCC, p.Leu465dup
c.1685C>T, p.Pro562Leuc.1797C>G, p.Cys599Trpc.1889T>A, p.Ile630Asnc.968T>C, p.Leu323Proc.388C>T, p.Gln130Ter
Inheritancede novode novode novode novode novode novode novode novode novode novode novo
Others information Karyotype, aCGH, MECP2 mutation and X-fragile
analysis, without relevant results
Family History- (seizures, ID or ASD)- (seizures, ID or ASD)- (seizures, ID or ASD)Paternal uncle epilepsy and behavioural problems- (seizures, ID or ASD)Mother FS. Paternal uncle learning difficultiesMaternal first cousin ASD- (seizures, ID or ASD)- (seizures, ID or ASD)- (epilepsy or DD) NR
E
ReferenceKuchenbuch 2020 dKuchenbuch 2020 eLo barco 2021 eLo barco 2021Lo barco 2021Lo barco 2021 dLo barco 2021 bLo barco 2021Lo barco 2021
Patient1324568910
Clinical featuresgendermalemalemalemalefemalemalemalefemalefemale
Age5.6 yr 3.5 yr 3 yr 4 months11 yr 3 months 6 yr 3 months5 yr 4 months6 yr 6 months14 yr7 yr
DD/IDNRNR + (severe/moderate)+ (severe) + (severe/moderate) + (moderate) + (severe) + (severe/moderate) + (severe/moderate)
Behavioral featuresmotor stereotypies, heteroaggressivity, ASDNRASD, behavior disorderASD, behavior disorderASD, behavioral and sleep problemsASD, behavior disorderASD, feeding problemsASD, behavioral and sleep problemssleep, behavior and eating disorders
Other parametresNR NRNRhead growth slowdown, absence of languagegrowth delay, absence of languageNRnystagmus, absence of languagehead growth slowdown, absence of languagehead growth slowdown, absence of language
EpilepsyAge of onset3.5 yr8 months8 months27 months18 months36 months20 months20 months30 months
Abscence seizures+ (AA)+ (MA)+ (AA, AAM)+ (AA)+ (AA, AAM, AAOC, AAA)+ (AA, AAOC, MA)+ (AAM)+ (AA, AAM)+ (AAM)
Eyelid myoclonia++NR++ (EMA)+ (EMA)NRNR+ (EMA)
Photosensitivity+NRNRNRNRNRNRNRNR
Other seizuresFS, MS, upper limb MJ, DA. Triggered by sleep and IPSDA, upper limb MJ, reflex seizures self-induced by eye closureMS, FSDAASNR MS, TSMSNR
EEGPPRNRNR+-++-+-
othersNR2-HZ GPSWSleep: Sporadic low-voltage multifocal spikes; sporadic bursts of generalized irregular polyspike or PSW in sleep. EM, AA, AAM, F. Self stimulation wirh eyes closure.Wake: (P)SW on frontal regions; Sleep: higher frequency of generalized discharges. EM, AA. Self stimulation wirh eyes closure. Sleep: Multifocal spikes, prominent on frontal and occipital regions; bursts of generalized irregular polyspike or PSW. EM, EMA, AA, AAOC, AS, MS, AAA. Self stimulation wirh eyes closure.Sleep: Low-voltage centrooccipital spikes. AA, AAOC, MAWake: Diffuse GPSW; Sleep: PSW on frontal regions. EM, EMA, AA, AAM, MS, AS, MATS. Self stimulation wirh eyes closure.Wake: Diffuse SW, predominant on frontal regions; Sleep: Numerous frontal SW. EMA, AAMWake: Temporo-parietal SW; Sleep: PSW on frontal regions
MRICranialNormal NRNormalNormalBilateral hypersignal of WM (4 yr); cerebellar atrophy (6 yr)NormalAspecific WM hypersignalNRDefect in frontal lobes develoment
TreatmentAEDVPA, LEV, ETX, LTG, CBDETX, LEV, LTG, VPA, CLB, ZNS, PER, CBDVPA, ETX, ZNS, LTGLEV, VPA VPA, CLB, ETX, LTG, RUF, ZNSLEV, VPA, LTG, ETXLEV, VPA, TPM, CLB, CLZ, ZNS, LTG, PERVPA, LEV, TPMLEV, VPA, LTG, ETX, CLB, CLZ, ZNS
OtherKDKDKD KD, VNSKDKD
Genetic inform.Genomic change (Hg19)chr6:33409002; G>G/Tchr6:33409095; C>C/Tchr6:33409095; C>C/Tchr6:33411544delAchr6:33405604; T>T/Cchr6:33409002; G>G/Tchr6:33414346; G>G/Achr6:33411127; A>A/Gchr6:33400531-33400532insG
cDNA/aa changec.1966G>T, p.Glu656*c.2059C>T, p.Arg687*c.2059C>T, p.Arg687*c.3215_3224del, p.Lys1072Serfs*2c.922T>C, p.Trp308Argc.1966G>T, p.Glu656*c.3583-6G>A, p.Val1195Alafs*27c.2798A>G, p.His933Argc.456insG, p.Thr153Aspfs*15
Inheritancede novode novode novode novode novode novode novode novode novo
Family HistoryNRPaternal grandmother with unspecified epilepsyNRNRNRNRNRNRNR
1 Syndromic diagnosis of EMA; 2 Syndromic diagnosis of MAE; a,b,c,d,e Different cases with the same genomic change. aa: amino acid; aCGH: Array comparative genomic hybridization; AS: Angelman syndrome; ASD: Autism spectrum disorder; CSF: Cerebrospinal fluid; DD: Developmental delay; DDD: Deciphering Developmental Disorders; del: deletion; EEG: Electroencephalogram; FOS: Fixation of the sensitivity; ID: Intellectual disability; IPS: Intermittent Photic Stimulation; MRI: Magnetic resonance imaging; NGS: Next generation sequencing; NR: not reported; p: percentile; OCD: Obsessive compulsive disorder; PPR: Photoparoxysmal response; PS: Photosensitivity; REM: Rapid eye movement; VUS: variant of unknown significance; WES: whole exome sequencing; WM: White matter; yr: year; -: Feature not found. Seizure types: AA: Atypical absence; AAA: Atypical absences with atonic phenomena, AAM: Atypical absence with myoclonia; AAOC: Atypical absences with oculoclonic movements; AS: Atonic seizures; DA: drop attack; EM: Eyelid myoclonia; F: focal seizures; FIAS: Focal impaired awareness seizures; FS: Febrile seizures; GS: Generalized seizures; GTCS: Generalized tonic clonic seizures; MA: Myoclonic absence; MAt: myoclonic-atonic seizures; MATS: Myoclonic-atonic-tonic seizures; MFD: multifocal discharges; MJ: Myoclonic jerks; MS: Myoclonic seizures; NCSE: Non-convulsive status epilepticus; TCS: Tonic-clonic seizures; TS: Tonic seizure. EGG: BG: Background; DS: diffuse slowing; ED: epileptiform discharge; FD: focal discharges; GD: General discharges; GPSW: Generalized polyspike wave; GSW: Generalized spike wave, PSW: polyspike wave; SSW: slow spike and wave; SW: spike wave. Treatment: CBD: cannabidiol; CBZ: carbamazepine; CLB: clobazam; CLZ: clonazepam; KD: Ketonic diet; ETX: ethosuximide; LCM: lacosamide; LEV: levetiracetam; LTG: lamotrigine; LZP: Lorazepam; AD: modified Atkins diet; NZP: nitrazepam; PER: perampanel; PHT: Phenyltoin; RUF: Rufinamide; TPM: topiramate; VGB: vigabatrin; VNS: vagal nerve stimulation; VPA: valproate; ZNS: zonisamide.
Table 2. Summary of the cases reported with a pathogenic (or probably pathogenic) alteration in NEXMIF (NM_ 001008537.3) and an EMA/EMA-like phenotype.
Table 2. Summary of the cases reported with a pathogenic (or probably pathogenic) alteration in NEXMIF (NM_ 001008537.3) and an EMA/EMA-like phenotype.
A
ReferenceSamanta 2020 1Wu 2020Stamberger 2021 1,2Stamberger 2021 1,2Stamberger 2021 1,2Stamberger 2021 1Stamberger 2021 1Stamberger 2021 1,2/Myers 2018 2
Patient 1 (F1)2 (F2)4 (F4)7 (F5)8 (F6)10 (F7)/T990 (family 12)
Clinical featuresgenderFemaleFemaleMaleMaleFemaleFemaleFemaleFemale
Age9 yr29 yr8 yr12 yr12 yr14 yr18 yr28 yr
DD/ID+ (mild)+ (mild)+ (severe)+ (moderate)+ (severe)+ (moderate)+ (moderate) + (moderate-severe)
Behavioral featuresADHDNRRegression, ASD, behavioral problemsRegression, ASD, severe tantrumsRegression, ASD, ADHDRegression, obsessive, repetitive behaviours, anxietyRegression, stereotypes, agressive behaviour, impulsive, attention problems, anxietyASD traits
Other parametresmild hypotoniaMinor dysmorphic features (flat nasal bridge and ocular hypertelorism), diabetes mellitus type 2Scaphocephaly, mild facial dysmorphisms (deep set eyes, wide spaced teetch, prominent lower lips, protruding tongue; tapering fingers), hypotonia/hupertonia, esotropiaNRUpslanting palpebral fissures, hypoplastic eyelashes, small rounded nasal tipventricular septal defect; primary enuresisNRoverweight, prominent eyebrows, hirsuitism, polycystisc ovarial syndrome
EpilepsyAge of onset2 yr6 yr21 months15 months12–14 months2 yr3 yr19 months
Abscence seizures+ + (AAS)++++++
Eyelid myoclonia+ + (rare)++++++
Photosensitivity+++---+-
Other seizuresRapid eye blinking with upward eye rolling associated with head bobbingGTCS, brief blanking, behavioral arrest and states of prolonged confusion AS, MS. Triggered by PSMS, MAS, GTCS, NCSE. Triggered by temperature (hot)Head nods, drop attack, AS, MS, likely NCSE. Triggered by fever, temperature, eye closureMS, NCSE (absence status) nocturnal MS, rare GTCSMS, DA, GTCS, NCSE
EEGPPR++NRNRNRNRNRNR
others3 Hz GSW. Eyelid jerking, generalized epileptiform discharges induced by eye cosureInterictal: paroxysmal GPSW induced by eye closure, PS. Ictal: persistent 1.5–2.5 Hz semi-rhythmic GPSW. Epileptiform discharges induced by eye closureInterictal: BG slowing, 2.5–3 Hz GPSW, PFA. Ictal: 2.5 Hz GPSW. Triggered by sleep abd IPSInterictal: BG slowing, 2.5–4 Hz G(P)SW. Ictal: 2.5–4 Hz GPSW (MS, MAS, head drops). Triggered by sleep, eye closureInterictal: BG slowing, G(P)SW. Ictal: irregular G(P)SW (eyeclosuse with EM). Triggered by eye closure, posible IPS Interictal: excessive beta activity, G(P)SW. Ictal: irregular GSW (A-EM, MS). Triggered by eye closure, IPS Interictal: BG slowing 2.5–5 Hz G(P)SW, MFD. Ictal: G(P)SW (EM, MS), NCSE in sleep. Triggered by sleep, eye closure, IPSInterictal: BG slowing, G(P)SW, PFA, left rhythmic delta activity, MFD
MRICranialNormalNormalShort medulla, thin, dysmorphic CC, asymmetrical hippocampi, right incompletely rotated, delayed myelination subcortical WM and increased FL/T2 signal in posterior PVWMSlightly small cerebellar vermis and mild tonsillar ectopia, bulky amygdalas and hippocampal heads. NormalPossible minimal atrophy superior cerebellar vermisNormalNormal
TreatmentAEDETX, LTG, MPH, GF, RD, LEV, VPA, RUF, TPM, ZNSCBZ, VPA, MZN, LTG, LEV, TPMVPA, LTG, LEVETX, VPA, FBM, RUF, TPM, CLB, CBZ, LEV, PLP, CLZ, VGB, LTG, GB, CSCS, CLB, LEV, VPA.ETX, ZNS, PB, CS, VPA, LTG, AZA, CLB, LEV, ATD, CBDCS, NZP, LTG, CBZ, VPA, TPM, CLB, ZNS, ETXCS, VPA, LEV, LCM, TPM, AZA, PB, ETX, LTG, PER, BRV, CBD
OtherKD, mAD, LHID, DAPGPO, STG KD KDKD
Genetic informationGenetic testNGS panel (1148 genes)WESNRNRNRNRNRNR
Genomic change (Hg19)chrX:73962671_73962674 delChrX:73963328; AG>AG/A-chrX:73963494; C>C/AchrX:73961747; G>G/CchrX:73962951;G>G/AchrX:73962417; G>G/AchrX:73961593; G>G/TchrX:73963428; G>G/A
cDNA/aa changec.1718_1721delATCA, p.Asp573Serfs*11c.1063delC, p.Leu355*c.898G>T, p.Glu300*c.2645C>G, p.Ser882*c.1441C>T, p.Arg481*c.1975C>T, p.Gln659*c.2799C>A, p.Tyr933*c.964C>T, p.Arg322*
Inheritancede novode novode novoNRinherited (maternal)de novode novoinherited (paternal gonadal mosaicism likely)
Others informationCXI 74:26 (random). CSF GLUT1 and aCGH normalCXI 51:49 (random) NR~30% mosaicism for NEXMIF alterationCXI ~90:10 (skewed). SCN1A:p.(Met1977Val), paternal - VUSCXI~60:40 (random)CXI~50:50 (random)CXI~80:20 (skewed)
Family History No family history of IDnor epilepsyFamily history of GEFS+ and hypotonia: Father: seizures, hypotonia, speech/language delay, unilateral hearing loss. Sister: FS. Paternal grandfather, paternal aunt and two paternal uncles: childhood epilepsy +- FS. Paternal cousin: FSMaternal great-great-grandmother: epilepsy Two sisters carriers of the alteration with ID but without seizures (patient 5 and 6). Two more affected siblings not included in the study with ID without seizures. One other sister is carrier with no disease activity to date. Carrier mother has mild ID Epileptic sister, also with MAE, carrier of the alteration (patient 9).
B
ReferenceStamberger 2021 1,#Stamberger 2021 1,#Stamberger 2021 1Stamberger 2021 1,&Stamberger 2021 1Stamberger 2021 1Stamberger 2021 1/Borlot 2017 1Stamberger 2021 1Stamberger 2021 1,2,&
Patient13 (F10)15 (F12)16 (F13)18 (F15)23 (F20)33 (F30)34 (31)/2737 (F34)41 (F38
Clinical featuresgenderFemaleFemaleFemaleFemaleFemaleFemaleFemaleFemaleFemale
Age8 yr12 yr10 yr15 yr16 yr15 yr26/23 yr10 yr4 yr
DD/ID + (mild) + (moderate) + (moderate) + (mild) + (moderate) + (moderate) + (mild) + (moderate) + (mild)
Behavioral featuresAggressive behaviour, attention problemsADHDASD, Agressive behaviourSelf-abasement, ASD traits (social difficulties)NREasily frustratedDepression, anxietyAttention deficiency and problems linked to communication difficulties during infancy, decreased satiety, tics (blinking), ASD traits.-
Other parametresoverweight, gastro-oesophageal reflux diseaseNRMild facial dysmorphisms (short philtrum, low-set hairline, mild prognathism with frontal bossing) NRHypotonia, hypermovilityNRoverweight, gastro-oesophageal reflux disease as infant/-Low set backward rotated ears, protruding underlip, hypotoniaMild hypotonia and hyperlaxity
EpilepsyAge of onset1 yr9 monts2–4 months2–4 yr18 months6.5 yr16 months30 months2 yr 10 months
Abscence seizures++++++++NR
Eyelid myoclonia+++++++++
PhotosensitivityNRNR-NR+---+
Other seizuresMS, GTCS. Triggered by sleep deprivationTriggered by fever, eye closureTriggered bu eye closureGTCSGTCS, NCSE (absences), Triguered by PSNRSingle GTCS/BCSMSAS (head drops) MS (blinking). Triggered by PS
EEGGPPRNRNRNRNRNRNRNRNRNR
othersInterictal: mild BG slowing, >3 Hz G(P)SW, MFD, GPFA. Ictal: G(P)SW (Absences +-EM), GSW (MS). Triggered by sleep, IPS, hiperventilation Interictal: normal BG, G(P)SW in sleep, MFD. Ictal: GSW (EM), Triggered by sleep, eye closure Interictal: normal BG, G(P)SW in sleep, MFD. Ictal: 3 Hz irregular GPSW (EM). Triggered by sleepInterictal: BG asimmetry, near continuous G(P)SW during wakefulness. Ictal: EM with impaired awarenessInterictal: Normal BG, MFD with (P)SW, multiple spikes. Triggered by hyperventilation, IPS, sleep, eye closureInterictal: G(P)SW, PFA. IctalG(P)SW (EM, MS). Triggered by hyperventilation, IPS, eye closure, fixation of sensitivityInterictal and ictal: sharply contoured runs of alpha activity at times/polyspike and generalized spike waves induced by eye closureInterictal: multiple spikes and spike-wave. Ictal: quick frontal and central activity (MS). Triggered by eye closure Interictal: BG slowing, G(P)SW, MFD, bifrontal disrythmic delta activity during sleep. Ictal: GPSW (MS). Triggered by sleep
Cranial MRINormalNormalNormalNormalNormalNormalNormalNormalNormal
TreatmentAEDETX, LEV, VPALTG, CLZ, LCM, VPA, ETX, CLB, LEVETX, CLZ, VPAVPA, LTGLEV, CLZ, ZNS, VPA, ETX, OXC, LTGVPA, CLBTPM, CBZ, VPALEV, LTG, ETX, VPACBD, VPA, CLB, LEV
Other KD, VNS vitamin B6
Genetic informationGenetic testNRNRNRNRNRNRaCGHNRNR
Genomic change (Hg19)chrX:73962510; G>G/AchrX:73962510; G>G/AchrX:73961016; C>C/AchrX:73961500; G>G/CchrX:73964056; C>C/T chrX:73963740; G>G/AChrX:73930523_74007913 del (0.08 Mb, 1 gene)chrX:73960934dupTchrX:73961500; G>G/C
cDNA/aa changec.1882C>T, p.Arg628*c.1882C>T, p.Arg628*c.3376G>T, p.Glu1126*c.2892C>G, p.Tyr964*c.336G>A, p.Trp112*c.652C>T, p.Arg218*Xq13.3 del (Ex 2–4) c.3458dupA, p.Asn1153Lysfs*8c.2892C>G, p.Tyr964*
InheritanceNRde novode novode novode novode novode novode novoNR
Others information CXI~65:35 (random)CXI~65:35 (random) SMA: 3p24.1(30,414,405–30,878,291)x3, maternal - VUS
ADGRV1: p.(Asp2942His), maternal - VUS
CXI ~60:40 (random) GRIN2A: p.(Asn106Lys), paternal - VUS/GLUT1 deficiency (SLC2A1 sequencing) and Epilepsy panel (476 genes) normalCXI ~50:50 (random)
Family History Maternal distant cousin: GTCS and learning disability. Distant maternal relative: absence seizures in childhood. Sister of paternal grandmother: "drop seizures" and questionable DDSister with normal development exhibited epilepticus status due to a fall in bicycle, attention deficiency
1 Syndromic diagnosis of EMA; 2 Syndromic diagnosis of MAE; #,& Different cases with the same genomic change. aa: amino acid; aCGH: Array comparative genomic hybridization; ADHD: Attention deficit hyperactivity disorder; AED: Antiepileptic drug; ASD: Autism spectrum disorder; CC: corpus callosum; CSF: Cerebrospinal fluid; CXI: X-inactivation; DD: Developmental delay; del: deletion; EEG: Electroencephalogram; Ex: exon; ID: Intellectual disability; IPS: Intermittent Photic Stimulation; MRI: Magnetic resonance imaging; NGS: Next generation sequencing; NR: not reported; PPR: Photoparoxysmal response; PS: Photosensitivity; PVWM: Periventricular white matter; VUS: variant of unknown significance; WM: White matter; yr: year; -: Feature not found. Seizure types: AAS: Atypical absence status; AS: Atonic seizures; DA: drop attack; EM: Eyelid myoclonia; FS: Febrile seizures; GTCS: Generalized tonic clonic seizures; MAS: Myoclonic-atonic seizures; MFD: multifocal discharges; MS: Myoclonic seizures; NCSE: Non-convulsive status epilepticus; PFA: paroxysmal fast activity. EGG: BG: Background; GPFA: Generalized paroxysmal fast activity; GPSW: Generalized polyspike wave; GSW: Generalized spike wave, PFA: paroxysmal fast activity. Treatment: AZA: acetazolamide; ATD: Amantadine; BRV: brivaracetam CBD: cannabidiol; CBZ: carbamazepine; CLB: clobazam; CLZ: clonazepam; CS: corticosteroids; KD: Ketonic diet; DAP: dexamphetamine; ETX: ethosuximide; FBM: felbamate; GB: gabapentin; GF: guanfacine; GPO: glimepiride; LCM: lacosamide; LEV: levetiracetam; LHID: low hypoglycemic index diet; LTG: lamotrigine; mAD: modified Atkins diet; MPH: methylphenidate; MZN: midazolam; NZP: nitrazepam; OXC: oxcarbazepine; PB: phenobarbital; PER: perampanel; PLP: Piridoxal phosphate; RD: risperidone; RUF: Rufinamide; STG: sitagliptin; TPM: topiramate; VGB: vigabatrin; VNS: vagal nerve stimulation; VPA: valproate; ZNS: zonisamide.
Table 3. Summary of the cases reported with a pathogenic (or probably pathogenic) alteration in RORB (NM_006914) and an EMA/EMA-like phenotype.
Table 3. Summary of the cases reported with a pathogenic (or probably pathogenic) alteration in RORB (NM_006914) and an EMA/EMA-like phenotype.
ReferenceBartnik 2012Rudolf 2016 1Rudolf 2016 1Rudolf 2016 1Rudolf 2016 1Rudolf 2016Rudolf 2016Sadleir 2020 1Sadleir 2020Morea 2021 1
Patient1241314209A1117GE0705Familly C II-2Family D II-1Case report
Clinical featuresgenderMaleFemaleFemaleFemaleFemaleFemaleFemaleFemaleMaleMale
AgeNRNRNRNRNR25 yr10 yr40 yr20 yr21 yr
DD/IDNR+ (mild)+ (mild)+ (mild)NR+ (mild)+NR- + (moderate)
Behavioral featuresASDNRNRNRNRNRNRNRNRADHD
Other parametresNR NRNRNRNRMacrocephal, overweight, and learning dificultiesconvergent strabismus, hypermetropia, learning dificultiesLearning dificulties Learning dificulties NR
EpilepsyAge of onset2 yr13 yr3 yr9 yr11 yr5 yr 5 months4 yr 9 month3 yr10 yr4 yr
Abscence seizuresNR+++++ (TA, absence status)+++ (absence status)+
Eyelid myoclonia++++++++++
PhotosensitivityNR++++-+++NR
Other seizuresGTCSGTCSGTCSGTCSGTCSGTCS, FS, TCnocturnal GTCSGTCS, occipital seizuresGTCS, occipital seizurures, Induced by television and videogame
exposure
EEGPPRNR++++NRNR++NR
othersCTS3 Hz GSW3 Hz GSW3 HZ GSW3 Hz GSWInterictal: normal BG rhythm and bilateral centrotemporal spikes. 3 Hz SW absence seizures activated by hyperventilation. Ictal Absence seizures. Interictal GSW, GPSW. Focal frontal or temporal occipital paroxysmal activityAbsence seizures ocassionally with EM triggered by IPS. 3 Hz GSWGSWGSWIctal: 3 Hz GSW. Interictal: asynchronous spikes on a physiological BG rhythm. Generalized epileptic discharges elicited by eye closure and hyperventilation
Cranial MRINR NRNRNRNRNormalNormal-NormalNormal
TreatmentAEDNR3 treated with VPA, one with ETX and PBCBZ, VPA, ETX, VGB, CLB, LTG, TPM, LEVTEX, VPA, LTG, LEVLTG, VPAVPA, LEV, LTGVPA, ETX, LEV
Other KD
Genetic informationGenetic testaCGHWESWESsanger sequencingWESaCGHaCGHaCGHSanger sequencingNGS
Genomic change (Hg19)chr9:7474,400_ 77306932 del (2.57 Mb, 6 genes)chr9:77249649; C>C/Tchr9:70984481_
79549501 del
(8.5 Mb, 47 genes)
chr9:77261322_
77313598 del
(52Kb)
Min:chr9:77249078_ 77251973del2896 Max:chr9.77248677_77251984del3308chr9:77286755; A>A/T 9q21
cDNA/aa change c.196C>T, p.Arg66* 9q31.13 del (Ex 5–10)c.96_237del141, p.Gly32_Ala79del48c.1162A>T, p.Ile388PheNR
Inheritancede novo(probably) Inheritedde novode novoinherited (maternal)inherited (paternal)de novo
Others informationFISH: 9q21.13 (RP 11-243A1) aCGH array normal Karyotype: mos 47,XX,+r [20]/46,XX,-21,+der(9)t(9;21) [5]/46,XX [25]. aGCH array: mosaic gain 9p. FISH: 9q13q21.13 del (RP11-404E6), mosaic i(9p), der(9)t(9;21) and r(9)qPCR to validate the resultNRNR
Family HistoryFather Asperger syndromeFamily members:
Patient 20; Patient 13 (Mother); Patient 14 (maternal aunt); Patient 4 (maternal grandmother).
Other two carriers: Patient 23 (sister): One episode of absence seizure (probably GGE with no EEG); Patient 10 (maternal great-aunt): EEG with isolated high-amplitude spike during IPS but seizure state not confirmed.
Several antecedents of PS without seizures
Maternal uncle and two of her first cousins had GTCSNo family history of
seizures
Alteration inherited from her mother (normal intelligence and no seizures). Her son, with intratable DEE and severe ID, has the same microdeletionAlteration inherited from his father, diagnosed with early onset abcense epilepsy and occipital lobe epilepsy, who also presented GTCS-
1 Syndromic diagnosis of EMA. aa: amino acid; aCGH: Array comparative genomic hybridization; ADHD: Attention deficit hyperactivity disorder; AED: Antiepileptic drug; ASD: Autism spectrum disorder; DD: developmental delay; DEE: developmental and epileptic encephalopathy; del: deletion; EEG: Electroencephalogram; Ex: exon; GGE: genetic generalized epilepsy; ID: Intellectual disability; IPS: Intermittent Photic Stimulation; MRI: Magnetic resonance imaging; NGS: Next generation sequencing; NR: not reported; PPR: Photoparoxysmal response; yr: year; -: Feature not found. Seizure types: FS: Febrile seizures; GTCS: Generalized tonic clonic seizures; TA: typical absence; TC: tonic-clinic seizure. EGG: BG: background; CTS: centro-temporal spike; GPSW: Generalized polyspike wave; GSW: Generalized spike wave. Treatment: CBZ: carbamazepine; CLB: clobazam; ETX: ethosuximide; KD: Ketonic diet; LEV: levetiracetam; LTG: lamotrigine; PB: phenobarbital, TPM: topiramate; VGB: vigabatrin; VPA: valproate.
Table 4. Summary of the cases reported with a pathogenic (or probably pathogenic) alteration in CHD2 (NM_001042572) and an EMA/EMA-like phenotype.
Table 4. Summary of the cases reported with a pathogenic (or probably pathogenic) alteration in CHD2 (NM_001042572) and an EMA/EMA-like phenotype.
ReferenceGalizia 2015 1Galizia 2015 1Galizia 2015 1Tomas 2015 1/Carvill 2013 2Tomas 2015 1Tomas 2015 1Tomas 2015 1/Mullen 2013
Patient7895/T38689/15 [57]
Clinical featuresgenderNRNRNRMaleFemaleMaleFemale
AgeNRNRNR18/17 yr 13 yr14 yr36/26 yr
DD/IDNRNRNR+ (moderate-severe/moderate)+ (moderate-severe)+ (mild)+ (mild)
Behavioral featuresASDNRNRASD, regression, aggression/ASD, No regressionASD, ADHD, aggresionADHD, regression, agressionautistic traits, regression, agression
Other parametresnephrolithiasis, migraine, scoliosisNRNRTransient ataxia on valproateShort statureShort stature, ataxiaNR
EpilepsyAge of onsetNRNRNR12 months30 months30 months34 months
Abscence seizures++++ (AMA, MA; TA)/++ (TA)++
Eyelid myoclonia+++++++
Photosensitivity++++ (Self induced with TV)+ (Self induced with TV)+(Self induced with TV; photic stimulation)+(Self induced with TV or light)
Other seizuresNRNRNRMS, FS, GTCS/AS, FS, MJ, TCMS (self-induced with TV), TS, GTCS AS, GTCS, MS (self-induced with TV), NCSE, CSEGTCS, MS (self-induced with TV or light),
EEGPPR+++- (interictal and BG)- (interictal and BG)+ (grade 4)NR
othersNRNRNR3–4-HZ GPSW during atonic myoclonic absence seizures. 9 yr: Diffusely slow BG with symmetrical theta and 3 Hz delta. 14 yr: Normal BG for brief bursts of 3–4 Hz regular rhythmic GSW/3.8 Hz GSW3 yr: Slow BG for age. Inter-ictal GSW GPSW, bi frontal slow spike wave (2 Hz). Eye flickering—bursts of 2 Hz bifrontal spike and wave. 4 yr: EMA, GSW, GPSW. Activated by eye closure. 7 yr: Normal BG, irregular GSW with a frontal predominance. GSW on eye closure and during eyelid myoclonia32 months: Normal BG, frontal predominant GSW, GPSW. 5.5 yr: Normal BG, multifocal GSW. 11 yr: Diffusely slow BG, 3 Hz GSW, bifrontal spikes, activated in sleep, 4–5 Hz posteriorly dominant GSW on eye closure. 12 yr: Continuous slowing in wake and marked generalized epileptiform activity in sleep. 14 yr: Diffuse theta slowing, active interictal GSW GPSW discharges >3 Hz increased by hyperventilation5 yr: Generalized epileptiform discharges every 1–2 minutes
MRICranealNRNRNRNormalGeneralized cerebellar atrophy with large v4 and prominent folia. The posterior corpus callosum is foreshortened and smaller posteriorlyAtrophy between scans, markedly in the cerebellum. The corpus callosum is hypoplastic posteriorly with a small spleniumNormal
Genetic dataGenetic testNGSNGSNGStarget NGStarget NGStarget NGSaCGH
Genomic change (Hg19)chr15:93540316; A> A/-chr15:93545442; ->-/Achr15:93482909; C>C/Tchr15:93545504_93545507delchr15:93557956delGchr15:93521611; C>C/Tchr15:91027533_93477874 del
cDNA/aa changec.3725delA, p.Lys1245Asnfs*4c.4173dupA, p.Gln1392Thrf*17c.C653T, p.Pro218Leuc.4235_4238 delAAGG, p.Glu1412Glyfs*64c.4720delG, p.Gly1575Valfs*17c.2725C>T, p.Gln909*15q26 del (2.4 Mb)
InheritanceNRde novoinheritedde novode novode novode novo
Family HistoryNRNRInherited from unaffected motherNRNRNRNR
1 Syndromic diagnosis of EMA; 2 Syndromic diagnosis of MAE. aa: amino acid; aCGH: Array comparative genomic hybridization; ADHD: Attention deficit hyperactivity disorder; AED: Antiepileptic drug; ASD: Autism spectrum disorder; DD: developmental delay; del: deletion; EEG: Electroencephalogram; ID: Intellectual disability; MRI: Magnetic resonance imaging; NGS: Next generation sequencing; NR: not reported; PPR: Photoparoxysmal response; yr: year. Seizure types: AMA: Atonic myoclonic absence; AS: Atonic seizure; CSE: Convulsive status epilepticus; FS: Febrile seizures; GTCS: Generalized tonic clonic seizures; MA: Myoclonic absence; MJ: Myoclonic jerks; MS: Myoclonic seizures; NCSE: Non-convulsive status epilepticus; TA: typical absence; TC: tonic-clinic seizure, TS: Tonic seizure. EGG: BG: Background; GPSW: Generalized polyspike wave; GSW: Generalized spike wave.
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Mayo, S.; Gómez-Manjón, I.; Fernández-Martínez, F.J.; Camacho, A.; Martínez, F.; Benito-León, J. Candidate Genes for Eyelid Myoclonia with Absences, Review of the Literature. Int. J. Mol. Sci. 2021, 22, 5609. https://doi.org/10.3390/ijms22115609

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Mayo S, Gómez-Manjón I, Fernández-Martínez FJ, Camacho A, Martínez F, Benito-León J. Candidate Genes for Eyelid Myoclonia with Absences, Review of the Literature. International Journal of Molecular Sciences. 2021; 22(11):5609. https://doi.org/10.3390/ijms22115609

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Mayo, Sonia, Irene Gómez-Manjón, Fco. Javier Fernández-Martínez, Ana Camacho, Francisco Martínez, and Julián Benito-León. 2021. "Candidate Genes for Eyelid Myoclonia with Absences, Review of the Literature" International Journal of Molecular Sciences 22, no. 11: 5609. https://doi.org/10.3390/ijms22115609

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